PMID: 28752218 (Patient)   Terms: retrospective
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0		Predicting IDH mutation status of intrahepatic cholangiocarcinomas based on contrast-enhanced CT features .
1		OBJECTIVES :
2		To explore the difference in contrast-enhanced computed tomography ( CT ) features of intrahepatic cholangiocarcinomas ( ICCs ) with different isocitrate dehydrogenase ( IDH ) mutation status .
3		METHODS :
4	Μ	Clinicopathological and contrast-enhanced CT features of 78 patients with 78 ICCs were retrospectively analysed and compared based on IDH mutation status .
5		RESULTS :
6		There were 11 ICCs with IDH mutation ( 11/78 , 141% ) and 67 ICCs without IDH mutation ( 67/78 , 859% ) .
7		IDH-mutated ICCs showed intratumoral artery more often than IDH-wild ICCs ( p = 0023 ) .
8	Μ	Most ICCs with IDH mutation showed rim and internal enhancement ( 10/11 , 909% ) , while ICCs without IDH mutation often appeared diffuse ( 26/67 , 388% ) or with no enhancement ( 4/67 , 60% ) in the arterial phase ( p = 0009 ) .
9		IDH-mutated ICCs showed significantly higher CT values , enhancement degrees and enhancement ratios in arterial and portal venous phases than IDH-wild ICCs ( all p <005 ) .
10		The CT value of tumours in the portal venous phase performed best in distinguishing ICCs with and without IDH mutation , with an area under the curve of 0.798 ( p = 0002 ) .
11		CONCLUSIONS :
12		ICCs with and without IDH mutation differed significantly in arterial enhancement mode , and the tumour enhancement degree on multiphase contrast-enhanced CT was helpful in predicting IDH mutation status .
13	Μ	KEY POINTS : * IDH mutation occurred frequently in ICCs . * ICCs with and without IDH mutation differed significantly in arterial enhancement mode . * ICCs with IDH mutation enhanced more than those without IDH mutation . * Enhancement ratio and tumour CT value can predict IDH mutation status .

PMID: 28736630 (None)   Terms: clinical trial
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0		Current biologics for treatment of biliary tract cancers .
1		Biliary tract cancers ( BTC ) is a group of malignancies that arise from the epithelial cells of the biliary tree .
2		These cancers are typically classified by anatomic site of origin : intrahepatic cholangiocarcinoma ( IHCC ) and extrahepatic cholangiocarcinoma ( EHCC ) , and gallbladder cancer ( GBC ) .
3		To date , complete surgical resection remains the mainstay of treatment especially for earlier stage disease .
4		Unfortunately , most patients present with advanced or metastatic disease , when systemic chemotherapy is the only treatment option .
5		Due to the paucity of effective treatments , BTCs have a dismal prognosis .
6		There is a tremendous need to better understand the disease biology , discover new therapies , and improve clinical outcomes for this challenging disease .
7		Next-generation sequencing has produced a more accurate and detailed picture of the molecular signatures in BTCs .
8		The three BTC histologic subtypes are , in fact , quite molecularly distinct .
9		IHCC commonly contain FGFR2 fusions and IDH 1 and 2 mutations , whereas EHCC and GBC tend to carry mutations in EGFR , HER2 , and MAPK pathway .
10		In light of this emerging knowledge , clinical trials have become more biomarker-driven , which allows capturing of subsets of patients that are most likely to respond to certain therapies .
11		Many new and promising targeted therapeutics are currently in the pipeline .
12		Here we review the genetic landscape of BTCs while focusing on new molecular targets and targeted therapeutics currently being investigated in biomarker-driven clinical trials .

PMID: 28667006 (None)   Terms:
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0		Whole - Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma .
1		Cholangiocarcinoma ( CCA ) is a hepatobiliary malignancy exhibiting high incidence in countries with endemic liver-fluke infection .
2		We analysed 489 CCAs from 10 countries , combining whole - genome ( 71 cases ) , targeted/exome , copy-number , gene expression , and DNA methylation information .
3		Integrative clustering defined four CCA clusters - Fluke-Positive CCAs ( Clusters 1/2 ) are enriched in ERBB2 amplifications and TP53 mutations , conversely Fluke-Negative CCAs ( Clusters 3/4 ) exhibit high copy-number alterations and PD-1/PD-L2 expression , or epigenetic mutations ( IDH1/2 , BAP1 ) and FGFR/PRKA-related gene rearrangements .
4		Whole - genome analysis highlighted FGFR2 3'UTR deletion as a mechanism of FGFR2 upregulation .
5		Integration of non-coding promoter mutations with protein -DNA binding profiles demonstrates pervasive modulation of H3K27me3-associated sites in CCA .
6	Μ	Clusters 1 and 4 exhibit distinct DNA hypermethylation patterns targeting either CpG islands or shores - mutation signature and subclonality analysis suggests that these reflect different mutational pathways .
7		Our results exemplify how genetics , epigenetics and environmental carcinogens can interplay across different geographies to generate distinct molecular subtypes of cancer .

PMID: 28628842 (Patient)   Terms: this review
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0		Matching genomic molecular aberrations with molecular targeted agents : Are biliary tract cancers an ideal playground ?
1		Biliary tract cancers ( BTCs ) are a heterogeneous group of tumours with geographical discrepancies in terms of incidence and risk factors .
2		However , a convergent genomic and epigenetic mutational landscape emerges from the genome -wide screens of BTCs in South East Asia , Latin America and in the Western World .
3	Μ	Specificities are observed for some alterations and anatomical subtypes : frequent fibroblast growth factor receptor 2 ( FGFR2 ) and isocitrate dehydrogenase 1/2 ( IDH1/2 ) alterations are specific to intrahepatic cholangiocarcinomas ( ICCs ) , whereas frequent ERBB2 oncogene alterations are specific to extrahepatic cholangiocarcinomas ( ECCs ) and gallbladder carcinomas ( GBCs ) .
4		Until now , the outcome of patients with BTCs treated by molecular targeted agents ( MTAs ) alone or in combination with conventional chemotherapy in non-biology driven trials remains poor and does not exceed the outcome of patients treated with chemotherapy alone .
5		Encouraging reports of biology-driven therapeutic approaches should accelerate the clinical development of MTAs in BTCs .
6		Additionally , frequent epigenetic aberrations such as IDH1/2 mutations and switch/sucrose non-fermenting ( SWI/SNF ) complex dysfunctions suggest that epidrugs must also be considered .
7		In this review , we expose the rationale and feasibility to biologically drive the treatment of BTC patients .

PMID: 28601826 (Patient)   Terms: phase I, clinical trial, phase II, NCT02496741
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0		Study protocol of a phase IB/II clinical trial of metformin and chloroquine in patients with IDH1-mutated or IDH2-mutated solid tumours .
1		INTRODUCTION :
2		High-grade chondrosarcoma , high-grade glioma and intrahepatic cholangiocarcinoma are aggressive types of cancer with a dismal outcome .
3		This is due to the lack of effective treatment options , emphasising the need for novel therapies .
4		Mutations in the genes IDH1 and IDH2 ( isocitrate dehydrogenase 1 and 2 ) occur in 60% of chondrosarcoma , 80% of WHO grade II-IV glioma and 20% of intrahepatic cholangiocarcinoma .
5		IDH1/2-mutated cancer cells produce the oncometabolite D-2-hydroxyglutarate ( D-2HG ) and are metabolically vulnerable to treatment with the oral antidiabetic metformin and the oral antimalarial drug chloroquine .
6		METHODS AND ANALYSIS :
7		We describe a dose-finding phase Ib/II clinical trial , in which patients with IDH1/2-mutated chondrosarcoma , glioma and intrahepatic cholangiocarcinoma are treated with a combination of metformin and chloroquine .
8		Dose escalation is performed according to a 3+3 dose-escalation scheme .
9		The primary objective is to determine the maximum tolerated dose to establish the recommended dose for a phase II clinical trial .
10		Secondary objectives of the study include (1) determination of pharmacokinetics and toxic effects of the study therapy , for which metformin and chloroquine serum levels will be determined over time ; (2) investigation of tumour responses to metformin plus chloroquine in IDH1/2-mutated cancers using CT/MRI scans ; and (3) whether tumour responses can be measured by non-invasive D-2HG measurements ( mass spectrometry and magnetic resonance spectroscopy ) of tumour tissue , serum , urine , and/or bile or next-generation sequencing of circulating tumour DNA ( liquid biopsies ) .
11		This study may open a novel treatment avenue for IDH1/2-mutated high-grade chondrosarcoma , glioma and intrahepatic cholangiocarcinoma by repurposing the combination of two inexpensive drugs that are already approved for other indications .
12		ETHICS AND DISSEMINATION :
13		This study has been approved by the medical-ethical review committee of the Academic Medical Center , Amsterdam , The Netherlands .
14		The report will be submitted to a peer-reviewed journal .
15		TRIAL REGISTRATION NUMBER :
16		This article was registered at ClinicalTrials .
17		gov identifier ( NCT02496741 ) : Pre-results .

PMID: 28567120 (None)   Terms:
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0		The potential role of comprehensive genomic profiling to guide targeted therapy for patients with biliary cancer .
1		Remarkable advancements in techniques of genomic profiling and bioinformatics have led to the accumulation of vast amounts of knowledge on the genomic profiles of biliary tract cancer ( BTC ) .
2		Recent largescale molecular profiling studies have not only highlighted genomic differences characterizing tumors of the intrahepatic and extrahepatic bile ducts and gallbladder , but have also revealed differences in genomic profiles pertaining to associated risk factors .
3		Novel genomic alterations such as FGFR2 fusions and IDH1/2 mutations in intrahepatic cholangiocarcinoma ( ICC ) and ERBB2 alterations in gallbladder cancer ( GBCA ) are emerging as targeted therapy options capable of advancing precision medicine for the care of these patients .
4		Moreover , variable genomic alterations also appear to impact prognosis and overall disease outcome independent from their therapy selection value .
5	Μ	High mutational burden and increased expression of immune checkpoint-related proteins observed in a subset of BTC also show a potential for guidance of immunotherapy .
6		Thus , comprehensive genomic profiling ( CGP ) is rapidly achieving status as an integral component of precision medicine and is starting to become invaluable in guiding the management of patients with BTC , a rare disease with dismal outcome .

PMID: 28431889 (None)   Terms:
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0		Clinicopathological , radiologic , and molecular study of 23 combined hepatocellular-cholangiocarcinomas with stem cell features , cholangiolocellular type .
1		Cholangiolocellular carcinoma is a type of intrahepatic cholangiocarcinoma ( ICC ) .
2		According to the 2010 World Health Organization classification , this carcinoma is a combined hepatocellular-cholangiocarcinoma with stem cell features , cholangiolocellular type ( CHC-SC-CLC ) .
3		The aim of this study was to compare the clinicopathological characteristics of CHC-SC-CLC and conventional ICC .
4		Based on the gross and histologic characteristics , we divided consecutive ICC tumors into CHC-SC-CLC ( n = 23 ) , mass-forming ( MF ; n = 57 ) , and non-MF ( n = 22 ) groups .
5		Compared with MF and non-MF groups , the CHC-SC-CLC group featured history of hepatolithiasis or bile duct operation in significantly fewer patients ( 43% versus 148% and 864% , respectively ; P <001 ) and was more common in the right lobe ( 70% versus 47% and 27% ; P = 033 ) but lower frequency of invasive growth or peritumoral Glisson sheath invasion ( 61% and 22% versus 77% and 33% and 100% and 86% , respectively ; P = 002 and P <001 ) and absence of mucous production ( 0 versus 77% and 96% ; P <001 ) .
6		In CHC-SC-CLCs , the mutation rate of isocitrate dehydrogenase 1 ( IDH1 ) or IDH2 was significantly higher ( 35% ) than in MF ( 4% ) or non-MF (0) ICCs ( P <001 ) .
7		The 1 - , 3 - , and 5-year postresection survival rates were also significantly better with CHC-SC-CLCs ( 93% , 79% , and 52% , respectively ) than with MF ( 72% , 46% , and 40% ) or non-MF ( 61% , 18% , and 0 ) ICCs ( P = 041 ) .
8	Μ	Thus , CHC-SC-CLC tumors demonstrated an indolent growth pattern , more frequent IDH1/2 gene mutations , and better prognosis than did MF or non-MF ICC tumors .

PMID: 28424193 (None)   Terms:
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0		Study Suggests Treatment Approaches for Cholangiocarcinomas .
1		A comprehensive genome profile of cholangiocarcinoma reveals that the tumors fall into four molecular classes .
2		The study suggests that patients with IDH1/2 mutations could benefit from drugs that inhibit oxidative phosphorylation or that target mutations in chromatin remodeling genes .
3		The work also shows that some liver cancers are closely related to cholangiocarcinomas .

PMID: 28403884 (Patient)   Terms:
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0		IDH1 R132C mutation is detected in clear cell hepatocellular carcinoma by pyrosequencing .
1		BACKGROUND :
2		Isocitrate dehydrogenase 1 ( IDH1 ) mutation is common in low-grade glioma ( approximately 80% ) and acute myeloid leukemia ( approximately 10% ) .
3		Other than brain tumor or hematologic malignancies , intrahepatic cholangiocarcinoma ( iCC ) is a well-known solid tumor with IDH1 mutation ( 68-20% ) .
4		Histologically , poor differentiation and clear cell change are associated with IDH1 mutation in iCC .
5		Since hepatocellular carcinoma ( HCC ) shares histologic features with iCC , some specific subtypes of HCC might show a higher IDH1 mutation rate than reported before ( 05-15% ) .
6		METHODS :
7		Forty-six cases of iCC and 48 cases of HCC ( including 20 cases of clear cell type and 13 cases of pseudoglandular pattern ) were tested for IDH1 mutation by pyrosequencing .
8		RESULTS :
9		Three cases in iCC ( 65% ) and five cases in HCC ( 104% ) had IDH1 mutation , all of which were Arg132Cys .
10		IDH1 mutant HCCs were all clear cell type .
11	Μ	Although the IDH1 mutation rate between iCC and HCC demonstrated no significant difference , clear cell HCC revealed statistically increased mutation rate compared to that of HCC without clear cell change ( P = 0009 ) .
12	✓	Presence of IDH1 mutation was related with poor survival in clear cell HCC patients ( P = 0004 ) .	GM-ASS-RO
13		CONCLUSIONS :
14	Μ	Clear cell HCC showed higher frequency of IDH1 mutation rate than other variants of HCC .
15		This result consolidates the assumption that morphological features of tumors reflect molecular alterations .

PMID: 28389139 (None)   Terms:
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0		Emerging molecular therapeutic targets for cholangiocarcinoma .
1		Cholangiocarcinomas ( CCAs ) are diverse epithelial tumors arising from the liver or large bile ducts with features of cholangiocyte differentiation .
2		CCAs are classified anatomically into intrahepatic ( iCCA ) , perihilar ( pCCA ) , and distal CCA ( dCCA ) .
3		Each subtype has distinct risk factors , molecular pathogenesis , therapeutic options , and prognosis .
4		CCA is an aggressive malignancy with a poor overall prognosis and median survival of less than 2years in patients with advanced disease .
5		Potentially curative surgical treatment options are limited to the subset of patients with early-stage disease .
6		Presently , the available systemic medical therapies for advanced or metastatic CCA have limited therapeutic efficacy .
7		Molecular alterations define the differences in biological behavior of each CCA subtype .
8		Recent comprehensive genetic analysis has better characterized the genomic and transcriptomic landscape of each CCA subtype .
9		Promising candidates for targeted , personalized therapy have emerged , including potential driver fibroblast growth factor receptor ( FGFR ) gene fusions and somatic mutations in isocitrate dehydrogenase ( IDH ) 1/2 in iCCA , LONGTOKEN gene fusions in pCCA , and ELF3 mutations in dCCA/ampullary carcinoma .
10		A precision genomic medicine approach is dependent on an enhanced understanding of driver mutations in each subtype and stratification of patients according to their genetic drivers .
11		We review the current genomic landscape of CCA , the potentially actionable molecular aberrations in each CCA subtype , and the role of immunotherapy in CCA .

PMID: 28375741 (None)   Terms: clinical trial
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0		Isocitrate Dehydrogenase Mutation and (R) -2-Hydroxyglutarate : From Basic Discovery to Therapeutics Development .
1		The identification of heterozygous mutations in the metabolic enzyme isocitrate dehydrogenase ( IDH ) in subsets of cancers , including secondary glioblastoma , acute myeloid leukemia , intrahepatic cholangiocarcinoma , and chondrosarcomas , led to intense discovery efforts to delineate the mutations' involvement in carcinogenesis and to develop therapeutics , which we review here .
2		The three IDH isoforms ( nicotinamide adenine dinucleotide phosphate -dependent IDH1 and IDH2 , and nicotinamide adenine dinucleotide -dependent IDH3 ) contribute to regulating the circuitry of central metabolism .
3		Several biochemical and genetic observations led to the discovery of the neomorphic production of the oncometabolite (R) -2-hydroxyglutarate ( 2-HG ) by mutant IDH1 and IDH2 ( mIDH ) .
4		Heterozygous mutation of IDH1/2 and accumulation of 2-HG cause profound metabolic and epigenetic dysregulation , including inhibition of normal cellular differentiation , leading to disease .
5		Crystallographic structural studies during the development of compounds targeting mIDH demonstrated common allosteric inhibition by distinct chemotypes .
6		Ongoing clinical trials in patients with mIDH advanced hematologic malignancies have demonstrated compelling clinical proof-of-concept , validating the biology and drug discovery approach .

PMID: 28338651 (Patient)   Terms:
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0		Dichotomy in intrahepatic cholangiocarcinomas based on histologic similarities to hilar cholangiocarcinomas .
1		Intrahepatic cholangiocarcinomas were classified into two types based on their microscopic appearance .
2		Tumors with histologic similarities to hilar cholangiocarcinomas ( predominantly ductal adenocarcinomas with minor tubular components , if present , restricted to the invasive front ) were defined as the perihilar type , whereas the others were classified as peripheral cholangiocarcinomas .
3		Among the 47 cases examined in the present study , 26 ( 55% ) were classified as the perihilar type , whereas 21 ( 45% ) were the peripheral type .
4		The perihilar type had higher pT stages and more frequently showed a periductal-infiltrating gross appearance and microscopic perineural infiltration than peripheral cholangiocarcinomas .
5		The presence of low-grade biliary intraepithelial neoplasia in the adjacent bile ducts was only found in perihilar cholangiocarcinomas ( 6/21 , 29% ) .
6		The immunophenotype also differed between the two types with MUC5AC and MUC6 being more commonly expressed in the perihilar type .
7		One-third of perihilar cholangiocarcinomas lacked the expression of SMAD4 , suggesting SMAD4 mutations , whereas the loss of BAP1 expression and IDH1 mutations were almost restricted to the peripheral type ( 35 and 15% , respectively ) .
8		Patients with perihilar cholangiocarcinoma had worse overall survival than those with peripheral cancer ( P = 0027 ) .
9		A multivariate analysis identified the histologic classification as an independent prognostic factor ( P = 0005 , HR = 3638 ) .
10		Comparisons between intrahepatic and hilar cholangiocarcinomas also revealed that the molecular features and prognosis of perihilar cholangiocarcinomas were very similar to those of hilar cholangiocarcinomas .
11		In conclusion , this histology-based classification scheme of intrahepatic cholangiocarcinomas will be useful and clinically relevant because it represents different underlying molecular features and has an independent prognostic value .

PMID: 28297679 (None)   Terms:
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0		Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles .
1		Cholangiocarcinoma ( CCA ) is an aggressive malignancy of the bile ducts , with poor prognosis and limited treatment options .
2		Here , we describe the integrated analysis of somatic mutations , RNA expression , copy number , and DNA methylation by The Cancer Genome Atlas of a set of predominantly intrahepatic CCA cases and propose a molecular classification scheme .
3		We identified an IDH mutant -enriched subtype with distinct molecular features including low expression of chromatin modifiers , elevated expression of mitochondrial genes , and increased mitochondrial DNA copy number .
4	Μ	Leveraging the multi-platform data , we observed that ARID1A exhibited DNA hypermethylation and decreased expression in the IDH mutant subtype .
5	Μ	More broadly , we found that IDH mutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA .
6		Our studies reveal insights into the molecular pathogenesis and heterogeneity of cholangiocarcinoma and provide classification information of potential therapeutic significance .

PMID: 28124097 (None)   Terms: in vivo, in vitro, mice
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0		Pan-mutant IDH1 inhibitor BAY 1436032 for effective treatment of IDH1 mutant astrocytoma in vivo .
1		Mutations in codon 132 of isocitrate dehydrogenase ( IDH ) 1 are frequent in diffuse glioma , acute myeloid leukemia , chondrosarcoma and intrahepatic cholangiocarcinoma .
2		These mutations result in a neomorphic enzyme specificity which leads to a dramatic increase of intracellular D-2-hydroxyglutarate ( 2-HG ) in tumor cells .
3		Therefore , mutant IDH1 protein is a highly attractive target for inhibitory drugs .
4		Here , we describe the development and properties of BAY 1436032 , a pan-inhibitor of IDH1 protein with different codon 132 mutations .
5	Μ	BAY 1436032 strongly reduces 2-HG levels in cells carrying IDH1-R132H , -R132C , -R132G , -R132S and -R132L mutations .
6	Μ	Cells not carrying IDH mutations were unaffected .
7		BAY 1436032 did not exhibit toxicity in vitro or in vivo .
8		The pharmacokinetic properties of BAY 1436032 allow for oral administration .
9	Μ	In two independent experiments , BAY 1436032 has been shown to significantly prolong survival of mice intracerebrally transplanted with human astrocytoma carrying the IDH1R132H mutation .
10		In conclusion , we developed a pan-inhibitor targeting tumors with different IDH1R132 mutations .

PMID: 28078132 (Patient)   Terms: case, control
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0		Impressive response to dual BRAF and MEK inhibition in patients with BRAF mutant intrahepatic cholangiocarcinoma-2 case reports and a brief review .
1		Intrahepatic cholangiocarcinoma ( ICC ) typically presents at an advanced stage and is associated with a poor oncological outcome .
2		The median survival for metastatic ICC is less than 1 year with standard chemotherapy .
3		ICC is associated with distinct oncogenic drivers including IDH ( isocitrate dehydrogenase ) , human HER-2 ( epidermal growth factor 2 ) , and BRAF ( v-Raf murine sarcoma viral oncogene homolog B ) , which may benefit from matching targeted therapies .
4		Hereby we report 2 cases of BRAF V600E refractory ICC treated with dual BRAF and MEK inhibitors ( dabrafenib and trametinib ) with excellent clinical and radiological response to therapy and with protracted duration of disease control .
5		Our first patient achieved CR ( complete remission ) at 6 months of treatment with ultimate disease progression at 9 months .
6		The second patient achieved a PR ( partial response ) at 2 months from starting treatment and remains progression free at 5 months .
7		Our results confirm the activity of dual BRAF and MEK targeting in BRAF mutated ICC , adding further support to 3 additional case-reports in the literature .
8		Dual targeting appears superior to other case reports with BRAF inhibition alone and appear favorable to historic data with cytotoxic chemotherapy .
9		Given the poor outlook and refractoriness of BRAF mutant ICC , future studies should focus on early integration of BRAF/MEK inhibition .

PMID: 28050146 (Patient)   Terms:
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0		Personalized oncogenomics in the management of gastrointestinal carcinomas-early experiences from a pilot study .
1		BACKGROUND :
2		Gastrointestinal carcinomas are genomically complex cancers that are lethal in the metastatic setting .
3		Whole - genome and transcriptome sequencing allow for the simultaneous characterization of multiple oncogenic pathways .
4		METHODS :
5		We report 3 cases of metastatic gastrointestinal carcinoma in patients enrolled in the Personalized Onco-Genomics program at the BC Cancer Agency .
6		Real-time genomic profiling was combined with clinical expertise to diagnose a carcinoma of unknown primary , to explore treatment response to bevacizumab in a colorectal cancer , and to characterize an appendiceal adenocarcinoma .
7		RESULTS :
8	Μ	In the first case , genomic profiling revealed an IDH1 somatic mutation , supporting the diagnosis of cholangiocarcinoma in a malignancy of unknown origin , and further guided therapy by identifying epidermal growth factor receptor amplification .
9		In the second case , a BRAF V600E mutation and wild-type KRAS profile justified the use of targeted therapies to treat a colonic adenocarcinoma .
10		The third case was an appendiceal adenocarcinoma defined by a p53 inactivation ; Ras/raf/mek , Akt/mtor , Wnt , and notch pathway activation ; and overexpression of ret , erbb2 ( her2 ) , erbb3 , met , and cell cycle regulators .
11		SUMMARY :
12		We show that whole - genome and transcriptome sequencing can be achieved within clinically effective timelines , yielding clinically useful and actionable information .

PMID: 27864835 (Patient)   Terms:
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0		Intrahepatic cholangiocarcinoma frequently shows loss of BAP1 and PBRM1 expression , and demonstrates specific clinicopathological and genetic characteristics with BAP1 loss .
1		AIMS :
2	Μ	BAP1 and PBRM1 expression loss has been observed in multiple cancers , including intrahepatic cholangiocarcinoma ( ICC ) .
3		We investigated BAP1 and PBRM1 expression in ICC using immunohistochemistry , and analysed its association with clinicopathological and genetic features , including two histological subtypes .
4		METHODS AND RESULTS :
5		Whole-section slides of 108 consecutive primary ICC cases were immunostained against BAP1 and PBRM1 .
6		Complete loss of BAP1 and PBRM1 was observed in 21 ( 194% ) and 25 ( 231% ) cases , respectively , and partial loss was identified in four ( 37% ) and nine ( 84% ) cases .
7		In all cases , normal bile ducts were strongly and diffusely positive for both BAP1 and PBRM1 .
8		ICC with BAP1 loss showed lower serum CA19-9 levels , less perineural invasion , rare mucin production , weaker immunoreactivity against S-100P and stronger immunoreactivity against N-cadherin and NCAM .
9	Μ	IDH mutations were identified more frequently in ICCs with BAP1 loss .
10		All ICC with BAP1 loss corresponded to small-duct type ICC .
11		Multivariate Cox regression analysis showed that BAP1 loss was an independent prognostic factor for both overall and recurrence-free survival ( P <005 ) .
12		Conversely , PBRM1 loss was found in both small-duct type and large-duct type ICC , and was not associated significantly with any specific characteristics , including prognosis .
13		CONCLUSION :
14		BAP1 and PBRM1 loss is seen frequently in ICC .
15		ICC with BAP1 loss shares features of small-duct type ICC .

PMID: 27829278 (None)   Terms: clinical trial
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0		Systemic therapy for biliary cancers .
1		Biliary tract cancers represent an uncommon , heterogenous malignant group of tumors that include gallbladder cancers ( GBC ) and cholangiocarcinomas that are frequently detected in the locally advanced or metastatic setting .
2		The randomized phase III ABC-02 trial established the combination regimen of cisplatin plus gemcitabine as standard of care therapy .
3		Nevertheless , despite prior and subsequent attempts utilizing a variety of treatment strategies clinical outcomes for these cancers remains disappointing , necessitating the innate call for improvements in treatment approaches .
4		In this article , we provide an overview of prior first line studies of single , doublet and triplet systemic chemotherapy regimens as well as attempts to incorporate agents that target the EGFR and VEGF pathways in combination with a cytotoxic backbone and the current role of chemotherapy in the second line setting .
5	Μ	Additionally , molecular profiling has the capability to identify genetic alterations to help guide rational treatment approaches ; we highlight the molecular diverse profile within biliary cancer and the prior , current and emergent role of targeted therapy in biliary cancers as well as the ongoing investigational assessment of immunotherapy .
6		Overall , combination therapy is superior to single agent therapy in the first line setting .
7		For second line therapy , enrollment on to clinical trials is paramount as no standard of care currently exists and no specific regimen has shown a significant better outcome .
8		Limitations of chemotherapy have been exposed and future trials must have a logical design with incorporation of biomarkers that can aid prognosis or predict benefit to therapy .
9		Advances in genomic sequencing can allow identification of potential actionable targets that can be exploited therapeutically which is already underway with the targeting of FGFR2 fusions and IDH1/2 mutations in intrahepatic cholangiocarcinoma ( IHCC ) .
10		With these approaches there is potential to gain improvements in outcomes for patients affected by these adverse group of cancers .

PMID: 27823638 (None)   Terms: clinical trial
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0		Molecular characteristics of biliary tract cancer .
1		Biliary tract cancers ( intrahepatic , perihilar and extrahepatic cholangiocarcinoma , and gallbladder and cystic duct cancers ) are uncommon but highly lethal malignancies .
2		Clinical presentation is often late , precluding curative surgical resection in most cases .
3		For advanced disease , therapeutic options are limited to systemic chemotherapy , with suboptimal outcomes .
4		An understanding of the molecular characteristics of biliary tract cancers may allow the clinical development of therapies targeting actionable alterations with the ultimate goal of improving clinical outcomes .
5		We present a comprehensive review of biliary tract cancer genomics and their clinical implications .
6		Alterations in genes in the EGFR-MAPK-PI3K pathway are seen most often .
7		KRAS alterations are highly prevalent ; BRAF alterations are mutually exclusive from RAS alterations and much less frequent .
8		PIK3CA alterations are seen mostly in extrahepatic cholangiocarcinoma and gallbladder cancers whereas HER2 amplification is most common in gallbladder cancers .
9		Various tumor suppressor genes , such as TP53 and p16 are also altered often in biliary tract cancers ; however , agents to "activate" silenced genes are currently lacking .
10		FGF and IDH pathway alterations are potential targets for therapeutic agents .
11		FGF alterations are typically fusions with other genes , resulting in altered proteins , and are seen most often in intrahepatic cholangiocarcinoma .
12		IDH pathway alterations affect cellular enzymatic processes and are most common in intrahepatic cholangiocarcinoma .
13		Ongoing clinical trials of agents targeting these pathways hold the promise of improving clinical outcomes .

PMID: 27658789 (None)   Terms: clinical trial, prospective
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0		Genomic Profiling of Biliary Tract Cancers and Implications for Clinical Practice .
1		OPINION STATEMENT : Biliary tract cancers are relatively uncommon , have an aggressive disease course and a dismal clinical outcome .
2		Until recently , there have been very few clinical advances in the management of these patients and gemcitabine-based chemotherapy has been the only widely accepted systemic therapy .
3		The advent of next generation sequencing technologies can potentially change the treatment paradigm of this disease .
4		Targeted therapy directed against actionable mutations and identification of molecular subsets with distinct prognostic significance is now feasible in clinical practice .
5		Mutation profiling has highlighted the genomic differences between the intra , extrahepatic cholangiocarcinoma , and gallbladder cancer .
6		The mutational spectrum of intrahepatic cholangiocarcinoma differs according to geographic location and ethnicity .
7		There is a higher incidence of chromatin modulating gene mutations in Western patients as compared with Asian patients with liver fluke-associated cholangiocarcinoma .
8		KRAS and p53 mutations are associated with an aggressive disease prognosis while FGFR mutations may signify a relatively indolent disease course of intrahepatic cholangiocarcinoma .
9		FGFR and IDH mutations have promising agents in clinical trials at this time .
10		An estimated 15 % of gallbladder cancers have Her2/neu amplification and can be targeted by trastuzumab .
11		On the other hand , an estimated 10-15 % of cholangiocarcinomas have DNA repair mutations and may be candidates for immune therapies with checkpoint inhibitors .
12		The promise of targeted therapies for biliary tract cancers can be fulfilled with well-designed , prospective , and multi-center clinical trials .

PMID: 27634656 (Patient)   Terms:
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0		Mutational landscape of combined hepatocellular carcinoma and cholangiocarcinoma , and its clinicopathological significance .
1		AIMS :
2		Combined hepatocellular carcinoma and cholangiocarcinoma ( cHC-CC ) , which generally has a poor prognosis , comprises hepatocellular carcinoma ( HCC ) , cholangiocarcinoma ( CC ) , and diverse components with intermediate features between HCC and CC .
3		Histological subtypes with stem cell ( SC ) features ( the SC subtype ) have different clinicopathological significance in cHC-CC .
4		The mutational status may reflect the clinicopathological subgroup of cHC-CC together with the histological subtype .
5		METHODS AND RESULTS :
6		We examined the mutational statuses of KRAS , IDH1 or IDH2 ( IDH1/2 ) , ARID1A , the TERT promoter , and TP53 , and their relationships with clinicopathological features in 53 patients with cHC-CC .
7		Background liver diseases were hepatitis B ( n = 9 ) , hepatitis C ( n = 22 ) , alcoholic liver disease ( n = 5 ) , non-alcoholic fatty liver disease ( NAFLD ) ( n = 8 ) , and unknown ( n = 9 ) .
8	Μ	Mutations in KRAS , IDH1/2 , ARID1A , the TERT promoter and TP53 were detected in four ( 75% ) , six ( 118% ) seven ( 132% ) , 16 ( 313% ) , and 24 patients ( 453% ) , respectively .
9		KRAS mutations correlated with higher histological diversity scores and a higher M - factor ( P <005 ) .
10		ARID1A mutations correlated with alcoholic liver disease , smaller tumour size , a lower grade of coexistent HCC , and alpha-fetoprotein ( AFP ) positivity , and were associated with cholangiolocellular carcinoma subtype predominance ( P <005 ) .
11		TERT promoter mutations correlated with hepatitis B , an intermediate subtype-predominant histology , higher clinical stage , and a higher N - factor ( P <005 ) , and were associated with gender ( female-predominant ) and previous therapy .
12		TP53 mutations correlated with AFP positivity ( P <005 ) .
13		CONCLUSIONS :
14	Μ	The results of the mutational analysis revealed that cHC-CC has diverse types of mutations , and also that mutations in the TERT promoter and ARID1A may reflect aetiological impact , different histological subtypes , histogenesis , and tumour aggressiveness .
15		These results suggest the potential efficacy of molecular-based subclassification of cHC-CC .

PMID: 27622582 (Patient)   Terms:
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0		Biliary cancer : Utility of next-generation sequencing for clinical management .
1		BACKGROUND :
2		Biliary tract cancers ( BTCs ) typically present at an advanced stage , and systemic chemotherapy is often of limited benefit .
3		METHODS :
4		Hybrid capture-based comprehensive genomic profiling ( CGP ) was performed for 412 intrahepatic cholangiocarcinomas ( IHCCAs ) , 57 extrahepatic cholangiocarcinomas ( EHCCAs ) , and 85 gallbladder carcinomas ( GBCAs ) .
5		The mutational profile was correlated with the clinical outcome of standard and experimental therapies for 321 patients .
6	Μ	Clinical variables , detected mutations , and administered therapies were correlated with overall survival ( OS ) in a Cox regression model .
7		RESULTS :
8		The most frequent genetic aberrations ( GAs ) observed were tumor protein 53 ( TP53 ; 27% ) , cyclin -dependent kinase inhibitor 2A/B ( CDKN2A/B ; 27% ) , KRAS ( 22% ) , AT-rich interactive domain -containing protein 1A ( ARID1A ; 18% ) , and isocitrate dehydrogenase 1 ( IDH1 ; 16% ) in IHCCA ; KRAS ( 42% ) , TP53 ( 40% ) , CDKN2A/B ( 17% ) , and SMAD4 ( 21% ) in EHCCA ; and TP53 ( 59% ) , CDKN2A/B ( 19% ) , ARID1A ( 13% ) , and ERBB2 ( 16% ) in GBCA .
9		Fibroblast growth factor receptor ( FGFR ; 11% ) and IDH mutations ( 20% ) were mostly limited to IHCCA but appeared to be mutually exclusive .
10	✓	In the IHCCA group , TP53 and KRAS mutations were associated significantly with poor OS , whereas FGFR2 mutations were associated with improved OS ( P = 001 ) , a younger age at onset , and female sex .	GM-ASS-RO
11		IDH1/2 mutations were not prognostic .
12		In a multivariate model , the effects of TP53 and FGFR GAs remained significant ( P <05 ) .
13		Patients with FGFR GAs had superior OS with FGFR-targeted therapy versus standard regimens ( P = 006 ) .
14		Targeted therapy in IHCCA was associated with a numerical OS improvement ( P = 07 ) .
15		CONCLUSIONS :
16		This is the largest clinically annotated data set of BTC cases with CGP and indicates the potential of CGP for improving outcomes .
17		CGP should be strongly considered in the management of BTC patients .
18		Cancer 2016 ; 122 : 3838-3847 .
19		(c) 2016 American Cancer Society .

PMID: 27621679 (None)   Terms: clinical trial
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0		IDH1 and IDH2 mutations as novel therapeutic targets : current perspectives .
1		Isocitrate dehydrogenase 1 and 2 ( IDH1 and IDH2 ) are key metabolic enzymes that convert isocitrate to alpha-ketoglutarate .
2		IDH1/2 mutations define distinct subsets of cancers , including low-grade gliomas and secondary glioblastomas , chondrosarcomas , intrahepatic cholangiocarcinomas , and hematologic malignancies .
3		Somatic point mutations in IDH1/2 confer a gain-of-function in cancer cells , resulting in the accumulation and secretion in vast excess of an oncometabolite , the D-2-hydroxyglutarate ( D-2HG ) .
4		Overproduction of D-2HG interferes with cellular metabolism and epigenetic regulation , contributing to oncogenesis .
5		Indeed , high levels of D-2HG inhibit alpha-ketoglutarate -dependent dioxygenases , including histone and DNA demethylases , leading to histone and DNA hypermethylation and finally a block in cell differentiation .
6		Furthermore , D-2HG is a biomarker suitable for the detection of IDH1/2 mutations at diagnosis and predictive of the clinical response .
7		Finally , mutant -IDH1/2 enzymes inhibitors have entered clinical trials for patients with IDH1/2 mutations and represent a novel drug class for targeted therapy .

PMID: 27595804 (Patient)   Terms: , rat
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0		Immunohistochemistry using monoclonal antibody MsMab-2 is useful to detect IDH1 R132L in intrahepatic cholangiocarcinoma .
1	Μ	Immunohistochemical analysis using specific antibodies is a useful and convenient method to detect proteins altered by somatic mutations .
2		We previously generated the rat monoclonal antibody MsMab-2 , which recognizes isocitrate dehydrogenase ( IDH ) 1 R132L and IDH2 R172M .
3		In the present study , we used an immunohistochemical method to examine MsMab-2 immunoreactivity in 95 cases of intrahepatic cholangiocarcinoma , including five IDH1 R132L and one IDH2 R172M mutant cases confirmed by direct sequencing .
4		Tissue microarray section slides of all IDH1/2-mutant and wild-type cases , as well as whole section slides of IDH1 R132L and IDH2 R172M cases were immunostained using an autostainer .
5	Μ	All IDH1 R132L cases showed positive staining for MsMab-2 , while other IDH1/2 mutant and IDH1/2 wild-type cases were negative .
6		Tumor cells of the immunopositive cases invariably showed strong reactivity using whole-section slides .
7		We consider immunohistochemical analysis using MsMab-2 to be a useful means of detecting IDH1 R132L .
8		Further analysis of its effectiveness against IDH2 R172M is necessary because of the small sample size in this study .

PMID: 27460275 (Patient)   Terms:
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0		Cancer related gene alterations can be detected with next-generation sequencing analysis of bile in diffusely infiltrating type cholangiocarcinoma .
1		Genome -wide association study in diffusely infiltrating type cholangiocarcinoma ( CC ) can be limited due to the difficulty of obtaining tumor tissue .
2		We aimed to evaluate the genomic alterations of diffusely infiltrating type CC using next-generation sequencing ( NGS ) of bile and to compare the variations with those of mass-forming type CC .
3		A total of 24 bile samples obtained during endoscopic retrograde cholangiopancreatography ( ERCP ) and 17 surgically obtained tumor tissue samples were evaluated .
4	Μ	Buffy coat and normal tissue samples were used as controls for a somatic mutation analysis .
5		After extraction of genomic DNA , NGS analysis was performed for 48 cancer related genes .
6		There were 27 men and 14 women with a mean age of 65.0+/-11.8years .
7	Μ	The amount of extracted genomic DNA from 3cm(3) of bile was 66.0+/-84.7mug and revealed a high depth of sequencing coverage .
8		All of the patients had genomic variations , with an average number of 19.4+/-2.8 and 22.3+/-3.3 alterations per patient from the bile and tumor tissue , respectively .
9		After filtering process , damaging SNPs ( 8 sites for each type of CC ) were predicted by analyzing tools , and their target genes showed relevant differences between the diffusely infiltrating and mass-forming type CC .
10	Μ	Finally , in somatic mutation analysis , tumor-normal paired 14 tissue and 6 bile samples were analyzed , genomic alterations of EGFR , FGFR1 , ABL1 , PIK3CA , and CDKN2A gene were seen in the diffusely infiltrating type CC , and TP53 , KRAS , APC , GNA11 , ERBB4 , ATM , SMAD4 , BRAF , and IDH1 were altered in the mass-forming type CC group .
11		STK11 , GNAQ , RB1 , KDR , and SMO genes were revealed in both groups .
12		The NGS analysis was feasible with bile sample and diffusely infiltrating type CC revealed genetic differences compared with mass-forming type CC .
13		Genome -wide association study could be performed using bile sample in the patients with CC undergoing ERCP and a different genetic approach for accurate diagnosis , pathogenesis study , and targeted therapy will be needed in diffusely infiltrating type CC .

PMID: 27355333 (None)   Terms: in vivo, in vitro, phase I, clinical trial
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0		Targeting isocitrate dehydrogenase ( IDH ) in cancer .
1		Isocitrate dehydrogenase ( IDH ) is an essential enzyme for cellular respiration in the tricarboxylic acid ( TCA ) cycle .
2		Recurrent mutations in IDH1 or IDH2 are prevalent in several cancers including glioma , acute myeloid leukemia ( AML ) , cholangiocarcinoma and chondrosarcoma .
3		The mutated IDH1 and IDH2 proteins have a gain-of-function , neomorphic activity , catalyzing the reduction of alpha-ketoglutarate ( alpha-KG ) to 2-hydroxyglutarate ( 2-HG ) by NADPH .
4		Cancer-associated IDH mutations block normal cellular differentiation and promote tumorigenesis via the abnormal production of the oncometabolite 2-HG .
5		High levels of 2-HG have been shown to inhibit alpha-KG dependent dioxygenases , including histone and deoxyribonucleic acid ( DNA ) demethylases , which play a key role in regulating the epigenetic state of cells .
6		Current targeted inhibitors of IDH1 ( AG120 , IDH305 ) , IDH2 (AG221) , and pan-IDH1/2 ( AG881 ) selectively inhibit mutant IDH protein and induce cell differentiation in in vitro and in vivo models .
7		Preliminary results from phase I clinical trials with IDH inhibitors in patients with advanced hematologic malignancies have demonstrated an objective response rate ranging from 31% to 40% with durable responses ( >1 year ) observed .
8	Μ	Furthermore , the IDH inhibitors have demonstrated early signals of activity in solid tumors with IDH mutations , including cholangiocarcinomas and low grade gliomas .

PMID: 27259014 (Patient)   Terms: retrospective
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0		Distinct Clinicopathologic and Genetic Features of 2 Histologic Subtypes of Intrahepatic Cholangiocarcinoma .
1		Previous studies have identified 2 clinically significant morphologic subtypes of intrahepatic cholangiocarcinoma ( ICC ) on the basis of anatomic location and/or histologic appearances .
2		Recognizing that these classification schemes are not always applicable practically , this study aimed to establish a novel classification system based on mucin productivity and immunophenotype and to determine the rationale of this classification by examining the clinicopathologic and genetic characteristics of the 2 subtypes defined by this method .
3		We retrospectively investigated 102 consecutive ICC cases and classified them on the basis of mucin productivity and immunophenotype ( S100P , N-cadherin , and NCAM ) .
4		We found that 42 and 56 cases were classified as type 1 and type 2 ICCs , respectively , and only 4 cases were of indeterminate type .
5		Type 1 ICC , generally characterized by mucin production and diffuse immunoreactivity to S100P , arose less frequently in chronic liver diseases and showed higher levels of serum CEA and CA 19-9 than did type 2 ICC , which generally showed little mucin production and exhibited immunoreactivity to N-cadherin and/or NCAM .
6		Type 1 ICC was characterized by several pathologic features , including higher frequencies of perineural invasion and lymph node metastasis .
7		Although the log-rank test demonstrated that type 1 ICC had significantly worse survival , the multivariate Cox regression analysis showed no prognostic significance of this histologic subtype .
8	Μ	Genetic analyses revealed that KRAS mutation was significantly more frequent in type 1 ICC , whereas IDH mutation and FGFR2 translocation were restricted to type 2 ICC .
9		In conclusion , the present classification of ICC based on mucin productivity and immunophenotype identified 2 subtypes with clinicopathologic significance .

PMID: 27231123 (Cell)   Terms: xenograft
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0		Isocitrate Dehydrogenase Mutations Confer Dasatinib Hypersensitivity and SRC Dependence in Intrahepatic Cholangiocarcinoma .
1		UNLABELLED :
2		Intrahepatic cholangiocarcinoma ( ICC ) is an aggressive liver bile duct malignancy exhibiting frequent isocitrate dehydrogenase (IDH1/IDH2) mutations .
3		Through a high-throughput drug screen of a large panel of cancer cell lines , including 17 biliary tract cancers , we found that IDH mutant ( IDHm ) ICC cells demonstrate a striking response to the multikinase inhibitor dasatinib , with the highest sensitivity among 682 solid tumor cell lines .
4	Μ	Using unbiased proteomics to capture the activated kinome and CRISPR/Cas9-based genome editing to introduce dasatinib-resistant "gatekeeper" mutant kinases , we identified SRC as a critical dasatinib target in IDHm ICC .
5		Importantly , dasatinib-treated IDHm xenografts exhibited pronounced apoptosis and tumor regression .
6		Our results show that IDHm ICC cells have a unique dependency on SRC and suggest that dasatinib may have therapeutic benefit against IDHm ICC .
7		Moreover , these proteomic and genome -editing strategies provide a systematic and broadly applicable approach to define targets of kinase inhibitors underlying drug responsiveness .
8		SIGNIFICANCE :
9		IDH mutations define a distinct subtype of ICC , a malignancy that is largely refractory to current therapies .
10		Our work demonstrates that IDHm ICC cells are hypersensitive to dasatinib and critically dependent on SRC activity for survival and proliferation , pointing to new therapeutic strategies against these cancers .
11		Cancer Discov ; 6(7) ; 727-39 .
12		(c) 2016 AACR .
13		This article is highlighted in the In This Issue feature , p. 681 .

PMID: 27102149 (None)   Terms: clinical trial, this review, rat
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0		The landscape of targeted therapies for cholangiocarcinoma : current status and emerging targets .
1		Cholangiocarcinoma ( CCA ) is a relatively rare malignancy that arises from the epithelial cells of the intrahepatic , perihilar and distal biliary tree .
2		Intrahepatic CCA ( ICC ) represents the second most common primary liver cancer , after hepatocellular cancer .
3		Two-thirds of the patients with ICC present with locally advanced or metastatic disease .
4		Despite standard treatment with gemcitabine and cisplatin , prognosis remains dismal with a median survival of less than one year .
5		Several biological plausibilities can account for its poor clinical outcomes .
6		First , despite the advent of next generation and whole exome sequencing , no oncogenic addiction loops have been validated as clinically actionable targets .
7		Second , the anatomical , pathological and molecular heterogeneity , and rarity of CCA confer an ongoing challenge of instituting adequately powered clinical trials .
8		Last , most of the studies were not biomarker-driven , which may undermine the potential benefit of targeted therapy in distinct subpopulations carrying the unique molecular signature .
9	Μ	Recent whole genome sequencing efforts have identified known mutations in genes such as epidermal growth factor receptor ( EGFR ) , rat Kirsten sarcoma viral oncogene homolog ( KRAS ) , v-raf murine sarcoma viral oncogene homolog ( BRAF ) and tumor protein p53 ( TP53 ) , novel mutations in isocitrate dehydrogenase ( IDH ) , BRCA1-Associated Protein 1 ( BAP1 ) and AT-rich interactive domain-containing protein 1A ( ARID1A ) , and novel fusions such as fibroblast growth factor receptor 2 ( FGFR2 ) and ROS proto-oncogene 1 ( ROS1 ) .
10		In this review , we will discuss the evolving genetic landscape of CCA , with an in depth focus on novel fusions ( e.g . FGFR2 and ROS1 ) and somatic mutations ( e.g . IDH1/2 ) , which are promising actionable molecular targets .

PMID: 26945443 (None)   Terms:
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0		Comparative Analysis of Methods for Detecting Isocitrate Dehydrogenase 1 and 2 Mutations and Their Metabolic Consequence , 2-Hydroxyglutarate , in Different Neoplasms .
1		Isocitrate dehydrogenase ( IDH ) mutations have been recognized in a few neoplasms including glioma , acute myeloid leukemia , chondrosarcoma , cholangiocarcinoma , and angioimmunoblastic T - cell lymphoma .
2	Μ	The direct methods to detect IDH mutations include DNA sequencing , immunohistochemistry ( IHC ) , or by measuring its byproduct , 2-hydroxyglutarate ( 2-HG ) , in the blood or urine .
3		Moreover , conventional magnetic resonance imaging can be modified to magnetic resonance spectroscopy ( MRS ) to measure 2-HG in tumor .
4	Μ	By conducting a search in Medline/PubMed and ISI/Web of Science for the published articles in English related to the methods for detection of IDH mutations and its byproduct 2-HG , we compared different methodologies to detect these mutations and discuss advantages and limitations of each method .
5		Studies in which a methodology of detection was compared with another modality were included .
6		Multiple studies have shown that both DNA sequencing and IHC are reliable methods for detecting IDH mutations in glioma and other solid neoplasms .
7		IHC appeared to be less costly , easier to perform , and may be slightly more accurate than DNA sequencing. 2-HG has also been measured in bone marrow aspirate , serum and urine of patients with mutant IDH acute myeloid leukemia , and correlated very well with sequencing and IHC .
8	Μ	Lastly , in some glioma patients , MRS detected IDH mutations noninvasively and reliably with excellent correlations with other modalities such as IHC and sequencing .
9		In conclusion , IHC , MRS , and 2-HG detection all are clinically useful and comparable with DNA sequencing in identifying IDH mutations in different neoplasms. 2-HG and MRS can be utilized for monitoring treatment response in a variety of neoplasms .

PMID: 26920730 (None)   Terms:
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0		Maffucci syndrome and neoplasms : a case report and review of the literature .
1		BACKGROUND :
2		Maffucci syndrome is characterized by the sporadic occurrence of multiple enchondromas together with multiple hemangiomas .
3		Patients with Maffucci syndrome are at increased risk of developing different kinds of malignant tumors .
4		CASE PRESENTATION :
5		We report on a 39-year-old woman who was diagnosed with Maffucci syndrome together with intrahepatic cholangiocarcinoma ( IHCC ) .
6		Heterozygous somatic mutations in the isocitrate dehydrogenase 1 and 2 ( IDH1/IDH2 ) genes are associated with a number of different tumor types ( e.g . IHCC ) and also with Maffucci syndrome .
7		For IHCC , mutations in IDH1/IDH2 are associated with higher survival rates .
8	Μ	IHCC tissue as well as normal liver tissue and peripheral blood were analyzed for IDH1/IDH2-mutations in our patient .
9	Μ	In the tumor sample , we identified a recurrent somatic IDH1-mutation affecting Arg132 , while in normal liver tissue and peripheral blood , no variants were detected , as expected .
10		CONCLUSION :
11		This case report presents the second patient in the literature exhibiting the features of Maffucci syndrome along with cholangiocarcinoma .
12		This supports the hypothesis that IDH1/2-mutations , which can be present in different types of tumor tissue simultaneously , arise during embryonic development in a mosaic pattern ; as a result , a more aggressive follow-up is proposed in patients with Maffucci syndrome to exclude neoplasms .

PMID: 26877611 (None)   Terms: , mice, mouse
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0		Oncogenic potential of IDH1R132C mutant in cholangiocarcinoma development in mice .
1		AIM :
2		To investigate whether IDH1R132C mutant in combination with loss of p53 and activated Notch signaling promotes intrahepatic cholangiocarcinoma ( ICC ) development .
3		METHODS :
4		We applied hydrodynamic injection and sleeping beauty mediated somatic integration to induce loss of p53 ( via shP53 ) , activation of Notch [via intracellular domain of Notch1 ( NICD )] and/or overexpression of IDH1R132C mutant together with the sleeping beauty transposase into the mouse liver .
5		Specifically , we co-expressed shP53 and NICD ( shP53/NICD , n = 4 ) , shP53 and IDH1R132C ( shP53/IDH1R132C , n = 3 ) , NICD and IDH1R132C ( NICD/IDH1R132C , n = 4 ) , as well as NICD , shP53 and IDH1R132C ( NICD/shP53/IDH1R132C , n = 9 ) in mice .
6		Mice were monitored for liver tumor development and euthanized at various time points .
7		Liver histology was analyzed by hematoxylin and eosin staining .
8		Molecular features of NICD/shP53/IDH1R132C ICC tumor cells were characterized by Myc tag , Flag tag , Ki-67 , p-Erk and p-AKT immunohistochemical staining .
9		Desmoplastic reaction in tumor tissues was studied by Picro-Sirius red staining .
10		RESULTS :
11	Μ	We found that co-expression of shP53/NICD , shP53/IDH1R132C or NICD/IDH1R132C did not lead to liver tumor formation .
12		In striking contrast , co-expression of NICD/shP53/IDH1R132C resulted in ICC development in mice ( P <001 ) .
13		The tumors could be identified as early as 12 wk post hydrodynamic injection .
14		Tumors rapidly progressed , and by 18 wk post hydrodynamic injection , multiple cystic lesions could be identified on the liver surface .
15		NICD/shP53/IDH1R132C liver tumors shared multiple histological features of human ICCs , including hyperplasia of irregular glands .
16		Importantly , all tumor cells were positive for the biliary epithelial cell marker cytokeratin 19 .
17		Extensive collagen fibers could be visualized in tumor tissues using Sirus red staining , duplicating the desmoplastic reaction observed in human ICC .
18		Tumors were highly proliferative and expressed ectopically injected genes .
19		Together these studies supported that NICD/shP53/IDH1R132C liver tumors were indeed ICCs .
20	Μ	Finally , no p-AKT or p-ERK positive staining was observed , suggesting that NICD/shP53/IDH1R132C driven ICC development was independent of AKT/mTOR and Ras/MAPK signaling cascades .
21		CONCLUSION :
22		We have generated a simple , non-germline murine ICC model with activated Notch , loss of p53 and IDH1R132C mutant .
23		The study supported the oncogenic potential of IDH1R132C .

PMID: 26819452 (None)   Terms: clinical trial
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0		Molecular Pathways : Isocitrate Dehydrogenase Mutations in Cancer .
1		IDH1 and IDH2 are homodimeric enzymes that catalyze the conversion of isocitrate to alpha-ketoglutarate ( alpha-KG ) and concomitantly produce reduced NADPH from NADP(+) Mutations in the genes encoding IDH1 and IDH2 have recently been found in a variety of human cancers , most commonly glioma , acute myeloid leukemia ( AML ) , chondrosarcoma , and intrahepatic cholangiocarcinoma .
2		The mutant protein loses its normal enzymatic activity and gains a new ability to produce the "oncometabolite" R(-) -2-hydroxyglutarate ( R-2-HG ) .
3		R-2-HG competitively inhibits alpha-KG -dependent enzymes which play crucial roles in gene regulation and tissue homeostasis .
4		Expression of mutant IDH impairs cellular differentiation in various cell lineages and promotes tumor development in cooperation with other cancer genes .
5		First-generation inhibitors of mutant IDH have entered clinical trials , and have shown encouraging results in patients with IDH-mutant AML .
6	✓	This article summarizes recent progress in our understanding of the role of mutant IDH in tumorigenesis .	GM-INV-RO
7		Clin Cancer Res ; 22(8) ; 1837-42 .
8		(c) 2016 AACR .

PMID: 26717940 (Patient)   Terms:
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0		Cholangiocarcinoma Heterogeneity Revealed by Multigene Mutational Profiling : Clinical and Prognostic Relevance in Surgically Resected Patients .
1		BACKGROUND :
2		Cholangiocarcinoma can be classified in intrahepatic cholangiocarcinoma ( ICC ) and perihilar cholangiocarcinoma ( PCC ) .
3		Moreover , PCC includes two different forms : extrahepatic ( EH ) PCC , which arises from the perihilar EH large ducts , and intrahepatic ( IH ) PCC , in which a significant liver mass invades the perihilar bile ducts .
4		In this study , we investigated the molecular profile and molecular prognostic factors in EH-PCC , IH-PCC , and ICC submitted to curative surgery .
5		METHODS :
6		Ninety-one patients with cholangiocarcinoma ( 38 EH-PCC , 18 IH-PCC , and 35 ICC ) , who underwent curative surgery in a single tertiary hepatobiliary surgery referral center were assessed for mutational status in 56 cancer-related genes .
7		RESULTS :
8	Μ	The most frequently mutated genes in EH-PCC were KRAS ( 474 % ) , TP53 ( 237 % ) and ARID1A ( 158 % ) ; in IH-PCC were KRAS ( 222 % ) , PBRM1 ( 167 % ) , and PIK3CA ( 167 % ) ; and in ICC were IDH1 ( 171 % ) , NRAS ( 171 % ) , and BAP1 ( 143 % ) .
9	✓	The presence of mutations in ALK , IDH1 , and TP53 genes was significantly associated with poor prognosis in patients with EH-PCC ( p <0001 , p = 0043 , and p = 0019 , respectively ) .	GM-ASS-RO
10	✓	Mutation of the TP53 gene was significantly associated with poor prognosis in patients with IH-PCC ( p = 0049 ) .	GM-ASS-RO
11	✓	The presence of mutations in ARID1A , PIK3C2G , STK11 , TGFBR2 , and TP53 genes was significantly associated with poor prognosis in patients with ICC ( p = 0012 , p = 0030 , p = 0030 , p = 0011 , and p = 0011 , respectively ) .	GM-ASS-RO
12		CONCLUSIONS :
13	Μ	Mutational gene profiling identified different gene mutations in EH-PCC , IH-PCC , and ICC .
14		Moreover , our study reported specific prognostic genes that can identify patients with poor prognosis after curative surgery who may benefit from traditional or target adjuvant treatments .

PMID: 26709801 (None)   Terms: clinical trial
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0		New genomic landscapes and therapeutic targets for biliary tract cancers .
1		Biliary tract cancers ( BTCs ) are a heterogeneous group of neoplasms characterized by a dismal prognosis .
2		At variance with most solid tumors , no effective molecular targeted agent has been currently approved for BTCs treatment and their molecular landscape has only been recently investigated .
3		Comprehensive mutational profiling studies identified IDH1/2 and BAP1 as characteristic of intrahepatic cholangiocarcinomas , while extrahepatic cholangiocarcinomas and gallbladder carcinomas were characterized by frequent KRAS and TP53 alterations .
4		Moreover , targeted next-generation sequencing has uncovered alterations in several key cellular pathways .
5		BTC-specific alterations include disorders of major regulators of cell cycle and chromatin remodeling processes , as well as deregulation of the mTOR - , TGF-beta/Smad - and receptor tyrosine kinases signaling .
6		The next step will be the correlation of these findings with clinical trials to identify predictive biomarkers for the development of personalized therapies .
7		This will permit early access for BTC patients to innovative drugs .

PMID: 26500333 (Patient)   Terms:
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0		Comprehensive genomic profiling of extrahepatic cholangiocarcinoma reveals a long tail of therapeutic targets .
1		AIM :
2	Μ	We queried whether extrahepatic cholangiocarcinoma featured clinically relevant genomic alterations that could lead to targeted therapy .
3		METHODS :
4		Comprehensive genomic profiling by hybridisation capture of up to 315 genes was performed on 99 clinically advanced extrahepatic cholangiocarcinoma .
5		RESULTS :
6		There were 60 male and 39 female patients with a median age of 60.5 years .
7	Μ	A total of 400 alterations were identified ( mean 40 ; range 0-13 ) in 84 genes .
8	Μ	Eighty-two ( 83% ) of extrahepatic cholangiocarcinoma patients featured atleast one clinically relevant genomic alterations including KRAS ( 43% ) ; ERBB2 ( 9% ) , PTEN ( 7% ) ; ATM and NF1 ( 6% ) and CCND1 , FBXW7 , GNAS , MDM2 and NRAS ( all at 5% ) .
9	Μ	BRAF , BRCA2 , CDK4 , CDK6 , FGFR1 , FGFR3 , PTCH1 , RAF1 and STK11 were each altered in a single patient .
10	Μ	No IDH1/2 mutations or FGFR2 gene fusions were identified .
11		CONCLUSIONS :
12		Comprehensive genomic profiling of extrahepatic cholangiocarcinoma differs significantly from intrahepatic cholangiocarcinoma and pancreatic adenocarcinoma , and reveals diverse opportunities for the use of targeted therapies .

PMID: 26405193 (None)   Terms: clinical trial, animal models
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0		Molecular Pathogenesis and Targeted Therapies for Intrahepatic Cholangiocarcinoma .
1		Intrahepatic cholangiocarcinoma ( iCCA ) is a molecularly heterogeneous hepatobiliary neoplasm with poor prognosis and limited therapeutic options .
2		The incidence of this neoplasm is growing globally .
3		One third of iCCA tumors are amenable to surgical resection , but most cases are diagnosed at advanced stages with chemotherapy as the only established standard of practice .
4		No molecular therapies are currently available for the treatment of this neoplasm .
5		The poor understanding of the biology of iCCA and the lack of known oncogenic addiction loops has hindered the development of effective targeted therapies .
6		Studies with sophisticated animal models defined IDH mutation as the first gatekeeper in the carcinogenic process and led to the discovery of striking alternative cellular origins .
7	Μ	RNA - and exome-sequencing technologies revealed the presence of recurrent novel fusion events ( FGFR2 and ROS1 fusions ) and somatic mutations in metabolic ( IDH1/2 ) and chromatin-remodeling genes ( ARID1A , BAP1 ) .
8		These latest advancements along with known mutations in KRAS/BRAF/EGFR and 11q13 high-level amplification have contributed to a better understanding of the landscape of molecular alterations in iCCA .
9		More than 100 clinical trials testing molecular therapies alone or in combination with chemotherapy including iCCA patients have not reported conclusive clinical benefits .
10		Recent discoveries have shown that up to 70% of iCCA patients harbor potential actionable alterations that are amenable to therapeutic targeting in early clinical trials .
11		Thus , the first biomarker-driven trials are currently underway .

PMID: 26320466 (None)   Terms: , animal model
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0		Altered Expression of Oxidative Metabolism Related Genes in Cholangiocarcinomas .
1		Cholangiocarcinoma ( CCA ) is a rare but highly fatal cancer for which the molecular mechanisms and diagnostic markers are obscure .
2		We therefore investigated the kinetic expression of isocitrate dehydrogenase-1 ( IDH1 ) , isocitrate dehydrogenase-2 ( IDH2 ) and homogentisate 1, 2-dioxygenase ( HGD ) during the tumorigenesis of O .
3		viverrini infection-associated CCA in an animal model , and confirmed down-regulation of expression in human cases of opisthorchiasis-associated CCA through real time PCR .
4		Kinetic expression of HGD , IDH1 and IDH2 in the animal model of O .
5		viverrini infection-induced CCA was correlated with human CCA cases .
6		In the animal model , expression of HGD was decreased at all time points ( p<001 ) and expression of both IDH1 and IDH2 was decreased in the CCA group .
7		In human cases , expression of HGD , IDH1 and IDH2 was decreased more than 2 fold in 55 cases ( 705% ) , 25 cases ( 321% ) and 24 cases ( 308% ) respectively .
8		The present study suggests that reduction of HGD , IDH1 and IDH2 may be involve in cholangiocarcinoma genesis and may be useful for molecular diagnosis .

PMID: 26260902 (Patient)   Terms:
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0		Genome wide DNA copy number analysis in cholangiocarcinoma using high resolution molecular inversion probe single nucleotide polymorphism assay .
1		In order to study molecular similarities and differences of intrahepatic ( IH-CCA ) and extrahepatic ( EH-CCA ) cholangiocarcinoma , 24 FFPE tumor samples ( 13 IH-CCA , 11 EH-CCA ) were analyzed for whole genome copy number variations ( CNVs ) using a new high-density Molecular Inversion Probe Single Nucleotide Polymorphism ( MIP SNP ) assay .
2		Common in both tumor subtypes the most frequent losses were detected on chromosome 1p , 3p , 6q and 9 while gains were mostly seen in 1q , 8q as well as complete chromosome 17 and 20 .
3		Applying the statistical GISTIC ( Genomic Identification of Significant Targets in Cancer ) tool we identified potential novel candidate tumor suppressor - ( DBC1 , FHIT , PPP2R2A ) and oncogenes ( LYN , FGF19 , GRB7 , PTPN1 ) within these regions of chromosomal instability .
4	Μ	Next to common aberrations in IH-CCA and EH-CCA , we additionally found significant differences in copy number variations on chromosome 3 and 14 .
5		Moreover , due to the fact that mutations in the Isocitrate dehydrogenase ( IDH-1 and IDH-2 ) genes are more frequent in our IH-CCA than in our EH-CCA samples , we suggest that the tumor subtypes have a different molecular profile .
6	Μ	In conclusion , new possible target genes within regions of high significant copy number aberrations were detected using a high-density Molecular Inversion Probe Single Nucleotide Polymorphism ( MIP SNP ) assay , which opens a future perspective of fast routine copy number and marker gene identification for gene targeted therapy .

PMID: 26245674 (Patient)   Terms: retrospective, clinical trial, prospective
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0		Prognosis and Clinicopathologic Features of Patients With Advanced Stage Isocitrate Dehydrogenase ( IDH ) Mutant and IDH Wild-Type Intrahepatic Cholangiocarcinoma .
1		BACKGROUND :
2		Conflicting data exist regarding the prognostic impact of the isocitrate dehydrogenase ( IDH ) mutation in intrahepatic cholangiocarcinoma ( ICC ) , and limited data exist in patients with advanced-stage disease .
3		Similarly , the clinical phenotype of patients with advanced IDH mutant ( IDHm ) ICC has not been characterized .
4		In this study , we report the correlation of IDH mutation status with prognosis and clinicopathologic features in patients with advanced ICC .
5		METHODS :
6		Patients with histologically confirmed advanced ICC who underwent tumor mutational profiling as a routine part of their care between 2009 and 2014 were evaluated .
7		Clinical and pathological data were collected by retrospective chart review for patients with IDHm versus IDH wild-type ( IDHwt ) ICC .
8		Pretreatment tumor volume was calculated on computed tomography or magnetic resonance imaging .
9		RESULTS :
10		Of the 104 patients with ICC who were evaluated , 30 ( 288% ) had an IDH mutation ( 250% IDH1 , 38% IDH2 ) .
11		The median overall survival did not differ significantly between IDHm and IDHwt patients ( 150 vs. 201 months , respectively ; p = 17 ) .
12		The pretreatment serum carbohydrate antigen 19-9 ( CA19-9 ) level in IDHm and IDHwt patients was 34.5 and 118.0 U/mL , respectively ( p = 04 ) .
13		Age at diagnosis , sex , histologic grade , and pattern of metastasis did not differ significantly by IDH mutation status .
14		CONCLUSION :
15	✓	The IDH mutation was not associated with prognosis in patients with advanced ICC .	GM-ASS-RO
16		The clinical phenotypes of advanced IDHm and IDHwt ICC were similar , but patients with IDHm ICC had a lower median serum CA19-9 level at presentation .
17		IMPLICATIONS FOR PRACTICE :
18		Previous studies assessing the prognostic impact of the isocitrate dehydrogenase ( IDH ) gene mutation in intrahepatic cholangiocarcinoma ( ICC ) mainly focused on patients with early-stage disease who have undergone resection .
19		These studies offer conflicting results .
20		The target population for clinical trials of IDH inhibitors is patients with unresectable or metastatic disease , and the current study is the first to focus on the prognosis and clinical phenotype of this population and reports on the largest cohort of patients with advanced IDH mutant ICC to date .
21		The finding that the IDH mutation lacks prognostic significance in advanced ICC is preliminary and needs to be confirmed prospectively in a larger study .

PMID: 26189129 (Patient)   Terms:
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0		Molecular profiling of intrahepatic and extrahepatic cholangiocarcinoma using next generation sequencing .
1		Cholangiocarcinoma is a heterogeneous malignant process , which is further classified into intrahepatic cholangiocarcinoma ( ICC ) and extrahepatic cholangiocarcinoma ( ECC ) .
2		The poor prognosis of the disease is partly due to the lack of understanding of the disease mechanism .
3	Μ	Multiple gene alterations identified by various molecular techniques have been described recently .
4		As a result , multiple targeted therapies for ICC and ECC are being developed .
5	Μ	In this study , we identified and compared somatic mutations in ICC and ECC patients using next generation sequencing ( NGS ) ( Ampliseq Cancer Hotspot Panel v2 and Ion Torrent 318v2 chips ) .
6		Eleven of 16 samples passed internal quality control established for NGS testing .
7	Μ	ICC cases ( n = 3 ) showed IDH1 ( 333% ) and NRAS ( 333% ) mutations .
8	Μ	Meanwhile , TP53 ( 75% ) , KRAS ( 50% ) , and BRAF ( 125% ) mutations were identified in ECC cases ( n = 8 ) .
9		Our study confirmed the molecular heterogeneity of ICC and ECC using NGS .
10		This information will be important for individual patients as targeted therapies for ICC and ECC become available in the future .

PMID: 25960387 (None)   Terms:
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0		IDH1 , lipid metabolism and cancer : Shedding new light on old ideas .
1		BACKGROUND :
2		Since the initial discovery of mutations in the isocitrate dehydrogenase 1 ( IDH1 ) gene in a large subset of human low-grade gliomas and acute myelogenous leukemia ( AML ) , much interest focused on the function of IDH1 and on the relationship between mutations in IDH1 and tumor progression .
3	Μ	To date , mutations in the IDH1 gene have been found in numerous cancers with the highest frequencies occurring in gliomas , chondrosarcomas/enchondromas and cholangiocarcinomas .
4		SCOPE OF REVIEW :
5		IDH1 was first described in the scientific literature as early as 1950 .
6		Early researchers proposed that the enzyme likely functions in cellular lipid metabolism based on the observation that the enzymatic reaction produces NADPH and partially localizes to peroxisomes .
7	Μ	This article highlights the studies implicating IDH1 in cytoplasmic and peroxisomal lipid metabolism from the early researchers to the recent studies examining mutant IDH1 (R132) , the most common IDH1 mutation found in cancer .
8		MAJOR CONCLUSIONS :
9		While a role for IDH1 in lipid biosynthesis in the liver and adipose tissue is now established , a role in lipid metabolism in the brain and tumors is beginning to be examined .
10		The recent discoveries that IDH1 (R132H) interferes with the metabolism of phospholipids in gliomas and that IDH1 activity could participate in the synthesis of acetyl-CoA from glutamine in hypoxic tumors highlight roles for IDH1 in lipid metabolism in a broad spectrum of tissues .
11		GENERAL SIGNIFICANCE :
12		Interferences in cytoplasmic and peroxisomal lipid metabolism by IDH1 (R132) may contribute to the more favorable clinical outcome in patients whose tumors express mutations in the IDH1 gene .

PMID: 25787993 (None)   Terms:
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0		Isocitrate dehydrogenase mutations : new opportunities for translational research .
1	Μ	Over the last decade , comprehensive genome -wide sequencing studies have enabled us to find out unexpected genetic alterations of metabolism in cancer .
2		An example is the identification of arginine missense mutations of isocitrate dehydrogenases-1 and -2 ( IDH1/2 ) in glioma , acute myeloid leukemia ( AML ) , chondrosarcomas , and cholangiocarcinoma .
3		These alterations are closely associated with the production of a new stereospecific metabolite , (R) -2-hydroxyglutarate ( R-2HG ) .
4		A large number of follow-up studies have been performed to address the molecular mechanisms of IDH1/2 mutations underlying how these events contribute to malignant transformation .
5		In the meanwhile , the development of selective mutant IDH1/2 chemical inhibitors is being actively pursued in the scientific community and pharmaceutical industry .
6		The present review article briefly discusses the important findings that highlight the molecular mechanisms of IDH1/2 mutations in cancer and provides a current status for development of selective mutant IDH1/2 chemical inhibitors .

PMID: 25693006 (None)   Terms:
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0		Genetics of Opisthorchis viverrini-related cholangiocarcinoma .
1		PURPOSE OF REVIEW :
2		We review the genetic , epigenetic and transcriptional landscape of liver fluke ( Opisthorchis viverrini , Ov ) -related cholangiocarcinoma ( CCA ) .
3		Its distinct alterations , as compared with non-Ov-related CCA may help shed light on its underlying molecular mechanisms .
4		RECENT FINDINGS :
5	Μ	Recent whole-exome and targeted sequencing not only confirmed frequent mutations in known CCA-related genes including TP53 ( 44% ) , KRAS ( 167% ) and SMAD4 ( 167% ) , but also revealed mutations in novel CCA-related genes associated with chromatin remodeling [BAP1 ( 28% ) , ARID1A ( 176% ) , MLL3 ( 13% ) and IDH1/2 ( 28% ) ] , WNT signaling [RNF43 ( 93% ) and PEG3 ( 56% ) ] and KRAS/G protein signaling [GNAS ( 93% ) and ROBO2 ( 93% ) ] .
6		Interestingly , there is a significant difference in the frequency of mutated genes between Ov-related CCA and non-Ov-related CCA , such as p53 and IDH1/2 , reflecting the impact of cause on pathogenesis .
7		Altered DNA methylation and transcriptional profiles associated with xenobiotic metabolism and pro-inflammatory responses were also found in Ov-related CCA .
8		SUMMARY : Liver fluke-induced chronic inflammation plays a crucial role in cholangiocarcinogenesis , resulting in distinct signatures of genetic , epigenetic and transcriptional alterations .
9		These alterations , when contrasted with non-Ov-related CCA , indicate a unique pathogenic process in Ov-related CCA and may have potential clinical implications on diagnostics , therapeutics and prevention .

PMID: 25636086 (None)   Terms:
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0		Whole - genome mutational landscape of liver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity .
1		Intrahepatic cholangiocarcinoma and combined hepatocellular cholangiocarcinoma show varying degrees of biliary epithelial differentiation , which can be defined as liver cancer displaying biliary phenotype ( LCB ) .
2		LCB is second in the incidence for liver cancers with and without chronic hepatitis background and more aggressive than hepatocellular carcinoma ( HCC ) .
3	Μ	To gain insight into its molecular alterations , we performed whole - genome sequencing analysis on 30 LCBs .
4		Here we show , the genome -wide substitution patterns of LCBs developed in chronic hepatitis livers overlapped with those of 60 HCCs , whereas those of hepatitis-negative LCBs diverged .
5	Μ	The subsequent validation study on 68 LCBs identified recurrent mutations in TERT promoter , chromatin regulators ( BAP1 , PBRM1 and ARID2 ) , a synapse organization gene (PCLO) , IDH genes and KRAS .
6	✓	The frequencies of KRAS and IDHs mutations , which are associated with poor disease-free survival , were significantly higher in hepatitis-negative LCBs .	GM-ASS-RO
7		This study reveals the strong impact of chronic hepatitis on the mutational landscape in liver cancer and the genetic diversity among LCBs .

PMID: 25608663 (Patient)   Terms: in vitro
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0		Massive parallel sequencing uncovers actionable FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma .
1		Intrahepatic cholangiocarcinoma ( iCCA ) is a fatal bile duct cancer with dismal prognosis and limited therapeutic options .
2	Μ	By performing RNA - and exome-sequencing analyses , we report a novel fusion event , FGFR2-PPHLN1 ( 16% ) , and damaging mutations in the ARAF oncogene ( 11% ) .
3		Here we demonstrate that the chromosomal translocation t ( 10 ; 12 ) ( q26 ; q12 ) leading to FGFR2-PPHLN1 fusion possesses transforming and oncogenic activity , which is successfully inhibited by a selective FGFR2 inhibitor in vitro .
4		Among the ARAF mutations , N217I and G322S lead to activation of the pathway and N217I shows oncogenic potential in vitro .
5	Μ	Screening of a cohort of 107 iCCA patients reveals that FGFR2 fusions represent the most recurrent targetable alteration ( 45% , 17/107 ) , while they are rarely present in other primary liver tumours ( 0/100 of hepatocellular carcinoma ( HCC ) ; 1/21 of mixed iCCA-HCC ) .
6		Taken together , around 70% of iCCA patients harbour atleast one actionable molecular alteration ( FGFR2 fusions , IDH1/2 , ARAF , KRAS , BRAF and FGF19 ) that is amenable for therapeutic targeting .

PMID: 25536104 (Patient)   Terms: clinical trial
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0		Mutation profiling in cholangiocarcinoma : prognostic and therapeutic implications .
1		BACKGROUND :
2		Cholangiocarcinoma ( CCA ) is clinically heterogeneous ; intra and extrahepatic CCA have diverse clinical presentations .
3		Next generation sequencing ( NGS ) technology may identify the genetic differences between these entities and identify molecular subgroups for targeted therapeutics .
4		METHODS :
5		We describe successful NGS-based testing of 75 CCA patients along with the prognostic and therapeutic implications of findings .
6		Mutation profiling was performed using either a ) NGS panel of hotspot regions in 46 cancer-related genes using a 318-chip on Ion PGM Sequencer or b ) Illumina HiSeq 2000 sequencing platform for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes to an average depth of 1000X .
7		Clinical data was abstracted and correlated with clinical outcome .
8		Patients with targetable mutations were referred to appropriate clinical trials .
9		RESULTS :
10		There were significant differences between intrahepatic ( n = 55 ) and extrahepatic CCA ( n = 20 ) in regard to the nature and frequency of the genetic aberrations ( GAs ) .
11	Μ	IDH1 and DNA repair gene alterations occurred more frequently in intrahepatic CCA , while ERBB2 GAs occurred in the extrahepatic group .
12		Commonly occurring GAs in intrahepatic CCA were TP53 ( 35% ) , KRAS ( 24% ) , ARID1A ( 20% ) , IDH1 ( 18% ) , MCL1 ( 16% ) and PBRM1 ( 11% ) .
13		Most frequent GAs in extrahepatic CCA ( n = 20 ) were TP53 ( 45% ) , KRAS ( 40% ) , ERBB2 ( 25% ) , SMAD4 ( 25% ) , FBXW7 ( 15% ) and CDKN2A ( 15% ) .
14		In intrahepatic CCA , KRAS , TP53 or MAPK/mTOR GAs were significantly associated with a worse prognosis while FGFR GAs correlated with a relatively indolent disease course .
15		IDH1 GAs did not have any prognostic significance .
16		GAs in the chromatin modulating genes , BAP1 and PBRM1 were associated with bone metastases and worse survival in extrahepatic CCA .
17		Radiologic responses and clinical benefit was noted with EGFR , FGFR , C-met , B-RAF and MEK inhibitors .
18		CONCLUSION :
19		There are significant genetic differences between intra and extrahepatic CCA .
20		NGS can potentially identify disease subsets with distinct prognostic and therapeutic implications .

PMID: 25526346 (Patient)   Terms:
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0		Mutational landscape of intrahepatic cholangiocarcinoma .
1		Intrahepatic cholangiocarcinoma ( ICC ) is a fatal primary liver cancer ( PLC ) that affects 5-10% of all PLCs .
2		Here we sequence tumour and matching control sample pairs of a large cohort of 103 ICC patients in China , resulting in the identification of an ICC-specific somatic mutational signature that is associated with liver inflammation , fibrosis and cirrhosis .
3		We further uncover 25 significantly mutated genes including eight potential driver genes ( TP53 , KRAS , IDH1 , PTEN , ARID1A , EPPK1 , ECE2 and FYN ) .
4	Μ	We find that TP53-defective ICC patients are more likely to be HBsAg-seropositive , whereas mutations in the oncogene KRAS are nearly exclusively found in HBsAg-seronegative ICC patients .
5		Three pathways ( Ras/phosphatidylinositol-4,5-bisphosphate 3 - kinase signalling , p53/cell cycle signalling and transforming growth factor -beta/Smad signalling ) , genes important for epigenetic regulation and oxidative phosphorylation are substantially affected in ICC .
6	Μ	We reveal mutations in this study that may be valuable for designing further studies , better diagnosis and effective therapies .

PMID: 25485496 (Patient)   Terms: in vitro, genetically engineered mouse, mouse models, mouse
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0		IDH mutations in liver cell plasticity and biliary cancer .
1		Intrahepatic cholangiocarcinoma ( ICC ) is an aggressive cancer associated with the bile ducts within the liver .
2		These tumors are characterized by frequent gain-of-function mutations in the isocitrate dehydrogenase 1 and 2 ( IDH1 and IDH2 ) genes -that are also common in subsets of neural , haematopoietic and bone tumors , but rare or absent in the other types of gastrointestinal malignancy .
3		Mutant IDH acts through a novel mechanism of oncogenesis , producing high levels of the metabolite 2-hydroxyglutarate , which interferes with the function of alpha-ketoglutarate -dependent enzymes that regulate diverse cellular processes including histone demethylation and DNA modification .
4		Recently , we used in vitro stem cell systems and genetically engineered mouse models ( GEMMs ) to demonstrate that mutant IDH promotes ICC formation by blocking hepatocyte differentiation and increasing pools of hepatic progenitors that are susceptible to additional oncogenic hits leading to ICC .
5		We found that silencing of HNF4A -encoding a master transcriptional regulator of hepatocyte identity and quiescence-was critical to mutant IDH -mediated inhibition of liver differentiation .
6		In line with these findings , human ICC with IDH mutations are characterized by a hepatic progenitor cell transcriptional signature suggesting that they are a distinct ICC subtype as compared to IDH wild type tumors .
7		The role of mutant IDH in controlling hepatic differentiation state suggests the potential of newly developed inhibitors of the mutant enzyme as a form of differentiation therapy in a solid tumor .

PMID: 25481493 (Patient)   Terms:
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0		Increased plasma d-2-hydroxyglutarate in isocitrate dehydrogenase 2-mutated blastic plasmacytoid dendritic cell neoplasm .
1		Blastic plasmacytoid dendritic cell neoplasm is an exceedingly rare hematologic malignancy derived from the precursors of plasmacytoid dendritic cells .
2		Mutations in isocitrate dehydrogenase ( IDH ) 1 and 2 genes have been discovered in a range of neoplasms including glioma , acute myeloid leukemia , chondrosarcoma , and intrahepatic cholangiocarcinoma .
3		Mutant IDH acquires neomorphic enzymatic activity to generate the oncometabolite d-2-hydroxyglutarate ( d-2HG ) .
4		Here , we describe the first case of an IDH2 R140Q-mutated blastic plasmacytoid dendritic cell neoplasm in a patient with markedly elevated plasma d-2HG .
5		This finding expands the spectrum of neoplasms with increased d-2HG in association with IDH mutation .
6		The roles of IDH mutation and d-2HG in disease pathogenesis and assessment of clinical response are discussed .

PMID: 25369307 (None)   Terms:
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0		Cholangiocarcinoma : molecular pathways and therapeutic opportunities .
1		Cholangiocarcinoma ( CCA ) is an aggressive biliary tract malignancy with limited treatment options and low survival rates .
2		Currently , there are no curative medical therapies for CCA .
3		Recent advances have enhanced our understanding of the genetic basis of this disease , and elucidated therapeutically relevant targets .
4		Therapeutic efforts in development are directed at several key pathways due to genetic aberrations including receptor tyrosine kinase pathways , mutant IDH enzymes , the PI3K-AKT-mTOR pathway , and chromatin remodeling networks .
5		A highly desmoplastic , hypovascular stroma is characteristic of CCAs and recent work has highlighted the importance of targeting this pathway via stromal myofibroblast depletion .
6		Future efforts should concentrate on combination therapies with action against the cancer cell and the surrounding tumor stroma .
7		As the mutational landscape of CCA is being illuminated , molecular profiling of patient tumors will enable identification of specific mutations and the opportunity to offer directed , personalized treatment options .

PMID: 25324168 (None)   Terms:
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0		Specific monoclonal antibodies against IDH1/2 mutations as diagnostic tools for gliomas .
1		Mutations of isocitrate dehydrogenase 1/2 ( IDH1/2 ) have been reported in gliomas and other types of tumors , such as acute myeloid leukemias , cartilaginous tumors , intrahepatic cholangiocarcinomas , osteosarcomas , and giant cell tumors of bone .
2		In gliomas , IDH mutations uniformly occur in the functionally critical arginine 132 residue (R132) of IDH1 and arginine 172 residue (R172) of IDH2 .
3		IDH1 and IDH2 catalyze the oxidative carboxylation of isocitrate to alpha-ketoglutarate ( alpha-KG ) in the cytosol and mitochondria , respectively .
4		In contrast , mutated IDH1/2 proteins possess a neomorphic enzymatic function that changes alpha-KG into the oncometabolite , R(-) -2-hydroxyglutarate , resulting in genomic hypermethylation , histone methylation , genetic instability , and malignant transformation .
5		To date , several monoclonal antibodies ( mAbs ) specific for IDH1/2 mutations such as anti-IDH1-R132H mAbs ( clone H09 , clone IMab-1 , and clone HMab-1 ) or an anti-IDH1-R132S mAb ( clone SMab-1 ) have been established .
6		Furthermore , one of multi-specific mAbs , MsMab-1 , recognizes IDH1 mutants ( R132H , R132S , R132G ) and IDH2 mutants ( R172S , R172G ) , which are observed in gliomas .
7		Another mAb , MsMab-2 , recognizes IDH1-R132L and IDH2-R172M .
8		These IDH1/2 mutation-specific mAbs are useful for the immunohistochemical determination of IDH1/2 mutation-bearing gliomas .

PMID: 25267595 (None)   Terms:
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0		Molecular diagnosis of intrahepatic cholangiocarcinoma .
1		Intrahepatic cholangiocarcinomas ( iCCA ) are primary intrahepatic malignancies originating from biliary epithelia .
2		While both hepatocellular cancer and iCCA can present as mass lesions within the liver , these cancers are distinct in their morphology , etiology , pathology , natural history and response to therapy .
3		There is a need for accurate and sensitive molecular markers for the diagnosis of iCCA .
4		Recent advances in elucidating molecular and genetic characteristics of iCCA offer the potential of molecular-based diagnosis of iCCA .
5		Specific genetic mutations of IDH1/2 , BAP1 , p53 , and KRAS , FGFR gene fusions and alterations in microRNA have all been described in iCCA .
6		Although there are no accurate serum or biliary biomarkers currently available for diagnosis of iCCA , several potential candidates have been identified .
7		Knowledge of specific genetic or molecular abnormalities offers potential for individualized approaches for the treatment of patients with iCCA in the future .

PMID: 25043045 (Patient)   Terms: , genetically engineered mouse, mouse models, mouse, mouse model
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0		Mutant IDH inhibits HNF-4alpha to block hepatocyte differentiation and promote biliary cancer .
1		Mutations in isocitrate dehydrogenase 1 ( IDH1 ) and IDH2 are among the most common genetic alterations in intrahepatic cholangiocarcinoma ( IHCC ) , a deadly liver cancer .
2		Mutant IDH proteins in IHCC and other malignancies acquire an abnormal enzymatic activity allowing them to convert alpha-ketoglutarate ( alphaKG ) to 2-hydroxyglutarate ( 2HG ) , which inhibits the activity of multiple alphaKG -dependent dioxygenases , and results in alterations in cell differentiation , survival , and extracellular matrix maturation .
3		However , the molecular pathways by which IDH mutations lead to tumour formation remain unclear .
4		Here we show that mutant IDH blocks liver progenitor cells from undergoing hepatocyte differentiation through the production of 2HG and suppression of HNF-4alpha , a master regulator of hepatocyte identity and quiescence .
5		Correspondingly , genetically engineered mouse models expressing mutant IDH in the adult liver show an aberrant response to hepatic injury , characterized by HNF-4alpha silencing , impaired hepatocyte differentiation , and markedly elevated levels of cell proliferation .
6		Moreover , IDH and Kras mutations , genetic alterations that co-exist in a subset of human IHCCs , cooperate to drive the expansion of liver progenitor cells , development of premalignant biliary lesions , and progression to metastatic IHCC .
7		These studies provide a functional link between IDH mutations , hepatic cell fate , and IHCC pathogenesis , and present a novel genetically engineered mouse model of IDH-driven malignancy .

PMID: 24995286 (None)   Terms:
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0		Potential mitochondrial isocitrate dehydrogenase R140Q mutant inhibitor from traditional Chinese medicine against cancers .
1		A recent research of cancer has indicated that the mutant of isocitrate dehydrogenase 1 and 2 ( IDH1 and 2 ) genes will induce various cancers , including chondrosarcoma , cholangiocarcinomas , and acute myelogenous leukemia due to the effect of point mutations in the active - site arginine residues of isocitrate dehydrogenase ( IDH ) , such as IDH1/R132 , IDH2/R140 , and IDH2/R172 .
2		As the inhibition for those tumor-associated mutant IDH proteins may induce differentiation of those cancer cells , these tumor-associated mutant IDH proteins can be treated as a drug target proteins for a differentiation therapy against cancers .
3		In this study , we aim to identify the potent TCM compounds from the TCM Database@Taiwan as lead compounds of IDH2 R140Q mutant inhibitor .
4		Comparing to the IDH2 R140Q mutant protein inhibitor , AGI-6780 , the top two TCM compounds , precatorine and abrine , have higher binding affinities with target protein in docking simulation .
5		After MD simulation , the top two TCM compounds remain as the same docking poses under dynamic conditions .
6		In addition , precatorine is extracted from Abrus precatorius L. , which represents the cytotoxic and proapoptotic effects for breast cancer and several tumor lines .
7		Hence , we propose the TCM compounds , precatorine and abrine , as potential candidates as lead compounds for further study in drug development process with the IDH2 R140Q mutant protein against cancer .

PMID: 24889489 (Patient)   Terms:
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0		Genomic profiling of intrahepatic cholangiocarcinoma : refining prognosis and identifying therapeutic targets .
1		BACKGROUND :
2		The molecular alterations that drive tumorigenesis in intrahepatic cholangiocarcinoma ( ICC ) remain poorly defined .
3		We sought to determine the incidence and prognostic significance of mutations associated with ICC among patients undergoing surgical resection .
4		METHODS :
5		Multiplexed mutational profiling was performed using nucleic acids that were extracted from 200 resected ICC tumor specimens from 7 centers .
6		The frequency of mutations was ascertained and the effect on outcome was determined .
7		RESULTS :
8	Μ	The majority of patients ( 615 % ) had no genetic mutation identified .
9	Μ	Among the 77 patients ( 385 % ) with a genetic mutation , only a small number of gene mutations were identified with a frequency of >5 % : IDH1 ( 155 % ) and KRAS ( 86 % ) .
10	Μ	Other genetic mutations were identified in very low frequency : BRAF ( 49 % ) , IDH2 ( 45 % ) , PIK3CA ( 43 % ) , NRAS ( 31 % ) , TP53 ( 25 % ) , MAP2K1 ( 19 % ) , CTNNB1 ( 06 % ) , and PTEN ( 06 % ) .
11		Among patients with an IDH1-mutant tumor , approximately 7 % were associated with a concurrent PIK3CA gene mutation or a mutation in MAP2K1 ( 4 % ) .
12		No concurrent mutations in IDH1 and KRAS were noted .
13	Μ	Compared with ICC tumors that had no identified mutation , IDH1-mutant tumors were more often bilateral ( odds ratio 275 ) , while KRAS-mutant tumors were more likely to be associated with R1 margin ( odds ratio 651 ) ( both P <005 ) .
14	✓	Although clinicopathological features such as tumor number and nodal status were associated with survival , no specific mutation was associated with prognosis .	GM-ASS-RO
15		CONCLUSIONS :
16	Μ	Most somatic mutations in resected ICC tissue are found at low frequency , supporting a need for broad-based mutational profiling in these patients .
17		IDH1 and KRAS were the most common mutations noted .
18		Although certain mutations were associated with ICC clinicopathological features , mutational status did not seemingly affect long-term prognosis .

PMID: 24880135 (None)   Terms:
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0		The driver and passenger effects of isocitrate dehydrogenase 1 and 2 mutations in oncogenesis and survival prolongation .
1		Mutations in isocitrate dehydrogenase 1 and 2 ( IDH1 and IDH2 ) are key events in the development of glioma , acute myeloid leukemia ( AML ) , chondrosarcoma , intrahepatic cholangiocarcinoma ( ICC ) , and angioimmunoblastic T - cell lymphoma .
2		They also cause D-2-hydroxyglutaric aciduria and Ollier and Maffucci syndromes .
3		IDH1/2 mutations are associated with prolonged survival in glioma and in ICC , but not in AML .
4		The reason for this is unknown .
5		In their wild-type forms , IDH1 and IDH2 convert isocitrate and NADP(+) to alpha-ketoglutarate ( alphaKG ) and NADPH .
6		Missense mutations in the active sites of these enzymes induce a neo-enzymatic reaction wherein NADPH reduces alphaKG to D-2-hydroxyglutarate ( D-2HG ) .
7		The resulting D-2HG accumulation leads to hypoxia-inducible factor 1alpha degradation , and changes in epigenetics and extracellular matrix homeostasis .
8		Such mutations also imply less NADPH production capacity .
9		Each of these effects could play a role in cancer formation .
10		Here , we provide an overview of the literature and discuss which downstream molecular effects are likely to be the drivers of the oncogenic and survival-prolonging properties of IDH1/2 mutations .
11		We discuss interactions between mutant IDH1/2 inhibitors and conventional therapies .
12		Understanding of the biochemical consequences of IDH1/2 mutations in oncogenesis and survival prolongation will yield valuable information for rational therapy design : it will tell us which oncogenic processes should be blocked and which "survivalogenic" effects should be retained .

PMID: 24867389 (Patient)   Terms: clinical trial
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0		Multigene mutational profiling of cholangiocarcinomas identifies actionable molecular subgroups .
1		One-hundred-fifty-three biliary cancers , including 70 intrahepatic cholangiocarcinomas ( ICC ) , 57 extrahepatic cholangiocarcinomas ( ECC ) and 26 gallbladder carcinomas ( GBC ) were assessed for mutations in 56 genes using multigene next-generation sequencing .
2		Expression of EGFR and mTOR pathway genes was investigated by immunohistochemistry .
3	Μ	At least one mutated gene was observed in 118/153 ( 77% ) cancers .
4		The genes most frequently involved were KRAS ( 28% ) , TP53 ( 18% ) , ARID1A ( 12% ) , IDH1/2 ( 9% ) , PBRM1 ( 9% ) , BAP1 ( 7% ) , and PIK3CA ( 7% ) .
5		IDH1/2 ( p = 00005 ) and BAP1 ( p = 00097 ) mutations were characteristic of ICC , while KRAS ( p = 00019 ) and TP53 ( p = 00019 ) were more frequent in ECC and GBC .
6	✓ Μ	Multivariate analysis identified tumour stage and TP53 mutations as independent predictors of survival .	GM-MRK-RO
7		Alterations in chromatin remodeling genes ( ARID1A , BAP1 , PBRM1 , SMARCB1 ) were seen in 31% of cases .
8	Μ	Potentially actionable mutations were seen in 104/153 ( 68% ) cancers : i ) KRAS/NRAS/BRAF mutations were found in 34% of cancers ; ii ) mTOR pathway activation was documented by immunohistochemistry in 51% of cases and by mutations in mTOR pathway genes in 19% of cancers ; iii ) TGF-ss/Smad signaling was altered in 10.5% cancers ; iv ) mutations in tyrosine kinase receptors were found in 9% cases .
9		Our study identified molecular subgroups of cholangiocarcinomas that can be explored for specific drug targeting in clinical trials .

PMID: 24760710 (Patient)   Terms:
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0		Isocitrate dehydrogenase 1 ( IDH1 ) mutation in breast adenocarcinoma is associated with elevated levels of serum and urine 2-hydroxyglutarate .
1		Mutations in the IDH1 and IDH2 ( isocitrate dehydrogenase ) genes have been discovered across a range of solid - organ and hematologic malignancies , including acute myeloid leukemia , glioma , chondrosarcoma , and cholangiocarcinoma .
2		An intriguing aspect of IDH-mutant tumors is the aberrant production and accumulation of the oncometabolite 2-hydroxyglutarate ( 2-HG ) , which may play a pivotal oncogenic role in these malignancies .
3		We describe the first reported case of an IDH1 p.R132L mutation in a patient with hormone receptor -positive ( HR+ ) breast adenocarcinoma .
4		This patient was initially treated for locally advanced disease , but then suffered a relapse and metastasis , at which point an IDH1-R132 mutation was discovered in an affected lymph node .
5	Μ	The mutation was subsequently found in the primary tumor tissue and all metastatic sites , but not in an uninvolved lymph node .
6		In addition , the patient's serum and urine displayed marked elevations in the concentration of 2-HG , significantly higher than that measured in six other patients with metastatic HR+ breast carcinoma whose tumors were found to harbor wild-type IDH1 .
7		In summary , IDH1 mutations may impact a rare subgroup of patients with breast adenocarcinoma .
8		This may suggest future avenues for disease monitoring through noninvasive measurement of 2-HG , as well as for the development and study of targeted therapies against the aberrant IDH1 enzyme .

PMID: 24569570 (None)   Terms:
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0		Mutations of isocitrate dehydrogenase 1 and 2 in intrahepatic cholangiocarcinoma .
1		PURPOSE OF REVIEW :
2		Exome sequencing studies have recently expanded the genetic characterization of intrahepatic cholangiocarcinomas .
3		Among a number of novel genes , isocitrate dehydrogenase ( IDH ) is recurrently mutated in intrahepatic cholangiocarcinomas .
4		We review the effects of these mutations on several biochemical pathways , as well as potential changes to downstream signaling pathways .
5		RECENT FINDINGS :
6		Hotspot mutations in IDH isoforms 1 or 2 occur in approximately 15% of intrahepatic cholangiocarcinomas .
7		These mutations result in elevated levels of an oncometabolite , 2-hydroxyglutarate , which is associated with higher DNA CpG methylation and altered histone methylation that accompany a block in cellular differentiation .
8		Exploratory studies have suggested additional phenotypes associated with IDH1/2 mutations .
9		SUMMARY :
10		Tumors with IDH1 or IDH2 mutations may represent a distinct subtype of cholangiocarcinomas .
11		Further studies are required to elucidate the exact role that mutant IDH1/2 and 2-hydroxyglutarate play in tumorigenesis , and what are the best strategies to target these tumor types .

PMID: 24563076 (Patient)   Terms:
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0		New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing .
1		BACKGROUND :
2		Intrahepatic cholangiocarcinoma ( ICC ) is a subtype of primary liver cancer that is rarely curable by surgery and is rapidly increasing in incidence .
3		Relapsed ICC has a poor prognosis , and current systemic nontargeted therapies are commonly extrapolated from those used in other gastrointestinal malignancies .
4	Μ	We hypothesized that genomic profiling of clinical ICC samples would identify genomic alterations that are linked to targeted therapies and that could facilitate a personalized approach to therapy .
5		METHODS :
6		DNA sequencing of hybridization-captured libraries was performed for 3,320 exons of 182 cancer-related genes and 36 introns of 14 genes frequently rearranged in cancer .
7		Sample DNA was isolated from 40 mum of 28 formalin-fixed paraffin-embedded ICC specimens and sequenced to high coverage .
8		RESULTS :
9	Μ	The most commonly observed alterations were within ARID1A ( 36% ) , IDH1/2 ( 36% ) , and TP53 ( 36% ) as well as amplification of MCL1 ( 21% ) .
10	Μ	Twenty cases ( 71% ) harbored atleast one potentially actionable alteration , including FGFR2 ( 14% ) , KRAS ( 11% ) , PTEN ( 11% ) , CDKN2A ( 7% ) , CDK6 ( 7% ) , ERBB3 ( 7% ) , MET ( 7% ) , NRAS ( 7% ) , BRCA1 ( 4% ) , BRCA2 ( 4% ) , NF1 ( 4% ) , PIK3CA ( 4% ) , PTCH1 ( 4% ) , and TSC1 ( 4% ) .
11		Four ( 14% ) of the ICC cases featured novel gene fusions involving the tyrosine kinases FGFR2 and NTRK1 ( FGFR2-KIAA1598 , FGFR2-BICC1 , FGFR2-TACC3 , and RABGAP1L-NTRK1 ) .
12		CONCLUSION :
13	Μ	Two thirds of patients in this study harbored genomic alterations that are associated with targeted therapies and that have the potential to personalize therapy selection for to individual patients .

PMID: 24532422 (Patient)   Terms:
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0		Genomic and transcriptional alterations of cholangiocarcinoma .
1		Cholangiocarcinoma ( CCA ) is one of the representative cancers refractory to any therapeutic approach .
2		The incidence of CCA is highest in the northeastern part of Thailand , where chronic inflammation caused by liver fluke ( Opisthorchis viverrini : Ov ) infection is a major etiologic factor .
3		The incidence of CCA is also increasing in other countries , including Japan .
4		Here , we overview the genetic and transcriptional alterations of CCA with and without association with Ov infection .
5		CCA with Ov shows enhanced expression of the genes involved in xenobiotic metabolism and chronic inflammatory responses , including cytokine signaling , whereas CCA without Ov shows enhanced expression of growth factor signaling , such as HER2 .
6	Μ	Exome and the following prevalence sequencing identified mutations of the BAP1 , ARID1A , IDH1 and IDH2 genes in CCA , in addition to the high incidence of known mutations in the TP53 , KRAS2 SMAD4 , and CDKN2A genes , suggesting the role of chromatin modulators in CCA pathogenesis .
7	Μ	CCA with Ov shows significantly higher incidence of the TP53 gene mutation , whereas CCA without Ov showed significantly more frequent mutations of the BAP1 , IDH1 and IDH2 genes .
8		However , CCAs with Ov and without Ov share a similar mutation spectrum dominated by C : G >T : A transitions mainly at CpG dinucleotides , suggesting that CCA shares etiologic factors with pancreatic ductal carcinoma but not with hepatocellular carcinoma .
9	Μ	Comprehensive analyses of the genetic and transcriptional alterations of CCA with and without Ov infection would provide useful information for the prevention , early diagnosis , and treatment of CCA .

PMID: 24478380 (Patient)   Terms:
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0		Circulating oncometabolite 2-hydroxyglutarate is a potential surrogate biomarker in patients with isocitrate dehydrogenase-mutant intrahepatic cholangiocarcinoma .
1		PURPOSE :
2		Mutations in the IDH1 and IDH2 ( IDH1/2 ) genes occur in approximately 20% of intrahepatic cholangiocarcinoma and lead to accumulation of 2-hydroxyglutarate ( 2HG ) in the tumor tissue .
3		However , it remains unknown whether IDH1/2 mutations can lead to high levels of 2HG circulating in the blood and whether serum 2HG can be used as a biomarker for IDH1/2 mutational status and tumor burden in intrahepatic cholangiocarcinoma .
4		EXPERIMENTAL DESIGN :
5		We initially measured serum 2HG concentration in blood samples collected from 31 patients with intrahepatic cholangiocarcinoma in a screening cohort .
6		Findings were validated across 38 resected patients with intrahepatic cholangiocarcinoma from a second cohort with tumor volume measures .
7		Circulating levels of 2HG were evaluated relative to IDH1/2 mutational status , tumor burden , and a number of clinical variables .
8		RESULTS :
9		Circulating levels of 2HG in the screening cohort were significantly elevated in patients with IDH1/2-mutant ( median , 478 ng/mL ) versus IDH1/2-wild-type ( median , 118 ng/mL ) tumors ( P <0001 ) .
10		This significance was maintained in the validation cohort ( 343 ng/mL vs. 55 ng/mL , P <00001 ) and levels of 2HG directly correlated with tumor burden in IDH1/2-mutant cases ( P <005 ) .
11		Serum 2HG levels >/ = 170 ng/mL could predict the presence of an IDH1/2 mutation with a sensitivity of 83% and a specificity of 90% .
12		No differences were noted between the allelic variants IDH1 or IDH2 in regard to the levels of circulating 2HG .
13		CONCLUSIONS :
14		This study indicates that circulating 2HG may be a surrogate biomarker of IDH1 or IDH2 mutation status in intrahepatic cholangiocarcinoma and that circulating 2HG levels may correlate directly with tumor burden .
15		Clin Cancer Res ; 20(7) ; 1884-90 .
16		(c) 2014 AACR .

PMID: 24406866 (Patient)   Terms:
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0		Morphological subclassification of intrahepatic cholangiocarcinoma : etiological , clinicopathological , and molecular features .
1		On the basis of morphological features , we subclassified 189 intrahepatic cholangiocarcinomas into two subtypes : bile duct and cholangiolar .
2		The cholangiolar type is composed of cuboidal to low columnar tumor cells that contain scanty cytoplasm .
3		The bile duct type is composed of tall columnar tumor cells arranged in a large glandular pattern .
4		In this study , 77 ( 41% ) tumors were classified as the cholangiolar type and 112 ( 59% ) tumors were classified as the bile duct type .
5		The cholangiolar-type intrahepatic cholangiocarcinoma was more frequently associated with viral hepatitis , whereas all but one intrahepatic cholangiocarcinoma associated with intrahepatic lithiasis were classified as the bile duct type .
6		Biliary intraepithelial neoplasm or intraductal papillary neoplasm of the bile duct could be identified in 50 bile duct-type intrahepatic cholangiocarcinomas ( 45% ) , but in only 3 cholangiolar-type intrahepatic cholangiocarcinomas ( 4% ) .
7		Cholangiolar-type intrahepatic cholangiocarcinomas frequently expressed N-cadherin , whereas bile duct intrahepatic cholangiocarcinomas were more likely to express S100P , Trefoil factor 1 , and anterior gradient 2 .
8		KRAS is mutated in 23 of 98 ( 23% ) bile duct-type intrahepatic cholangiocarcinomas and in only 1 of 76 ( 1% ) cholangiolar-type intrahepatic cholangiocarcinomas .
9	✓	Cholangiolar-type intrahepatic cholangiocarcinomas had a higher frequency of IDH1 or 2 mutations than did the bile duct-type intrahepatic cholangiocarcinomas .	GM-ASS-DS
10		The molecular features of the bile duct-type intrahepatic cholangiocarcinoma were similar to those of hilar cholangiocarcinoma .
11		Patients with the cholangiolar-type intrahepatic cholangiocarcinoma had higher 5-year survival rates than those of patients with the bile duct-type intrahepatic cholangiocarcinoma .
12		Our results indicated that intrahepatic cholangiocarcinoma was a heterogeneous tumor .
13		Subclassification of intrahepatic cholangiocarcinomas based on cholangiocytic differentiation divides them into two groups with different etiologies , clinical manifestations , and molecular pathogeneses .

PMID: 24185513 (Patient)   Terms:
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0		Exome sequencing identifies distinct mutational patterns in liver fluke-related and non-infection-related bile duct cancers .
1		The impact of different carcinogenic exposures on the specific patterns of somatic mutation in human tumors remains unclear .
2		To address this issue , we profiled 209 cholangiocarcinomas ( CCAs ) from Asia and Europe , including 108 cases caused by infection with the liver fluke Opisthorchis viverrini and 101 cases caused by non-O .
3		viverrini-related etiologies .
4	Μ	Whole-exome sequencing ( n = 15 ) and prevalence screening ( n = 194 ) identified recurrent somatic mutations in BAP1 and ARID1A , neither of which , to our knowledge , has previously been reported to be mutated in CCA .
5		Comparisons between intrahepatic O .
6		viverrini-related and non-O .
7	Μ	viverrini-related CCAs demonstrated statistically significant differences in mutation patterns : BAP1 , IDH1 and IDH2 were more frequently mutated in non-O .
8		viverrini CCAs , whereas TP53 mutations showed the reciprocal pattern .
9		Functional studies demonstrated tumor suppressive functions for BAP1 and ARID1A , establishing the role of chromatin modulators in CCA pathogenesis .
10		These findings indicate that different causative etiologies may induce distinct somatic alterations , even within the same tumor type .

PMID: 24185509 (None)   Terms:
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0		Exome sequencing identifies frequent inactivating mutations in BAP1 , ARID1A and PBRM1 in intrahepatic cholangiocarcinomas .
1		Through exomic sequencing of 32 intrahepatic cholangiocarcinomas , we discovered frequent inactivating mutations in multiple chromatin-remodeling genes ( including BAP1 , ARID1A and PBRM1 ) , and mutation in one of these genes occurred in almost half of the carcinomas sequenced .
2	Μ	We also identified frequent mutations at previously reported hotspots in the IDH1 and IDH2 genes encoding metabolic enzymes in intrahepatic cholangiocarcinomas .
3	Μ	In contrast , TP53 was the most frequently altered gene in a series of nine gallbladder carcinomas .
4		These discoveries highlight the key role of dysregulated chromatin remodeling in intrahepatic cholangiocarcinomas .

PMID: 24140396 (None)   Terms:
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0		Pathogenesis , diagnosis , and management of cholangiocarcinoma .
1		Cholangiocarcinomas ( CCAs ) are hepatobiliary cancers with features of cholangiocyte differentiation ; they can be classified anatomically as intrahepatic CCA ( iCCA ) , perihilar CCA ( pCCA ) , or distal CCA .
2		These subtypes differ not only in their anatomic location , but in epidemiology , origin , etiology , pathogenesis , and treatment .
3		The incidence and mortality of iCCA has been increasing over the past 3 decades , and only a low percentage of patients survive until 5 years after diagnosis .
4		Geographic variations in the incidence of CCA are related to variations in risk factors .
5		Changes in oncogene and inflammatory signaling pathways , as well as genetic and epigenetic alterations and chromosome aberrations , have been shown to contribute to the development of CCA .
6		Furthermore , CCAs are surrounded by a dense stroma that contains many cancer-associated fibroblasts , which promotes their progression .
7		We have gained a better understanding of the imaging characteristics of iCCAs and have developed advanced cytologic techniques to detect pCCAs .
8		Patients with iCCAs usually are treated surgically , whereas liver transplantation after neoadjuvant chemoradiation is an option for a subset of patients with pCCAs .
9		We review recent developments in our understanding of the epidemiology and pathogenesis of CCA , along with advances in classification , diagnosis , and treatment .

PMID: 23863747 (None)   Terms: Meta-analysis
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0		Meta-analysis of IDH-mutant cancers identifies EBF1 as an interaction partner for TET2 .
1	Μ	Isocitrate dehydrogenase ( IDH ) genes 1 and 2 are frequently mutated in acute myeloid leukaemia ( AML ) , low-grade glioma , cholangiocarcinoma ( CC ) and chondrosarcoma ( CS ) .
2		For AML , low-grade glioma and CC , mutant IDH status is associated with a DNA hypermethylation phenotype , implicating altered epigenome dynamics in the aetiology of these cancers .
3		Here we show that the IDH variants in CS are also associated with a hypermethylation phenotype and display increased production of the oncometabolite 2-hydroxyglutarate , supporting the role of mutant IDH-produced 2-hydroxyglutarate as an inhibitor of TET -mediated DNA demethylation .
4		Meta-analysis of the acute myeloid leukaemia , low-grade glioma , cholangiocarcinoma and CS methylation data identifies cancer-specific effectors within the retinoic acid receptor activation pathway among the hypermethylated targets .
5		By analysing sequence motifs surrounding hypermethylated sites across the four cancer types , and using chromatin immunoprecipitation and western blotting , we identify the transcription factor EBF1 ( early B-cell factor 1 ) as an interaction partner for TET2 , suggesting a sequence -specific mechanism for regulating DNA methylation .

PMID: 23796461 (None)   Terms: in vitro, mouse models, mouse
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0		Down-regulation of ANXA7 decreases metastatic potential of human hepatocellular carcinoma cells in vitro .
1		Heterozygous mutations in catalytic arginine residues of isocitrate dehydrogenases 1 and 2 ( IDH1 and IDH2 ) are common in glioma , acute myeloid leukemia , chondrosarcoma , cholangiocarcinoma , and angioimmunoblastic T - cell lymphoma .
2		The mutant enzymes acquire a neomorphic activity that converts alpha-ketoglutarate ( alpha-KG ) to D-2-hydroxyglutarate ( D2HG ) , a rare metabolite .
3		In cells and tissues expressing mutant IDH , D2HG concentrations are highly elevated .
4		D2HG may act as an "oncometabolite" by inhibiting a class of alpha-KG -dependent enzymes involved in epigenetic regulation , collagen synthesis , and cell signaling .
5		Knock-in mouse models of IDH1 mutations have shed light on these mechanisms and will provide valuable animal models for further investigation .

PMID: 23391413 (Patient)   Terms:
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0		Molecular profiling of cholangiocarcinoma shows potential for targeted therapy treatment decisions .
1		Cholangiocarcinoma is a highly lethal cancer of the biliary tract .
2		The intrahepatic subtype of cholangiocarcinoma is increasing in incidence globally .
3		Despite technologic advancements over the past decade , little is known about the somatic changes that occur in these tumors .
4		The goal of this study was to determine the frequency of common oncogenes in resected cholangiocarcinoma specimens that could provide potential therapeutic targets for patients diagnosed with cholangiocarcinoma .
5		Formalin-fixed , paraffin-embedded tissue blocks from 94 resected cholangiocarcinomas were used to extract DNA from areas comprising more than 20% tumor .
6		Specimens were evaluated using the Sequenom MassARRAY OncoCarta Mutation Profiler Panel ( San Diego , CA ) .
7		This matrix-assisted laser desorption/ionization-time of flight mass spectrometry single genotyping panel evaluates 19 oncogenes for 238 somatic mutations .
8	Μ	Twenty-five mutations were identified in 23 of the 94 cholangiocarcinomas within the following oncogenes : KRAS ( n = 12 ) , PIK3CA ( n = 5 ) , MET ( n = 4 ) , EGFR ( n = 1 ) , BRAF ( n = 2 ) , and NRAS ( n = 1 ) .
9	Μ	Mutations were identified in 7 ( 26% ) of 27 extrahepatic cholangiocarcinomas and 16 ( 24% ) of 67 intrahepatic cholangiocarcinomas .
10		When combined with IDH1/2 testing , 40 ( 43% ) of the 94 cholangiocarcinomas had a detectable mutation .
11	Μ	MassARRAY technology can be used to detect mutations in a wide variety of oncogenes using paraffin-embedded tissue .
12		Clinical testing for somatic mutations may drive personalized therapy selection for cholangiocarcinomas in the future .
13	Μ	The variety of mutations detected suggests that a multiplexed mutation detection approach may be necessary for managing patients with biliary tract malignancy .

PMID: 23318457 (None)   Terms: clinical trial, This review
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0		Intrahepatic cholangiocarcinoma : pathogenesis and rationale for molecular therapies .
1		Intrahepatic cholangiocarcinoma ( ICC ) is an aggressive malignancy with very poor prognosis .
2		Genome -wide , high-throughput technologies have made major advances in understanding the molecular basis of this disease , although important mechanisms are still unclear .
3	Μ	Recent data have revealed specific genetic mutations ( for example , KRAS , IDH1 and IDH2 ) , epigenetic silencing , aberrant signaling pathway activation ( for example , interleukin ( IL ) -6/signal transducer and activator of transcription 3 ( STAT3 ) , tyrosine kinase receptor -related pathways ) and molecular subclasses with unique alterations ( for example , proliferation and inflammation subclasses ) .
4		In addition , some ICCs share common genomic traits with hepatocellular carcinoma .
5		All this information provides the basis to explore novel targeted therapies .
6		Currently , surgery at early stage is the only effective therapy .
7		At more advanced stages , chemotherapy regimens are emerging ( that is , cisplatin plus gemcitabine ) , along with molecular targeted agents tested in several ongoing clinical trials .
8		Nonetheless , a first - line conclusive treatment remains an unmet need .
9		Similarly , there are no studies assessing tumor response related with genetic alterations .
10		This review explores the recent advancements in the knowledge of the molecular alterations underlying ICC and the future prospects in terms of therapeutic strategies leading towards a more personalized treatment of this neoplasm .

PMID: 22824796 (None)   Terms:
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0		Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas .
1		Mutations in the genes encoding isocitrate dehydrogenase , IDH1 and IDH2 , have been reported in gliomas , myeloid leukemias , chondrosarcomas and thyroid cancer .
2		We discovered IDH1 and IDH2 mutations in 34 of 326 ( 10% ) intrahepatic cholangiocarcinomas .
3		Tumor with mutations in IDH1 or IDH2 had lower 5-hydroxymethylcytosine and higher 5-methylcytosine levels , as well as increased dimethylation of histone H3 lysine 79 ( H3K79 ) .
4	✓	Mutations in IDH1 or IDH2 were associated with longer overall survival ( P = 0028 ) and were independently associated with a longer time to tumor recurrence after intrahepatic cholangiocarcinoma resection in multivariate analysis ( P = 0021 ) .	GM-ASS-RO
5	Μ	IDH1 and IDH2 mutations were significantly associated with increased levels of p53 in intrahepatic cholangiocarcinomas , but no mutations in the p53 gene were found , suggesting that mutations in IDH1 and IDH2 may cause a stress that leads to p53 activation .
6		We identified 2309 genes that were significantly hypermethylated in 19 cholangiocarcinomas with mutations in IDH1 or IDH2 , compared with cholangiocarcinomas without these mutations .
7		Hypermethylated CpG sites were significantly enriched in CpG shores and upstream of transcription start sites , suggesting a global regulation of transcriptional potential .
8		Half of the hypermethylated genes overlapped with DNA hypermethylation in IDH1-mutant gliobastomas , suggesting the existence of a common set of genes whose expression may be affected by mutations in IDH1 or IDH2 in different types of tumors .

PMID: 22594888 (None)   Terms:
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0		IDH mutations : new genetic signatures in cholangiocarcinoma and therapeutic implications .
1		[ Combinational effects of K-ras and IGF-IR antisense oligodeoxynucleotide on proliferation and apoptosis of human pancreatic cancer Patu8988 cells ] .

PMID: 22503487 (Patient)   Terms:
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0		Isocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma .
1		Somatic mutations in isocitrate dehydrogenase 1 and 2 genes are common in gliomas and help stratify patients with brain cancer into histologic and molecular subtypes .
2		However , these mutations are considered rare in other solid tumors .
3		The aims of this study were to determine the frequency of isocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma and to assess histopathologic differences between specimens with and without an isocitrate dehydrogenase mutation .
4		We sequenced 94 formalin-fixed , paraffin-embedded cholangiocarcinoma ( 67 intrahepatic and 27 extrahepatic ) assessing for isocitrate dehydrogenase 1 ( codon 132 ) and isocitrate dehydrogenase 2 ( codons 140 and 172 ) mutations .
5		Multiple histopathologic characteristics were also evaluated and compared with isocitrate dehydrogenase 1/2 mutation status .
6		Of the 94 evaluated specimens , 21 ( 22% ) had a mutation including 14 isocitrate dehydrogenase 1 and 7 isocitrate dehydrogenase 2 mutations .
7	✓ Μ	Isocitrate dehydrogenase mutations were more frequently observed in intrahepatic cholangiocarcinoma than in extrahepatic cholangiocarcinoma ( 28% versus 7% , respectively ; P = 030 ) .	GM-ASS-DS
8		The 14 isocitrate dehydrogenase 1 mutations were R132C ( n = 9 ) , R132S ( n = 2 ) , R132G ( n = 2 ) , and R132L ( n = 1 ) .
9		The 7 isocitrate dehydrogenase 2 mutations were R172K ( n = 5 ) , R172M ( n = 1 ) , and R172G ( n = 1 ) .
10	Μ	Isocitrate dehydrogenase mutations were more frequently observed in tumors with clear cell change ( P <001 ) and poorly differentiated histology ( P = 012 ) .
11		The results of this study show for the first time that isocitrate dehydrogenase 1 and 2 genes are mutated in cholangiocarcinoma .
12		The results of this study are encouraging because it identifies a new potential target for genotype-directed therapeutic trials and may represent a potential biomarker for earlier detection of cholangiocarcinoma in a subset of cases .

PMID: 22180306 (Patient)   Terms:
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0		Frequent mutation of isocitrate dehydrogenase ( IDH ) 1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping .
1		Cancers of origin in the gallbladder and bile ducts are rarely curable with current modalities of cancer treatment .
2		Our clinical application of broad-based mutational profiling for patients diagnosed with a gastrointestinal malignancy has led to the novel discovery of mutations in the gene encoding isocitrate dehydrogenase 1 ( IDH1 ) in tumors from a subset of patients with cholangiocarcinoma .
3		A total of 287 tumors from gastrointestinal cancer patients ( biliary tract , colorectal , gastroesophageal , liver , pancreatic , and small intestine carcinoma ) were tested during routine clinical evaluation for 130 site -specific mutations within 15 cancer genes .
4	Μ	Mutations were identified within a number of genes , including KRAS ( 35% ) , TP53 ( 22% ) , PIK3CA ( 10% ) , BRAF ( 7% ) , APC ( 6% ) , NRAS ( 3% ) , AKT1 ( 1% ) , CTNNB1 ( 1% ) , and PTEN ( 1% ) .
5		Although mutations in the metabolic enzyme IDH1 were rare in the other common gastrointestinal malignancies in this series ( 2% ) , they were found in three tumors ( 25% ) of an initial series of 12 biliary tract carcinomas .
6		To better define IDH1 and IDH2 mutational status , an additional 75 gallbladder and bile duct cancers were examined .
7	Μ	Combining these cohorts of biliary cancers , mutations in IDH1 and IDH2 were found only in cholangiocarcinomas of intrahepatic origin ( nine of 40 , 23% ) and in none of the 22 extrahepatic cholangiocarcinomas and none of the 25 gallbladder carcinomas .
8		In an analysis of frozen tissue specimens , IDH1 mutation was associated with highly elevated tissue levels of the enzymatic product 2-hydroxyglutarate .
9		Thus , IDH1 mutation is a molecular feature of cholangiocarcinomas of intrahepatic origin .
10		These findings define a specific metabolic abnormality in this largely incurable type of gastrointestinal cancer and present a potentially new target for therapy .

PMID: AACR_2016-3172 (Patient)   Terms:
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0		Comprehensive analysis of intrahepatic cholangiocarcinoma based on viral infections and mutational status in the IDH1/2 and KRAS genes .
1		Background : Intrahepatic cholangiocarcinoma ( ICC ) is a primary liver cancer with poor prognosis and limited therapeutic options .
2		Recently comprehensive genetic profiles have elucidated novel fusion genes and somatic mutations .
3	Μ	Although somatic mutations in the isocitrate dehydrogenase ( IDH ) and KRAS gene were frequently found in ICC , the clinical features of this malignancy with mutations in these genes remain unclear .
4		Materials and Methods : A cohort of 49 patients with ICC who underwent curative resection from 2000 to 2013 at Okayama University Hospital were enrolled and analyzed .
5		KRAS ( exon2 ) , IDH1 ( codon132 ) , and IDH2 ( codon172 and codon140 ) mutations were confirmed by Sanger sequencing .
6		Associations between the mutational profiles of these genes and clinic-pathological features were investigated .
7		Kaplan-Meier curves were plotted , and survival rates were compared using the log-rank analysis .
8	Μ	Results : KRAS mutations were observed in twelve ICC patients ( 245% , KRAS-mutant ) .
9	Μ	IDH mutations were found in eight patients ( 163% ) ; five patients harbored IDH1 mutations and three patients harbored IDH2 mutations ( IDH1/2-mutant ) .
10	Μ	Among three patients with IDH2 mutations , a rare IDH2 R140L was identified .
11	Μ	One patient harbored both KRAS G12A and IDH2 R172K mutations ( classified as KRAS-mutant ) .
12	Μ	The rest of 30 ICCs harbored no mutation in either KRAS or IDH1/2 gene , thus categorized as Wild-type .
13	Μ	Infection of Hepatitis B ( HBV ) or C ( HCV ) was observed in 10 ICCs ( 6 ICCs were HBV-positive and 4 ICCs were HCV-positive ) .
14	Μ	Of 10 ICCs with viral infection , only two ICCs harbored KRAS mutations ( categorized as virus-infected ) and eight ICCs with viral infection harbored no mutation in KRAS and IDH1/2 genes .
15		Finally , ICCs were divided into four subsets ; viral-infected , KRAS-mutant , IDH1/2-mutant , and others ) .
16		With regard to clinic-pathological features , lymph node metastasis was more frequently observed in KRAS-mutant ( p = 0039 ) compared with the others .
17	Μ	IDH1/2 -mutant were more frequently observed in mass-forming type ( p = 0047 ) .
18		By survival analysis , 3-years survival rate was 85.7% in IDH1/2-mutant , 58.3% in the others , 36.3% in viral-infected , and 22.2% in KRAS-mutant , respectively ( p = 005 ) .
19		Thus , our cohort suggests that IDH1/2 , as well as KRAS mutations , have the potential to serve as prognostic biomarkers in ICC .
20		Conclusion : We conclude that not only viral infections , but also IDH1/2 and KRAS mutations could be potential predictive markers for the identification of good and worse prognosis in ICCs .
21		Hence the mutational profiles of these genes provide an attractive rationale for developing a molecular signature for the development of non-invasive screening for ICCs in future .

PMID: AACR_2013-2339 (Patient)   Terms: NCT01285037
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0		Prevalence of MET expression , activating mutations of KRAS and IDH1/2 , and ROS1 fusions in cholangiocarcinoma patient tumor samples. .
1		Cholangiocarcinoma ( CCA ) originates from biliary tract epithelium and can be classified anatomically into intrahepatic or extrahepatic CCA .
2		Although a relatively rare disease in the United States and Europe , the incidence of intrahepatic CCA is on the rise with unknown causes .
3		CCA incidence is higher in Asia and the etiology is associated with infections such as liver fluke and hepatitis B/C .
4		Prognosis at diagnosis is poor with median survival time of < 1 year , and only 10-20% of patients are eligible for tumor resection at diagnosis .
5	Μ	This study examined the prevalence of MET over-expression , activating single point mutations of KRAS and IDH1/2 , and ROS1 gene fusions in 100 intrahepatic and extrahepatic CCA FFPE tumor tissues obtained from non-Asian ( n = 40 ) and Asian ( n = 60 ) patients .
6		Immunohistochemistry performed with an anti-MET-specific antibody ( A2 ) demonstrated that MET is expressed in the majority of all intrahepatic CCA samples analyzed , with 50% of samples reported with membranocytoplasmic scores of 2+ ( moderate intensity ) or 3+ ( strong intensity ) on a 0-3+ scale .
7		Interestingly , most non-malignant bile ducts and much vascular endothelia also stained lightly positive for MET .
8		To determine mutation frequencies of KRAS and IDH1/2 , competitive allele -specific Taqman PCR ( castPCR ) was performed on DNA extracted from FFPE CCA tissue ( limit of mutation detection 01% ) .
9		Fourteen KRAS activating mutations ( G12S , G12R , G12A , G13C , G13S , G13R , G12D , G13D , G12V , G12C , Q61R , Q61L , Q61H ( c183A > C and c183A > T for Q61H ) , 5 IDH1 mutations ( R132G , R132S , R132H , R132C , R132L ) , and 5 IDH2 mutations ( R172G , R172M , R172K , R172W , R172S ) were analyzed .
10	Μ	Overall , 25% of analyzed samples were positive for KRAS mutation , and G12D was the predominant mutation ( 60% ) .
11		One-third of Asian samples were positive for KRAS mutation , whereas less than one-fifth of non-Asian samples contained KRAS mutations .
12		For IDH1 , the frequency of mutation was less than 10% overall , and the majority of patients with IDH1 mutations were non-Asian .
13		The R132C mutation was the predominant IDH1 mutation , and all tissues that were positive for IDH1 mutations were of intrahepatic origin .
14		Interestingly , 2 out of the 7 samples positive for IDH1 mutations (R132C) were also positive for G12D KRAS mutation .
15		There is no trend of MET expression correlating with either KRAS or IDH1 mutations .
16	Μ	IDH2 analyses by castPCR and FISH studies examining ROS1 gene fusion are ongoing .
17		Based on these data , inhibitors of receptor tyrosine kinases and their signaling pathways such as MET and ROS1 may merit clinical evaluation in CCA patients .
18		LY2801653 , a MET inhibitor which also has inhibitory activity against ROS1 and MKNK1/2 is currently in phase 1 clinical testing in patients with advanced cancer ( trial I3O-MC-JSBA , NCT01285037 ) .

PMID: AACR_2015-3514 (Cell)   Terms:
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0		A novel inhibitor of IDH1 abrogates 2-HG production and reverses aberrant epigenetic alterations in IDH1 mutant cells .
1		The isocitrate dehydrogenase 1 ( IDH1 ) and IDH2 genes are mutated in acute myelogenous leukemia , low-grade glioma , intrahepatic cholangiocarcinoma , and chondrosarcomas .
2		IDH1 and IDH2 normally function to convert isocitrate into alpha-ketoglutarate .
3		However , when these enzymes are mutated at select residues the mutant enzymes now convert -KG into 2-hydroxyglutarate ( 2-HG ) .
4		In normal cells , 2-HG levels are typically extremely low , but IDH1/2 mutant cells can accumulate up to 10 mM 2-HG .
5	Μ	In an effort to counteract the neomorphic activity of mutant IDH enzymes , we identified and developed potent inhibitors of IDH1 .
6		The compounds inhibit IDH1 catalytic activity in biochemical assays and reduce 2-HG production in IDH1-mutant cell lines .
7		Consistent with the fact that 2-HG inhibits -KG dependent enzymes including histone demethylases and Tet family hydroxylases , these IDH1 inhibitors induce a decrease in several histone methylation marks and also DNA methylation .
8		These data demonstrate that small molecule inhibitors can reverse many of the epigenetic effects of mutant IDH1 .
9		Note : This abstract was not presented at the meeting .

PMID: AACR_2016-2645 (Cell)   Terms: in vitro, in vivo, Phase I study, tumor models
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0		BAY 1436032 : A highly selective , potent and orally available inhibitor of mutant forms of IDH1 .
1	Μ	Isocitrate dehydrogenase 1 ( IDH1 ) is a metabolic enzyme that is frequently mutated in certain cancers , with incidence rates ranging from 7-90% for glioma , chondrosarcoma , intrahepatic cholangiocarcinoma and AML .
2		Wildtype IDH1 ( wtIDH1 ) catalyzes the conversion of isocitrate to -ketoglutarate ( KG ) , while tumor-associated mutant IDH1 ( mIDH1 ) catalyzes a rogue reaction : the production of 2-hydroxyglutarate ( 2-HG ) from KG. 2-HG therefore represents an oncometabolite that is believed to play a role in cancer by interfering with KG -dependent enzymes , which in turn causes hypermethylation of histones/DNA and a block of normal cellular differentiation .
3		Mutant IDH1 is a driver oncogene and the inhibition of this altered enzyme will decrease the growth of mIDH1 dependent tumors .
4		We report for the first time the preclinical profile and structure of BAY 1436032 , a novel selective mIDH1 inhibitor .
5		An optimization program based on a high throughput screening resulted in the identification of the clinical candidate BAY 1436032 for the treatment of mIDH1 dependent cancer .
6		BAY 1436032 is a double-digit nanomolar and selective pan-inhibitor of the enzymatic activity of various IDH1-R132X mutants in vitro and displayed potent inhibition of 2-HG release ( nanomolar range ) in patient derived and engineered cell lines expressing different IDH1 mutants .
7		In line with the proposed mode of action , a concentration -dependent lowering of 2-HG was observed in vitro accompanied by differentiation and maturation of mIDH1 tumor cells .
8		Furthermore , BAY 1436032 showed a favourable selectivity profile against wtIDH1/2 and a large panel of off-targets in vitro .
9		To the best of our knowledge we were able to show for the first time single agent in vivo efficacy in mIDH1 patient derived glioma and intrahepatic cholangiocarcinoma solid tumor models with this clinical candidate along with monitoring of intratumoral 2-HG levels as a predictive biomarker .
10		The BBB penetration profile of BAY 1436032 is further supported by preclinical data on in vivo brain-plasma ratios .
11		In conclusion , our data provide in vitro and in vivo proof of concept for BAY 1436032 as a potent and highly selective inhibitor of mutant forms of IDH1 .
12		The start of a Phase I study with BAY 1436032 is currently in preparation to determine the safety , tolerability , pharmacokinetics and preliminary anti-tumor and pharmacodynamic biomarker responses in patients with solid tumors .

PMID: ASCO_183678-199 (Patient)   Terms:
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0		Simultaneous molecular alterations in solid tumors with IDH1 or IDH2 mutations. .
1		Background : The evaluation of ALK rearrangement in non-small-cell lung cancer ( NSCLC ) is a useful and significant tool for the decision of crizotinib treatment .
2		However , tumor biopsy in patients with recurrent and/or metastatic disease is not always possible .
3		Here , we suggest isolation and culturing of circulating tumor cells ( CTCs ) as an alternative to tumor tissue biopsy for the diagnostic test of ALK rearrangement .
4		Methods : The blood samples ( 10 ml ) were collected in ACDA tubes from 21 patients with NSCLC harboring ALK rearrangement .
5		The blood samples were divided into two parts : one for immunofluorescent staining and other for culturing .
6		Both samples were processed by size-base filtration using CTC isolation kit ( Cytigen , Inc ) .
7		Cultured CTCs were analyzed for EML4-ALK translocation by fluorescence in situ hybridization ( FISH ) using Vysis ALK break apart FISH probe kit .
8		Results : CTCs were detected in 10 of 22 patients ( 476% , range 1-8 ) .
9		CTC culturing was successful in 18 of 22 cases ( 818% ) .
10		Among 18 cases of successful CTC cultures , 13 cases showed ALK rearrangement positivity ( 722% ) .
11		Interestingly , the patients sensitive to crizotinib , did not show ALK rearrangement positivity of cultured CTCs .
12		Conclusions : In this study , we suggest that the isolation and culture of CTCs can be a substitute method for tumor tissue biopsy , and may provide clinical applications , including serial blood samplings for the personalized cancer therapy based on their genomic information .

PMID: ASCO_182082-199 (Patient)   Terms:
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0		Pharmacokinetic/pharmacodynamic ( PK/PD ) profile of AG-120 in patients with IDH1-mutant cholangiocarcinoma from a phase 1 study of advanced solid tumors. .
1		Background : Somatic mutations in isocitrate dehydrogenase 1 ( IDH1 ) produce the oncometabolite D-2-hydroxyglutarate ( 2-HG ) .
2		AG-120 is a first-in-class selective inhibitor of mutant IDH1 ( mIDH1 ) under evaluation in an ongoing phase 1 study in patients with mIDH1 advanced solid tumors , including cholangiocarcinoma ( CC ) (NCT02073994) .
3		Objectives for this abstract were to 1 ) characterize the PK profile of AG-120 and the relationship between AG-120 exposure and 2-HG suppression , and 2 ) evaluate the influence of intrinsic patient factors on AG-120 clearance , in patients with mIDH1 CC .
4		Methods : AG-120 was administered orally once daily ( QD ) or twice daily ( BID ) in continuous 28-day cycles .
5		As of Dec 5 , 2016 , 60 of 73 patients enrolled with mIDH1 CC had PK/PD samples available for analysis at 100 mg BID , 300 mg QD , 400 mg QD , 500 mg QD , 800 mg QD , and 1200 mg QD in dose escalation ( n = 24 ) and 500 mg QD ( n = 36 ) in dose expansion .
6		Blood ( n = 60 ) and fresh tumor biopsy samples ( n = 14 ) were collected to assess AG-120 and 2-HG using qualified liquid chromatography-tandem mass spectrometry methods .
7		Results : Following both single and multiple doses , AG-120 plasma exposure increased less than dose proportionally from 100 to 1200 mg .
8		Mean terminal half-life was 38.485.8 h , supporting a QD dosing regimen .
9		Following multiple doses , steady state was reached within 15 days , with approximately 2-fold accumulation in plasma AG-120 exposure .
10		No patient-specific factors were identified as clinically significant covariates affecting AG-120 plasma clearance .
11		After multiple doses , plasma 2-HG levels were reduced ( up to 984% inhibition , achieving levels similar to those in healthy volunteers ) and tumor biopsy 2-HG levels were also substantially reduced ( by up to 999% ) at all dose levels tested .
12		The 500 mg QD dose resulted in the largest magnitude of 2-HG inhibition vs.other dose levels .
13		Conclusions : AG-120 demonstrated a long half-life in patients with mIDH1 CC and robustly inhibited 2-HG in plasma and tumor samples .
14		These PK/PD data , along with emerging safety and clinical activity data , support the selection of 500 mg QD for future clinical investigation .

PMID: ASCO_182001-199 (Patient)   Terms:
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0		Mutational profiling of resected intrahepatic cholangiocarcinoma. .
1		Background : Intrahepatic cholangiocarcinoma ( ICC ) is an aggressive neoplasm with increasing incidence and mortality .
2		Resection is the only potential curative treatment and is associated with 5-year survival up to 44% .
3		The objective of this study was to characterize the mutational landscape of patients with ICC undergoing resection and to identify potential prognostic genetic markers that may be unique to these patients .
4		Methods : Sixty-six resected ICC tumor specimens were assessed for genetic alterations using next-generation sequencing of 410 cancer genes by LONGTOKEN .
5	Μ	We identified the gene alterations occurring with greatest frequency and grouped mutations by known cancer pathways and families , such as RAS-MAPK pathway , mTOR pathway , Notch signaling pathway , chromatin-remodeling gene family , and DNA repair gene family .
6		Overall survival ( OS ) was calculated from time of resection until death and disease-free survival ( DFS ) was calculated from resection until recurrence or death .
7		Kaplan Meier 5-year estimates and the log-rank test were used to evaluate the associations with OS and DFS , adjusted for multiple comparisons with false discovery rate ( FDR ) correction .
8		Results : The median age of all patients was 65 years ( range 29-87 years ) .
9		Majority of tumors were T1 ( 24/66 , 36% ) or T2 ( 35/66 , 53% ) , and of moderate differentiation ( 46/66 , 70% ) .
10		Lymphovascular invasion , perineural invasion , and periductal infiltration were present in 34 ( 52% ) , 20 ( 30% ) , and 8 ( 12% ) patients , respectively .
11		The median number of genetic alterations per tumor was 3 ( range 0-26 ) .
12		The most common genetic alterations were PBRM1 ( 16/66 , 24% ) , IDH1 ( 15/66 , 23% ) , ARID1A ( 14/66 , 21% ) and TP53 ( 8/66 , 12% ) .
13		FGFR2 fusion mutations ( 5/66 , 8% ) were relatively rare .
14		The median OS for all patients was 53.4 months ( 95%CI : 43.0-79.3 months ) and median DFS was 17.4 months ( 95%CI : 10.4-32.6 months ) .
15		None of the gene alterations or pathways were associated with OS ( p = 029-084 ) or DFS ( p = 023-065 ) .
16		Conclusions : In this cohort of resected ICC patients , genetic alterations or alterations within gene families , by themselves , did not stratify risk of disease recurrence or death .

PMID: ASCO_180737-199 (None)   Terms: Phase I study, phase III
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0		Phase I study of AG-120 , an IDH1 mutant enzyme inhibitor : Results from the cholangiocarcinoma dose escalation and expansion cohorts. .
1		Background : Mutations in the metabolic enzyme isocitrate dehydrogenase 1 ( mIDH1 ) occur in patients ( pts ) with cholangiocarcinoma ( CC ) and are detected in up to 25% of intrahepatic CC .
2		mIDH1 produce the oncometabolite , D-2-hydroxyglutarate ( 2-HG ) , resulting in epigenetic and genetic dysregulation and oncogenesis .
3		AG-120 is a first-in-class , potent , oral inhibitor of mIDH1 tested in this phase I study in mIDH1 solid tumors , including CC .
4		Methods : AG-120 was escalated in a 3+3 design from 100 mg twice daily to 1200 mg once daily ( QD ) in 28-day cycles ( N = 60 , mIDH1 advanced solid tumors ) .
5		Key eligibility for CC : recurrence of progressive mIDH1 CC following standard therapy ( dose escalation ) or atleast a prior gemcitabine-based regimen ( expansion cohort ) .
6		Response ( RECIST 11 ) was assessed every 8 weeks .
7		Plasma and tumor tissue were collected for exploratory analyses .
8		Results : Based on the safety , pharmacokinetic , and pharmacodynamic data from dose escalation , the 500 mg QD dose was selected for expansion in mIDH1 CC and other mIDH1 solid tumors .
9		As of Dec 16 , 2016 , 73 pts with mIDH1 CC had been dosed in the dose escalation ( n = 24 ) and expansion ( n = 49 ) cohorts .
10		Demographics : M/F = 24/49 , median number of prior therapies = 2 ( range 15 ) , ECOG 01 = 26/47 .
11		There were no dose-limiting toxicities .
12		Treatment-related adverse events ( AEs ) in 5% pts : fatigue ( 21% ) , nausea ( 18% ) , vomiting ( 12% ) , diarrhea ( 10% ) , decreased appetite ( 8% ) , dysgeusia ( 5% ) , QT prolongation ( 5% ) .
13		Two ( 3% ) pts experienced related grade 3 AEs : fatigue and low phosphorus .
14		There were no AG-120-related AEs leading to discontinuation .
15		Among the 72 efficacy evaluable ( 1 post baseline response assessment or discontinued prematurely ) mIDH1 CC pts ( 24 in escalation and 48 in expansion cohort ) , 6% ( n = 4 ) had a confirmed partial response and 56% ( n = 40 ) experienced stable disease .
16		The progression-free survival rate at 6 months was 40% , and 8 pts have been treated with AG-120 for 1 year .
17		Conclusions : In this pretreated mIDH1 CC population , AG-120 was associated with a favorable safety profile and prolonged stable disease .
18		A global , phase III , randomized , placebo-controlled study of AG-120 in mIDH1 CC has been initiated ( ClarIDHy ) .

PMID: AACR_2012-1058 (Patient)   Terms:
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0		Mutations in isocitrate dehydrogenase 1 and 2 are associated with DNA hypermethylation in intrahepatic cholangiocarcinomas .
1		Cholangiocarcinomas are rare but aggressive cancers , with an increasing incidence and a dismal 5-year survival rate of less than 5% .
2		Mutations in the genes encoding isocitrate dehydrogenase , IDH1 and IDH2 , have been reported in 70% of gliomas , 20% of myeloid leukemias , 56% of chondrosarcomas , and 10% of melanomas .
3		We discovered IDH1 and IDH2 mutations in 29 of 305 ( 9% ) intrahepatic cholangiocarcinomas .
4		Tumors with mutations in IDH1 or IDH2 had lower 5-hydroxymethylcytosine and higher 5-methylcytosine levels , as well as increased dimethylation of histone H3K79 .
5		Mutations in IDH1 or IDH2 were independently associated with longer time to recurrence of cholangiocarcinoma in multivariate analysis ( p = 0046 ) .
6	Μ	We identified 2,267 genes that were significantly hypermethylated in tumors with mutations in IDH1 or IDH2 .
7		Hypermethylated CpG sites were significantly enriched in CpG shores and in the 1500 bp upstream of annotated transcription start sites , suggesting a global regulation of transcriptional potential .
8	Μ	Gene expression profiling of 7 IDH1/2-mutant and 20 IDH1/2-wildtype tumors revealed increased expression of citric acid cycle and oxidative phosphorylation enzymes , as well as decreased expression of cytoskeleton organization genes .
9	Μ	Integrated analyses of DNA methylation and gene expression identified interleukin-6 and several of its downstream targets as candidates for silencing by DNA methylation .
10		Conclusions : Cholangiocarcinomas with mutations in IDH1 or IDH2 represent a molecular subclass with distinct signaling pathway alterations .

PMID: ASCO_140039-158 (Patient)   Terms:
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0		Tumor profiling of biliary tract carcinomas to reveal distinct molecular alterations and potential therapeutic targets. .
1		Background : Extrahepatic cholangiocarcinoma ( EHCC ) , intrahepatic cholangiocarcinoma ( IHCC ) , and gallbladder carcinoma ( GBCA ) are rare tumors with poor prognosis that tend to be chemo-resistant .
2		The underlying molecular alterations and their correlation with altered responses to therapies are not well understood .
3		We hypothesized that delineation of different molecular alterations in the cancer types might potentially yield different therapeutic options .
4		Methods : 815 cases ( 126 EHCC , 434 IHCC , 244 GBCA , 11 NOS ) were tested by a commercial multiplatform profiling service ( Caris Life Sciences , Phoenix , AZ ) .
5		Tests included sequencing ( Sanger , NGS ) , gene amplification ( CISH/FISH ) , and protein expression (IHC) .
6		Results : 24 of 47 genes tested had mutations , with the highest rates in TP53 ( 28% ) , KRAS ( 18% ) , IDH1 ( 9% ) , and SMAD4 ( 6% ) .
7		BRCA1/2 mutations were seen in 3/41 ( 73% ) and 5/40 ( 125% ) cases .
8	Μ	Overall , IHC showed high TOPO1 , TOP2A , PD-1 , SPARC and PD-L1 in 56% , 49% , 40% , 39% and 15% of cases and low RRM1 , ERCC1 and TS in 82% , 72% and 79% , respectively , suggesting potential utility of chemotherapeutic and immunomodulatory agents targeting these alterations in selected cases .
9		Mutually exclusive protein loss of chromatin modifiers BAP1 and PBRM1 were seen in 17% and 27% .
10	Μ	ROS1 break-apart FISH showed negative results in 16 cases tested .
11		Comparing the three carcinomas ( EHCC , IHCC and GBCA , Table ) , EHCC had the highest KRAS mutation rate ; IHCC had the highest IDH1 mutation ; GBCA and EHCC had significantly higher TP53 mutation and HER2 amplification than IHCC .
12	✓	IDH1 and TP53 mutations were mutually exclusive , and IDH1-mutated IHCC had higher P-glycoprotein expression than TP53-mutated IHCC ( 82% vs. 37% ) .	GE-ASS-DS
13		GBCA had high TOP2A by FISH and IHC , and a high loss of PBRM1 ( all p < 0.05 ) .
14		Conclusions : Multiplatform cancer profiling reveals distinctbiomarker characteristics of biliary tract carcinomas , offering insights into disease biology and suggests potential sensitivity to novel and conventional therapies .
15		Further analyses with clinical correlation are warranted .

PMID: ASCO_169730-176 (Patient)   Terms: clinical trial
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0		Comprehensive profiling of biliary tract cancers ( BTC ) to reveal molecular heterogeneity with implications for matched targeted therapies ( MTT ) . .
1		Background : BTC is an heterogeneous disease that includes intrahepatic cholangiocarcinoma ( IHC ) , extrahepatic cholangiocarcinoma ( EHC ) , gallbladder carcinomas ( GBC ) and ampulloma ( AM ) , typically present an advanced stage at diagnosis and chemotherapy ( chemo ) has limited efficacy .
2		We describe potentially targetable genomic alterations ( ptGA ) of BTC and impact of MTT in these patients ( pts ) .
3		Methods : From 2011 to 2015 , 104 chemorefractory patients ( pts ) with BTC ( 62 IHC , 23 EHC , 15 GBC , 4 AM ) were referred to molecular profiling at our institution .
4		Archived tumor samples were analyzed using different panels ( FoundationOne in 27 , Amplicon-MiSeq in 25 , MassARRAY-Sequenom in 23 , Fusion-Nanostring in 31 and protein expression in 13 ) and pts were offered MTT in Phase 1 trials according to specific eligibility criteria and logistics .
5		Results : Median age was 57 y ( 27-82 ) ; metastatic sites were liver ( 81% ) , nodes ( 43% ) and lung ( 21% ) ; median time to progression on first - line chemo was 5.1 months (m) ( CI95% 41-63 ) ; 27% received 2 or more chemo lines .
6		At least one ptGA was detected in 49% of the samples , with proportional increase according to the size and spectrum of gene alterations tested ( p < 0001 ) .
7		Type of ptGA differed across tumor types ( see Table ) .
8		Additional ptGA in IHC ( BRAF D594 , ERBB2 S310 , RNF43 and BRCA2 mut ) and EHC ( BRAF G469 and ERBB2 S310 mut ) were found in single cases .
9		A total of 22 pts were enrolled in Phase 1 trials , 13 of them with a direct MTT ( 5 PI3K , 2 MEK , 2 MET , 2 IDH1 , 1 ERBB2 and 1 FGFR inhibitor [inh] ) .
10		Partial response was observed in 1 case ( MET ampl IHC with MET inh ) and prolonged stable disease in 3 pts ( 1 FGFR2 fusion IHC with FGFR inh ; 1 IDH1 mut IHC with IDH1 inh ; 1 NRAS mut GBC with MEK inh ) .
11		Conclusions : The diverse landscape of ptGA in BTC is a rich source for MTT in early clinical trials , and has the potential to improve outcomes of individual pts .
12	Μ	Expanding gene panels to identify these driver alterations ( mut , ampl and fusions ) is key for precision medicine in BTC .

PMID: ASCO_182088-199 (None)   Terms: NCT02989857
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0		ClarIDHy : A phase 3 , multicenter , randomized , double-blind study of AG-120 vs placebo in patients with an advanced cholangiocarcinoma with an IDH1 mutation. .
1		Background : Advanced cholangiocarcinoma ( CC ) is a life-threatening disease for which there are limited therapeutic options .
2		Mutations in isocitrate dehydrogenase 1 ( mIDH1 ) occur in up to 25% of intrahepatic CC cases .
3		mIDH1 lead to epigenetic and genetic changes that promote oncogenesis via production of the oncometabolite , D-2-hydroxyglutarate ( 2-HG ) .
4		AG-120 is a first-in-class oral inhibitor of the mIDH1 enzyme , and is being tested in a phase 1 study that enrolled 73 patients ( pts ) with mIDH1 CC who had received a median of 2 prior therapies ( range 15 ) .
5		AG-120 has demonstrated a favorable safety profile and clinical activity in this study .
6		Among the 72 efficacy evaluable pts ( 1 post-baseline response assessment or discontinued prematurely ) , 6% ( n = 4 ) had a confirmed partial response and 56% ( n = 40 ) had stable disease .
7		Progression-free survival ( PFS ) rate at 6 months was 40% as of Dec 16 , 2016 .
8		The 500 mg once daily ( QD ) dose of AG-120 was selected for the ongoing phase 3 study in mIDH1 CC described here .
9		Methods : ClarIDHy is a global , phase 3 , multicenter , double-blind study randomizing 186 pts with mIDH1 CC in a 2 : 1 ratio to AG-120 ( 500 mg QD ) or matched placebo ( NCT02989857 ) .
10		Key eligibility criteria : nonresectable or metastatic CC ; documented mIDH1 based on central laboratory testing ; ECOG 01 ; measurable disease ( RECIST v11 ) ; documented disease progression following 2 prior systemic therapies in the advanced setting , including atleast 1 gemcitabine - or 5-fluorouracil-containing regimen ; and no prior mIDH inhibitor therapy .
11		Crossover from the placebo arm to the AG-120 arm will be permitted .
12		The primary endpoint is PFS as assessed by an independent review .
13		Secondary endpoints include safety , tolerability , overall response rate , overall survival , pharmacokinetic and pharmacodynamic analyses on plasma , and quality of life as assessed by the EORTC QLQ-C30 , EORTC QLQ-BIL21 , and EQ-5D-5L instruments .
14		An independent data monitoring committee will monitor the data throughout the study .
15		The ClarIDHy study is currently activated at participating sites in the US and will be activated in centers throughout Europe and in South Korea .

PMID: ASCO_139827-158 (Cell)   Terms: xenograft, in vivo, in vitro, Phase I, tumor xenograft models
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0		Comprehensive genomic profiling of biliary tract cancers to reveal tumor-specific differences and genomic alterations. .
1	Μ	Background : The PI3K/AKT pathway is frequently activated in cancer by multiple mechanisms including PI3K activating mutations , PTEN loss , RTK activation , and other means .
2		GDC-0068 is a potent , highly selective , ATP-competitive pan-AKT inhibitor that is currently in Phase 1a and Phase 1b clinical development .
3		Here , we describe the cell line screening efforts and xenograft studies that provide rationale for a predictive biomarker strategy both for single agent studies and combinations with chemotherapeutic agents .
4		Methods : Cell line screening using GDC-0068 as a single agent and in combination with other agents provided a means of identifying predictive markers across various indications and drug combinations .
5		Single agent screens were performed with GDC-0068 in 9 prostate , 54 breast , and 18 ovarian cell lines .
6		We evaluated combination activity of GDC-0068 with docetaxel , doxorubicin , rapamycin and MEK inhibitor in a panel of 24 cell lines and combination activity of GDC-0068 with 5FU/Cisplatin ( Folfox ) in a panel of 11 gastric and 15 head and neck cancer cell lines .
7		We also evaluated both single agent activity and combination activity in select xenograft models .
8	Μ	Results : Single agent screens identified PTEN loss , PIK3CA activating mutations , and RTK activation ( HER2 in breast ) as key predictive markers in breast , ovarian and prostate cell lines .
9		Similarly , in prostate cancer xenograft models , the highest tumor growth inhibition was seen in models with PI3K pathway activation , e.g.via PTEN loss .
10		In the GDC-0068 combination studies , MEK inhibitors provided the most significant synergy across different targeted and chemotherapy agents tested ( rapamycin , docetaxel , doxurubicin ) .
11	Μ	In combination with 5FU/Cisplatin , we observed additive effects in gastric and head and neck cell lines and this response was best observed in cell lines with pathway activation : PTEN loss , PI3K mutations or amplifications , and/or high pAKT .
12		The in vitro results were recapitulated in vivo with the combination of GDC-0068 with either docetaxel or carboplatin enhancing the antitumor efficacy compared to either single agent alone in multiple tumor xenograft models .
13		All combinations were well tolerated as assessed by animal body weights and mortalities .
14		Conclusions : Across various indications , PTEN loss or PI3K pathway activation via PIK3CA activating mutations are strong predictive biomarkers of GDC-0068 activity either as a single agent or in combination studies and provide a strong diagnostic hypothesis for evaluation in the clinic .
15		Based on these results and others , GDC-0068 is currently being tested for single agent activity in a diagnostically selected Phase 1a expansion cohort in breast and prostate cancer , and in multiple combination Phase Ib trials .

PMID: ASCO_146614-156 (None)   Terms: clinical trial
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0		Comprehensive genomic profiling of biliary tract cancers to reveal tumor-specific differences and frequency of clinically relevant genomic alterations. .
1		Background : Intrahepatic cholangiocarcinoma ( IHCCA ) , extrahepatic cholangiocarcinoma ( EHCCA ) and gallbladder carcinomas ( GBCA ) typically present at an advanced stage and chemotherapy provides only modest benefit in most cases .
2	Μ	We queried whether comprehensive genomic profiling ( GCP ) of IHCCA , EHCCA and GBCA would reveal distinctive patterns of genomic alterations ( GA ) and identify clinically relevant GA ( CRGA ) that could lead to targeted therapies .
3		Methods : DNA was extracted from 412 IHCCA , 57 EHCCA and 85 GBCA .
4		CGP was performed on hybridization-captured libraries to a mean coverage depth of > 600X for 236 cancer-related genes .
5		The CGP assay included base substitutions , INDELs , copy number alterations and fusions/rearrangements .
6		CRGA were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials .
7		Results : Patient characteristics were similar for all three tumor types .
8		IHCCA and GBCa were more common in females and EHCCA were more common males .
9		Findings in the table below .
10		Multiple antitumor responses to targeted therapies in each of the 3 tumor types will be presented .
11		Conclusions : IHCCA , EHCCA and GBCA share frequent GA in cell cycle regulation (CDKN2B) and chromatin remodeling ( ARID1A ) .
12		IHCCA is further characterized by FGFR fusions , IDH1/2 substitutions , BRAF substitutions and MET amplification with a low KRAS mutation frequency .
13		EHCCA and GBCA have frequent ERBB2 amplifications (GBCA > EHCCA) and PIK3CA/MTOR pathway alterations .
14		KRAS mutation frequency is high in EHCCA and low in GBCA .
15		The diverse landscape of CRGA in biliary tract cancers can serve as targets for therapies , either approved or in clinical trials for the majority of patients with CCA , BDCA and GBCA and have the potential to improve outcomes for patients with these aggressive forms of malignancy .

PMID: AACR_2017-5687 (None)   Terms:
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0		Detection and monitoring of IDH mutations in unamplified plasma cell -free DNA in patients with advanced cancers treated with IDH inhibitors. .
1		Background : Cell -free ( cf ) DNA from plasma of patients with advanced cancers offers an easily obtainable material for detection of IDH mutations , which can be used for diagnostics and monitoring purposes .

PMID: ASCO_116129-132 (Patient)   Terms:
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0		Circulating oncometabolite 2-hydroxyglutarate ( 2HG ) as a potential surrogate biomarker in patients with isocitrate dehydrogenase mutant ( IDHm ) intrahepatic cholangiocarcinoma ( ICC ) . .
1		Background : Mutations in the genes encoding for IDH1 and IDH2 occur in ~20% of ICC patients ( pts ) , and they lead to the production of the oncometabolite 2HG .
2		We examined whether serum 2HG levels in IDHm ICC pts may 1 ) serve as a surrogate biomarker for IDH status , 2 ) correlate with tumor burden , and 3 ) correlate with circulating proangiogenic biomarkers .
3		Methods : Blood samples from 33 ICC pts [11 IDHm , 22 IDH wild-type ( IDHwt ) ] of different AJCC stages from MGH and 39 surgically resected ICC patients ( 7 IDHm , 32 IDHwt ) from HKU were analyzed for serum 2HG concentration by reverse-phase liquid chromatography coupled to mass spectrometry .
4		Eight circulating proangiogenic biomarkers were measured in plasma using multiplex ELISA .
5		Results : In the MGH cohort , median serum 2HG levels were significantly elevated in IDHm ( 478 ng/ml [interquartile range 174643] ) versus IDHwt ICC pts ( 118ng/ml [68160] ) ( p < 0.001 ) .
6		Similarly , in the HKU cohort , the pre-resection median serum 2HG levels were significantly elevated in IDHm ( 343ng/ml [192596] ) versus IDHwt ICC pts ( 56ng/ml [4281] ) ( p < 00001 ) .
7		The area under ROC curve for prediction of an IDH mutation using 2HG was 93% ; with a threshold of 2HG170ng/ml , the sensitivity was 83% and specificity was 90% .
8		IDH2 mutations were more frequent in the HKU cohort ( 3/7 , 43% ) compared with the MGH cohort ( 0/11 , 0% ) ( p < 005 ) , but 2HG levels did not differ among the specific IDH1 or IDH2 allelic variants. 2HG levels correlated directly with tumor burden ( Spearmans rho = 089 ; p < 005 ) in the HKU cohort .
9		Median plasma levels of PlGFa growth factor from the VEGF-familywere higher in IDHm ( 35pg/ml [3340] ) versus IDHwt ICC pts ( median 26pg/ml [2434] ) from the HKU cohort ( p < 005 ) .
10		No other associations were seen between proangiogenic biomarkers and IDH status .
11		Conclusions : IDHm ICC pts had significantly higher serum 2HG levels compared to IDHwt ICC pts .
12		High serum 2HG correlated with increased tumor burden .
13		Pre-resection circulating PlGF levels were higher in IDHm ICC versus IDHwt pts .
14		These data support further exploration of circulating 2HG as potential surrogate and response biomarker in IDHm ICC .

PMID: AACR_2014-5184 (Patient)   Terms:
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0		Distinct mutational patterns in liver fluke-related and non-infection-related bile duct cancers revealed by whole exome sequencing .
1		Cholangiocarcinoma , the second most common liver cancer , is known to be caused by different etiologies such as liver fluke infection , choledochal cyst and primary sclerosing cholangitis .
2		Thus , this cancer provides a good model to study the impact of different carcinogenic exposures on the specific patterns of somatic mutations in human tumors .
3		To address this issue , we profiled 209 cholangiocarcinomas ( CCAs ) from Asia and Europe , including 108 cases caused by liver fluke Opisthorchis viverrini ( O viverrini )- infection and 101 cases due to non-O .
4		viverrini etiologies .
5	Μ	Whole-exome ( N = 15 ) and prevalence screening ( N = 194 ) revealed recurrent somatic mutations in BAP1 and ARID1A , neither of which has been previously reported to be mutated in CCA .
6		Comparisons between intrahepatic O .
7		viverrini and non-O .
8	Μ	viverrini CCAs demonstrated statistically significant different mutation patterns : BAP1 and IDH1/2 were more frequently mutated in non-O .
9		viverrini CCAs , while TP53 displayed the reciprocal pattern .
10		Functional studies demonstrated tumor suppressive roles of BAP1 and ARID1A , establishing the role of chromatin modulators in CCA pathogenesis .
11		These findings indicate that different causative etiologies may induce distinct somatic alterations even within the same tumor type .