PMID: 28407996 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		A Multigene Test Could Cost-Effectively Help Extend Life Expectancy for Women at Risk of Hereditary Breast Cancer .
1		BACKGROUND :
2		The National Comprehensive Cancer Network recommends that women who carry gene variants that confer substantial risk for breast cancer consider risk-reduction strategies , that is , enhanced surveillance ( breast magnetic resonance imaging and mammography ) or prophylactic surgery .
3	Μ	Pathogenic variants can be detected in women with a family history of breast or ovarian cancer syndromes by multigene panel testing .
4		OBJECTIVES :
5		To investigate whether using a seven - gene test to identify women who should consider risk-reduction strategies could cost-effectively increase life expectancy .
6		METHODS :
7		We estimated effectiveness and lifetime costs from a payer perspective for two strategies in two hypothetical cohorts of women ( 40-year-old and 50-year-old cohorts ) who meet the National Comprehensive Cancer Network-defined family history criteria for multigene testing .
8		The two strategies were the usual test strategy for variants in BRCA1 and BRCA2 and the seven - gene test strategy for variants in BRCA1 , BRCA2 , TP53 , PTEN , CDH1 , STK11 , and PALB2 .
9	Μ	Women found to have a pathogenic variant were assumed to undergo either prophylactic surgery or enhanced surveillance .
10		RESULTS :
11		The incremental cost-effectiveness ratio for the seven - gene test strategy compared with the BRCA1/2 test strategy was $42,067 per life-year gained or $69,920 per quality-adjusted life-year gained for the 50-year-old cohort and $23,734 per life-year gained or $48,328 per quality-adjusted life-year gained for the 40-year-old cohort .
12		In probabilistic sensitivity analysis , the seven - gene test strategy cost less than $100,000 per life-year gained in 95.7% of the trials for the 50-year-old cohort .
13		CONCLUSIONS :
14		Testing seven breast cancer-associated genes , followed by risk-reduction management , could cost-effectively improve life expectancy for women at risk of hereditary breast cancer .

PMID: 28133246 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		[ A Family with Peutz-Jeghers Syndrome Having Various Malignant Diseases ] .
1		We report a 27-year-old female who was diagnosed with adenocarcinoma of the uterine cervix associated with Peutz - Jeghers syndrome ( PJS ) .
2		She had undergone 5 surgeries for intestinal intussusception and had been diagnosed with PJS .
3		She was referred to our hospital , complaining of watery vaginal discharge , and was diagnosed with adenocarcinoma of the uterine cervix .
4		Following neoadjuvant chemotherapy , radical hysterectomy and small intestinal polypectomy by intraoperative endoscopy were performed .
5		Among the third-degree relatives of her family , 10 had been diagnosed with PJS ; of these 10 , uterine cervical adenocarcinoma occurred in 3 relatives , pancreatic cancer in 2 , cholangiocellular carcinoma in 1 , and colon cancer in 1 .
6		Patients with PJS are at increased risk of developing malignant tumors in various organs .
7		A recent review of the literature from Japan revealed that the cumulative cancer risk was estimated to be 83%by the age of 70 years , with especially high incidence rates of uterine cervical adenocarcinoma , colorectal cancer , and pancreas cancer .
8		Surveillance for malignant neoplasms in patients with PJS is recommended , focusing on the sex and age of the patients .

PMID: 27910069 (None)   Terms: in vivo, mouse models, mouse
Sent#	Symbols	Sentence	Mnemonics
0		LKB1 as a Tumor Suppressor in Uterine Cancer : Mouse Models and Translational Studies .
1	Μ	The LKB1 tumor suppressor was identified in 1998 as the gene mutated in the Peutz-Jeghers Syndrome ( PJS ) , a hereditary cancer predisposition characterized by gastrointestinal polyposis and a high incidence of cancers , particularly carcinomas , at a variety of anatomic sites including the gastrointestinal tract , lung , and female reproductive tract .
2		Women with PJS have a high incidence of carcinomas of the uterine corpus ( endometrium ) and cervix .
3		The LKB1 gene is also somatically mutated in human cancers arising at these sites .
4		Work in mouse models has highlighted the potency of LKB1 as an endometrial tumor suppressor and its distinctive roles in driving invasive and metastatic growth .
5		These in vivo models represent tractable experimental systems for the discovery of underlying biological principles and molecular processes regulated by LKB1 in the context of tumorigenesis and also serve as useful preclinical model systems for experimental therapeutics .
6		Here we review LKB1's known roles in mTOR signaling , metabolism , and cell polarity , with an emphasis on human pathology and mouse models relevant to uterine carcinogenesis , including cancers of the uterine corpus and cervix .

PMID: 27734215 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Time to incorporate germline multigene panel testing into breast and ovarian cancer patient care .
1		PURPOSE :
2		Genetic evaluation is increasingly becoming an integral part of the management of women with newly diagnosed breast and ovarian cancer ( OC ) , and of individuals at high risk for these diseases .
3		Genetic counseling and testing have been incorporated into oncological care to help and complete management and treatment strategies .
4		Risk assessment and early detection strategies in individuals with BRCA1/2 mutations and with Lynch syndrome have been quite extensively studied , whereas much less is known about the management of mutation carriers with less common high-penetrance cancer susceptibility genes ( PTEN , TP53 , STK11 , CDH1 ) , and particularly those who carry mutations in moderate-penetrance genes ( e.g. , PALB2 , CHEK2 , ATM , NF1 , RAD51C , RAD51D , BRIP1 ) .
5		METHODS :
6		The latter patient groups represent important ongoing research opportunities to enable informed counseling about appropriate clinical management .
7		CONCLUSION :
8		We summarize the current guidelines for the management of high and moderate-penetrance mutations for breast and OC susceptibility .
9		Continuous updating of guidelines for proper clinical management of these individuals is ongoing because of rapid advances in technology and knowledge in this field .
10		Thus , we exhort the use of multigene panels for the assessment of cancer risk beyond the classic predisposition syndromes as a new standard of care in cancer genetics .
11		We further support an increase of genetic counselors in Europe and use of their expertise to support genetic testing in specialist multidisciplinary teams .

PMID: 27581326 (Patient)   Terms: clinical trial
Sent#	Symbols	Sentence	Mnemonics
0		Comprehensive transcriptome analysis identifies pathways with therapeutic potential in locally advanced cervical cancer .
1		OBJECTIVE :
2		The objective of the present study was to provide genomic and transcriptomic information that may improve clinical outcomes for locally advanced cervical cancer ( LACC ) patients by searching for therapeutic targets or potential biomarkers through the analysis of significantly altered signaling pathways in LACC .
3		METHODS :
4		Microarray-based transcriptome profiling of 89 tumor samples from women with LACC was performed .
5		Through Kyoto Encyclopedia of Genes and Genomes ( KEGG ) analysis , significantly over-expressed genes in LACC were identified ; these genes were validated by quantitative reverse transcription-polymerase chain reaction in an independent cohort , and the protein expression data were obtained from the Human Protein Atlas .
6		RESULTS :
7		A transcriptome analysis revealed 7530 significantly over-expressed genes in LACC samples .
8		By KEGG analysis , we found 93 dysregulated signaling pathways , including the JAK-STAT , NOTCH and mTOR-autophagy pathways , which were significantly upregulated .
9		We confirmed the overexpression of the relevant genes of each pathway , such as NOTCH1 , JAK2 , STAM1 , SOS1 , ADAM17 , PSEN1 , NCSTN , RPS6 , STK11/LKB1 and MLTS8/GBL in LACC compared with normal cervical tissue epithelia .
10		CONCLUSIONS :
11		Through comprehensive genomic and transcriptomic analyses , this work provides information regarding signaling pathways with promising therapeutic targets , suggesting novel target therapies to be considered in future clinical trials for LACC patients .

PMID: 27550049 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		A Pyloric Gland-Phenotype Ovarian Mucinous Tumor Resembling Lobular Endocervical Glandular Hyperplasia in a Patient with Peutz-Jeghers Syndrome .
1		We describe an ovarian mucinous neoplasm that histologically resembles lobular endocervical glandular hyperplasia ( LEGH ) containing pyloric gland type mucin in a patient with Peutz-Jeghers syndrome ( PJS ) .
2		Although ovarian mucinous tumors rarely occur in PJS patients , their pyloric gland phenotype has not been clearly determined .
3		The histopathologic features of the ovarian mucinous tumor were reminiscent of LEGH .
4		The cytoplasmic mucin was stained with periodic acid -Schiff reaction after diastase treatment but was negative for Alcian blue pH 2.5 , suggesting the presence of neutral mucin .
5		Immunohistochemically , the epithelium expressed various gastric markers , including MUC6 , HIK1083 , and carbonic anhydrase-IX .
6	Μ	Multiple ligation -dependent probe amplification detected a germline heterozygous deletion mutation at exons 1-7 of the STK11 gene ( c1-? 920+?del ) in peripheral blood leukocytes and mosaic loss of heterozygosity in ovarian tumor tissue .
7	Μ	Considering that LEGH and/or gastric-type cervical adenocarcinoma can be found in patients with PJS carrying germline and/or somatic STK11 mutations , our case indicates that STK11 mutations have an important role in the proliferation of pyloric-phenotype mucinous epithelium at various anatomical locations .

PMID: 27546620 (None)   Terms: , mouse, mice, syngeneic mice
Sent#	Symbols	Sentence	Mnemonics
0	✓	LKB1 inhibits HPV-associated cancer progression by targeting cellular metabolism .	GE-REG-RO
1		Liver kinase B1 ( LKB1 ) is mutationally inactivated in Peutz-Jeghers syndrome and in a variety of cancers including human papillomavirus ( HPV )- caused cervical cancer .
2		However , the significance of LKB1 mutations in cervical cancer initiation and progress has not been examined .
3		Herein , we demonstrated that , in mouse embryonic fibroblasts , loss of LKB1 and transduction of HPV16 E6/E7 had an additive effect on constraining cell senescence while promoting cell proliferation and increasing glucose consumption , lactate production and ATP generation .
4		Knockdown of LKB1 increased and ectopic expression of LKB1 decreased glycolysis , anchorage -independent cell growth , and cell migration and invasion in HPV -transformed cells .
5		In the tumorigenesis and lung metastasis model in syngeneic mice , depletion of LKB1 markedly increased tumor metastatic colonies in lungs without affecting subcutaneous tumor growth .
6	Μ	We showed that HPV16 E6/E7 enhanced the expression of hexokinase -ll ( HK-II ) in the glycolytic pathway through elevated c-MYC .
7		Ectopic LKB1 reduced HK-II along with glycolysis .
8		The inverse relationship between HK-II and LKB1 was also observed in normal and HPV-associated cervical lesions .
9		We propose that LKB1 acts as a safeguard against HPV -stimulated aerobic glycolysis and tumor progression .
10		These findings may eventually aid in the development of therapeutic strategy for HPV-associated malignancies by targeting cell metabolism .

PMID: 20301443 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Peutz-Jeghers Syndrome .
1		Peutz-Jeghers syndrome ( PJS ) is an autosomal dominant condition characterized by the association of gastrointestinal polyposis , mucocutaneous pigmentation , and cancer predisposition .
2		Peutz-Jeghers-type hamartomatous polyps are most common in the small intestine ( in order of prevalence : in the jejunum , ileum , and duodenum ) but can also occur in the stomach , large bowel , and extraintestinal sites including the renal pelvis , bronchus , gall bladder , nasal passages , urinary bladder , and ureters .
3		Gastrointestinal polyps can result in chronic bleeding and anemia and also cause recurrent obstruction and intussusception requiring repeated laparotomy and bowel resection .
4		Mucocutaneous hyperpigmentation presents in childhood as dark blue to dark brown macules around the mouth , eyes , and nostrils , in the perianal area , and on the buccal mucosa .
5		Hyperpigmented macules on the fingers are common .
6		The macules may fade in puberty and adulthood .
7		Individuals with Peutz-Jeghers syndrome are at increased risk for a wide variety of epithelial malignancies ( colorectal , gastric , pancreatic , breast , and ovarian cancers ) .
8		Females are at risk for sex cord tumors with annular tubules ( SCTAT ) , a benign neoplasm of the ovaries , and adenoma malignum of the cervix , a rare aggressive cancer .
9		Males occasionally develop large calcifying Sertoli cell tumors ( LCST ) of the testes , which secrete estrogen and can lead to gynecomastia , advanced skeletal age , and ultimately short stature , if untreated .
10		The diagnosis of Peutz-Jeghers syndrome is based on clinical findings .
11		Identification of a heterozygous pathogenic variant in STK11 by molecular genetic testing confirms the diagnosis and allows for family studies .
12		Treatment of manifestations : Routine endoscopic surveillance with polypectomy decreases the frequency of emergency laparotomy and bowel loss resulting from intussusception .
13		Diagnosis and management of small-bowel polyps is challenging .
14		New advances in small-bowel imaging include video capsule endoscopy , CT enterography , and MR enterography .
15		Balloon-assisted enteroscopy allows for removal of deep small-bowel polyps .
16		Occasionally intraoperative enteroscopy and enterotomy is needed for removal of large distal small-bowel polyps .
17		Intussusception and malignancies should be treated in the standard manner .
18		Prevention of primary manifestations : Although not specifically studied in individuals with PJS , the following could be considered based on family history or other clinical factors : prophylactic mastectomy to manage high risk for breast cancer and prophylactic hysterectomy and bilateral salpingo-oophorectomy after age 35 years or after child bearing has been completed to prevent gynecologic malignancy .
19		Surveillance : Protocols have been suggested for monitoring stomach , small and large bowel , breasts , testicles , ovaries , uterus , and pancreas by various procedures as early as birth and as frequently as once a year .
20		Evaluation of relatives at risk : If the pathogenic variant in the family is known , offer molecular genetic testing to at-risk relatives so that morbidity and mortality can be reduced by early diagnosis and prevention of disease through appropriate surveillance and consideration of prophylactic measures in affected family members .
21		If the family variant is not known , offer clinical diagnostic evaluations to all at-risk family members , who will benefit from early treatment and appropriate surveillance .
22		Peutz-Jeghers syndrome is inherited in an autosomal dominant manner .
23		However , approximately 45% of affected individuals have no family history of PJS ; the exact proportion of cases caused by a de novo pathogenic variant is unknown as the frequency of subtle signs of the disorder in parents has not been thoroughly evaluated and molecular genetic data are insufficient .
24		The risk to the offspring of an individual with a pathogenic STK11 variant is 50% .
25	Μ	Once the STK11 pathogenic variant has been identified in an affected family member , prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible .

PMID: 27378194 (None)   Terms: in vitro, meta-analysis, observational studies, phase II-III, clinical trial
Sent#	Symbols	Sentence	Mnemonics
0		Metformin use and gynecological cancers : A novel treatment option emerging from drug repositioning .
1		Metformin exerts antitumor effects mainly through AMP -activated protein kinase [AMPK] activation and phosphatidylinositol 3 - kinase [PI3K] -Akt-mammalian target of rapamycin [mTOR] inhibition .
2		This drug leads to activation of the cellular energy-sensing liver kinase B1 [LKB1] /AMPK pathway .
3		LKB1 is implicated as a tumor suppressor gene in molecular pathogenesis of different malignancies .
4		AMPK is a serine/threonine protein kinase that acts as an ultra-sensitive cellular energy sensor maintaining the energy balance within the cell .
5		AMPK activation inhibits mRNA translation and proliferation in cancer cells via down-regulation of PI3K/Akt/mTOR pathway .
6		Moreover , metformin decreases the production of insulin , insulin-like growth factor , inflammatory cytokines and vascular endothelial growth factor , and therefore it exerts anti-mitotic , anti-inflammatory and anti-angiogenetic effects .
7		Recent in vitro and experimental data suggest that metformin electively targets cancer stem cells , and acts together with chemotherapy to block tumor growth in different cancers .
8		Several epidemiological studies and meta-analysis have shown that metformin use is associated with decreased cancer risk and/or reduced cancer mortality for different malignancies .
9		The present review analyzes the recent biological and clinical data suggesting a possible growth-static effect of metformin also in gynecological cancers .
10		The large majority of available clinical data on the anti-cancer potential of metformin are based on observational studies .
11		Therefore long-term phase II-III clinical trials are strongly warranted to further investigate metformin activity in gynecological cancers .

PMID: 27241107 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Peutz-Jeghers Syndrome : Pathobiology , Pathologic Manifestations , and Suggestions for Recommending Genetic Testing in Pathology Reports .
1		Peutz-Jeghers syndrome ( PJS ) , in most cases , is attributed to mutation in STK11/LKB1 and is clinically characterized by gastrointestinal hamartomatous polyposis , mucocutaneous pigmentation , and predisposition to certain neoplasms .
2		There are currently no recommended gynecologic screening or clinical surveillance guidelines beyond those recommended for the general population ; however , cervical cytology samples must be examined with a high level of suspicion for cervical adenocarcinoma .
3		It is considered prudent to note the established association with PJS and recommend referral for genetic counseling .
4		Complete surgical excision after a diagnosis of atypical lobular endocervical glandular hyperplasia is recommended .

PMID: 26930387 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Hereditary non-BRCA gynecological tumors .
1		Early diagnosis and proper management of gynecologic malignancies represent a challenge in modern oncology .
2		A growing interest has arisen around the gynecological manifestations of hereditary cancer syndromes .
3		In particular , the discovery of the BRCA1 and BRCA2 genes in ovarian cancer and the mismatch repair genes ( MMR ) in endometrial carcinoma has revolutionized our approach to the diagnosis and screening of women for ovarian and uterine cancers .
4		The clinical , genetic and pathological features of hereditary cancer syndromes with gynecological manifestations are reviewed focusing on Lynch Syndrome , also known as hereditary nonpolyposis colorectal carcinoma ( HNPCC ) , Peutz-Jeghers Syndrome ( PJS ) , Cowden Syndrome or multiple hamartoma syndrome , Gorlin Syndrome or nevoid basal-cell carcinoma syndrome ( NBCCS ) and Reed's Syndrome or hereditary leiomyomatosis and renal cell cancer ( HLRCC ) .

PMID: 26898890 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Prioritizing Variants in Complete Hereditary Breast and Ovarian Cancer Genes in Patients Lacking Known BRCA Mutations .
1	Μ	BRCA1 and BRCA2 testing for hereditary breast and ovarian cancer ( HBOC ) does not identify all pathogenic variants .
2	Μ	Sequencing of 20 complete genes in HBOC patients with uninformative test results ( N = 287 ) , including noncoding and flanking sequences of ATM , BARD1 , BRCA1 , BRCA2 , CDH1 , CHEK2 , EPCAM , MLH1 , MRE11A , MSH2 , MSH6 , MUTYH , NBN , PALB2 , PMS2 , PTEN , RAD51B , STK11 , TP53 , and XRCC2 , identified 38,372 unique variants .
3		We apply information theory ( IT ) to predict and prioritize noncoding variants of uncertain significance in regulatory , coding , and intronic regions based on changes in binding sites in these genes .
4		Besides mRNA splicing , IT provides a common framework to evaluate potential affinity changes in transcription factor ( TFBSs ) , splicing regulatory ( SRBSs ) , and RNA -binding protein (RBBSs) binding sites following mutation .
5		We prioritized variants affecting the strengths of 10 splice sites ( four natural , six cryptic ) , 148 SRBS , 36 TFBS , and 31 RBBS .
6		Three variants were also prioritized based on their predicted effects on mRNA secondary ( 2 degrees ) structure and 17 for pseudoexon activation .
7	Μ	Additionally , four frameshift , two in-frame deletions , and five stop-gain mutations were identified .
8		When combined with pedigree information , complete gene sequence analysis can focus attention on a limited set of variants in a wide spectrum of functional mutation types for downstream functional and co-segregation analysis .

PMID: 26807963 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Non-Peutz-Jeghers syndrome-associated ovarian sex cord tumor with annular tubules : Report of a malignant case .
1		A sex cord tumor with annular tubules ( SCTAT ) is a rare but distinctive subtype of sex cord stromal tumor of the ovary .
2		Its clinical features depend on an association with Peutz-Jeghers syndrome ( PJS ) .
3		SCTAT associated with PJS typically manifests as bilateral , multifocal , and small lesions and is clinically benign .
4		In contrast , SCTAT not associated with PJS often manifests as a unilateral large mass and 20% of such tumors have malignant potential .
5		Most patients with SCTAT are diagnosed at stage I , and metastasis is rare .
6		Here we present a case of malignant SCTAT of stage III A1 ( ii ) ( retroperitoneal lymph node metastasis , largest dimension of metastasis >10 mm ) in a 14-year-old girl without PJS .

PMID: 26746637 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Update on our investigation of malignant tumors associated with Peutz-Jeghers syndrome in Japan .
1		PURPOSE :
2		To investigate the recent incidence of malignant tumors associated with Peutz-Jeghers syndrome ( PJS ) in Japan to clarify if there are any differences in malignant tumor risk and the spectrum of malignancies by reviewing the literature on this subject .
3		METHODS :
4		We reviewed PJS cases reported in 1115 papers in Japan between January , 1989 and December , 2014 .
5		RESULTS :
6		Malignant tumors were identified in 186 of the total 583 PJS cases from 523 evaluable studies .
7		The estimated cumulative risk of a malignant tumor was 83.0 % at 70 years of age .
8		Compared with a previous study , on a collective 91 cases reported up until 1988 in Japan , the reported proportion of gastrointestinal malignancies decreased , from 82.4 to 48.3 % , whereas that of gynecological malignancies increased , from 8.8 to 34.3 % ( P <001 ) .
9		Moreover , breast cancers were occasionally reported ( 48 % ) , even though none were reported in the previous study .
10		Adenocarcinoma of the uterine cervix was the most common malignant tumor ( 468 % ) among women with PJS .
11		CONCLUSIONS :
12		The increased number of reports of cervical adenocarcinoma in women with PJS is the prominent trend in Japan , and a subject of concern among gynecologists .
13		The risk of breast cancer seems to be increasing , but confirmation of this trend will require further investigation .

PMID: 26534844 (Patient)   Terms: case, control
Sent#	Symbols	Sentence	Mnemonics
0		Targeted massively parallel sequencing of a panel of putative breast cancer susceptibility genes in a large cohort of multiple-case breast and ovarian cancer families .
1		INTRODUCTION :
2		Gene panel testing for breast cancer susceptibility has become relatively cheap and accessible .
3		However , the breast cancer risks associated with mutations in many genes included in these panels are unknown .
4		METHODS :
5		We performed custom-designed targeted sequencing covering the coding exons of 17 known and putative breast cancer susceptibility genes in 660 non-BRCA1/2 women with familial breast cancer .
6		Putative deleterious mutations were genotyped in relevant family members to assess co-segregation of each variant with disease .
7		We used maximum likelihood models to estimate the breast cancer risks associated with mutations in each of the genes .
8		RESULTS :
9	Μ	We found 31 putative deleterious mutations in 7 known breast cancer susceptibility genes ( TP53 , PALB2 , ATM , CHEK2 , CDH1 , PTEN and STK11 ) in 45 cases , and 22 potential deleterious mutations in 31 cases in 8 other genes ( BARD1 , BRIP1 , MRE11 , NBN , RAD50 , RAD51C , RAD51D and CDK4 ) .
10		The relevant variants were then genotyped in 558 family members .
11		Assuming a constant relative risk of breast cancer across age groups , only variants in CDH1 , CHEK2 , PALB2 and TP53 showed evidence of a significantly increased risk of breast cancer , with some supportive evidence that mutations in ATM confer moderate risk .
12		CONCLUSIONS :
13		Panel testing for these breast cancer families provided additional relevant clinical information for <2% of families .
14		We demonstrated that segregation analysis has some potential to help estimate the breast cancer risks associated with mutations in breast cancer susceptibility genes , but very large case-control sequencing studies and/or larger family -based studies will be needed to define the risks more accurately .

PMID: 26413869 (None)   Terms: , mouse model, mouse
Sent#	Symbols	Sentence	Mnemonics
0	✓	LKB1 loss promotes endometrial cancer progression via CCL2 -dependent macrophage recruitment .	GM-REG-RO
1		Endometrial cancer is the most common gynecologic malignancy and the fourth most common malignancy in women .
2		For most patients in whom the disease is confined to the uterus , treatment results in successful remission ; however , there are no curative treatments for tumors that have progressed beyond the uterus .
3		The serine/threonine kinase LKB1 has been identified as a potent suppressor of uterine cancer , but the biological modes of action of LKB1 in this context remain incompletely understood .
4	✓	Here , we have shown that LKB1 suppresses tumor progression by altering gene expression in the tumor microenvironment .	GE-REG-RO
5		We determined that LKB1 inactivation results in abnormal , cell -autonomous production of the inflammatory cytokine chemokine ( C-C motif ) ligand 2 ( CCL2 ) within tumors , which leads to increased recruitment of macrophages with prominent tumor-promoting activities .
6		Inactivation of Ccl2 in an Lkb1-driven mouse model of endometrial cancer slowed tumor progression and increased survival .
7		In human primary endometrial cancers , loss of LKB1 protein was strongly associated with increased CCL2 expression by tumor cells as well as increased macrophage density in the tumor microenvironment .
8		These data demonstrate that CCL2 is a potent effector of LKB1 loss in endometrial cancer , creating potential avenues for therapeutic opportunities .

PMID: 26337050 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Do hereditary syndrome-related gynecologic cancers have any specific features ?
1		UNLABELLED : Hereditary syndromes are responsible for 10 % of gynaecologic cancers , among which hereditary breast-ovarian cancer and hereditary non-polyposis colon cancer syndromes , known as HBOC and Lynch syndromes respectively , present the highest relative risk .
2		The latter predisposes to endometrial cancer and both contribute to ovarian cancer .
3		Cowden syndrome-related endometrial cancer and the increased risk of ovarian , uterine and cervical cancers associated with Peutz-Jeghers syndrome , are also demonstrated , while Li-Fraumeni syndrome patients are prone to develop ovarian and endometrial cancers .
4		Despite these syndromes' susceptibility to gynaecologic cancers being consensual , it is still not clear whether these tumours have any epidemiologic , clinical , pathologic or imaging specific features that could allow any of the intervening physicians to raise suspicion of a hereditary syndrome in patients without known genetic risk .
5		Moreover , controversy exists regarding both screening and surveillance schemes .
6		Our literature review provides an updated perspective on the evidence-based specific features of tumours related to each of these syndromes as well as on the most accepted screening and surveillance guidelines .
7		In addition , some illustrative cases are presented .
8		TEACHING POINTS : * HBOC syndrome is mainly associated with ovarian HGSC , which arises in fallopian fimbriae . * LS-related endometrial tumours show histological diversity and predilection for lower uterine segment . * LS and CS-related ovarian cancers are mostly of non-serous type , usually endometrioid . * Ovarian SCTAT and cervical adenoma malignum are strongly associated with PJS . * Unfortunately , hereditary gynaecologic cancers do not seem to have distinctive imaging features .

PMID: 26191312 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		P16-positive continuous minimal deviation adenocarcinoma and gastric type adenocarcinoma in a patient with Peutz-Jeghers syndrome .
1		We report a case of Peutz-Jeghers syndrome ( PJS ) in a 33-year-old female patient with synchronous uterine cervical minimal deviation adenocarcinoma ( MDA ) and gastric type adenocarcinoma ( GTA ) .
2		The patient was diagnosed with PJS at the age of 10 .
3		At the time of consultation , she complained of watery discharge .
4		Magnetic resonance imaging of the pelvis showed a poorly circumscribed mass in the uterine cervix .
5		Histologically , both MDA and GTA components , as well as their transitional area , were observed .
6		Both components were diffusely positive for MUC6 , CK7 and , robustly , for p16 .
7	Μ	Moreover , the components were negative for ER , PgR and CEA , while HIK1083 and CK20 positive cells were found focally .
8		Ki-67 labeling index in the MDA component was 5% while that in the GTA component was 50% .
9		This case of GTA accompanied by MDA in a patient with PJS is distinct from the single previously-reported comparable case of which we are aware , with respect to the overexpression of p16 protein , an event considered rare in these tumors , and the continuity between the MDA and GTA components .
10		This continuity favors the hypothesis that GTA arises from the dedifferentiation of MDA .

PMID: 26068970 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Intact LKB1 activity is required for survival of dormant ovarian cancer spheroids .
1		Metastatic epithelial ovarian cancer ( EOC ) cells can form multicellular spheroids while in suspension and disperse directly throughout the peritoneum to seed secondary lesions .
2		There is growing evidence that EOC spheroids are key mediators of metastasis , and they use specific intracellular signalling pathways to control cancer cell growth and metabolism for increased survival .
3		Our laboratory discovered that AKT signalling is reduced during spheroid formation leading to cellular quiescence and autophagy , and these may be defining features of tumour cell dormancy .
4		To further define the phenotype of EOC spheroids , we have initiated studies of the Liver kinase B1 ( LKB1 ) -5'-AMP-activated protein kinase ( AMPK ) pathway as a master controller of the metabolic stress response .
5		We demonstrate that activity of AMPK and its upstream kinase LKB1 are increased in quiescent EOC spheroids as compared with proliferating adherent EOC cells .
6		We also show elevated AMPK activity in spheroids isolated directly from patient ascites .
7		Functional studies reveal that treatment with the AMP mimetic AICAR or allosteric AMPK activator A-769662 led to a cytostatic response in proliferative adherent ovarian cancer cells , but they fail to elicit an effect in spheroids .
8	✓	Targeted knockdown of STK11 by RNAi to reduce LKB1 expression led to reduced viability and increased sensitivity to carboplatin treatment in spheroids only , a phenomenon which was AMPK-independent .
9		Thus , our results demonstrate a direct impact of altered LKB1-AMPK signalling function in EOC .
10		In addition , this is the first evidence in cancer cells demonstrating a pro-survival function for LKB1 , a kinase traditionally thought to act as a tumour suppressor .

PMID: 25986173 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Targeted deep sequencing of mucinous ovarian tumors reveals multiple overlapping RAS-pathway activating mutations in borderline and cancerous neoplasms .
1		BACKGROUND :
2		Mucinous ovarian tumors represent a distinct histotype of epithelial ovarian cancer .
3		The rarest ( 2-4 % of ovarian carcinomas ) of the five major histotypes , their genomic landscape remains poorly described .
4		We undertook hotspot sequencing of 50 genes commonly mutated in human cancer across 69 mucinous ovarian tumors .
5		Our goals were to establish the overall frequency of cancer-hotspot mutations across a large cohort , especially those tumors previously thought to be "RAS-pathway alteration negative" , using highly-sensitive next-generation sequencing as well as further explore a small number of cases with apparent heterogeneity in RAS-pathway activating alterations .
6		METHODS :
7		Using the Ion Torrent PGM platform , we performed next generation sequencing analysis using the v2 Cancer Hotspot Panel .
8		Regions of disparate ERBB2-amplification status were sequenced independently for two mucinous carcinoma ( MC ) cases , previously established as showing ERBB2 amplification/overexpression heterogeneity , to assess the hypothesis of subclonal populations containing either KRAS mutation or ERBB2 amplification independently or simultaneously .
9		RESULTS :
10	Μ	We detected mutations in KRAS , TP53 , CDKN2A , PIK3CA , PTEN , BRAF , FGFR2 , STK11 , CTNNB1 , SRC , SMAD4 , GNA11 and ERBB2 .
11	Μ	KRAS mutations remain the most frequently observed alteration among MC ( 649 % ) and mucinous borderline tumors ( MBOT ) ( 923 % ) .
12	Μ	TP53 mutation occurred more frequently in carcinomas than borderline tumors ( 568 % and 115 % , respectively ) , and combined IHC and mutation data suggest alterations occur in approximately 68 % of MC and as many as 20 % of MBOT .
13		Proven and potential RAS-pathway activating changes were observed in all but one MC .
14	Μ	Concurrent ERBB2 amplification and KRAS mutation were observed in a substantial number of cases ( 7/63 total ) , as was co-occurrence of KRAS and BRAF mutations ( one case ) .
15		Microdissection of ERBB2-amplified regions of tumors harboring KRAS mutation suggests these alterations are occurring in the same cell populations , while consistency of KRAS allelic frequency in both ERBB2 amplified and non-amplified regions suggests this mutation occurred in advance of the amplification event .
16		CONCLUSIONS :
17	Μ	Overall , the prevalence of RAS-alteration and striking co-occurrence of pathway "double-hits" supports a critical role for tumor progression in this ovarian malignancy .
18		Given the spectrum of RAS -activating mutations , it is clear that targeting this pathway may be a viable therapeutic option for patients with recurrent or advanced stage mucinous ovarian carcinoma , however caution should be exercised in selecting one or more personalized therapeutics given the frequency of non-redundant RAS -activating alterations .

PMID: 25798842 (None)   Terms: ex vivo, In vitro
Sent#	Symbols	Sentence	Mnemonics
0	✓	Loss of LKB1 and p53 synergizes to alter fallopian tube epithelial phenotype and high-grade serous tumorigenesis .	GM-REG-RO
1		Liver kinase B1 ( LKB1 ) is a tumor suppressor ubiquitously expressed serine/threonine protein kinase involved in energy metabolism and cellular polarity .
2	Μ	In microarray experiments that compared normal tubal epithelium with high-grade serous carcinoma ( HGSC ) , we observed a decrease in LKB1 mRNA expression in HGSC .
3	Μ	In this study , we demonstrate that loss of cytoplasmic and nuclear LKB1 protein expression is frequently observed in tubal cancer precursor lesions as well as in both sporadic and hereditary HGSCs compared with other ovarian cancer histotypes .
4		Bi-allelic genomic loss of LKB1 in HGSC did not account for the majority of cases with a decrease in protein expression .
5		In vitro , shLKB1-fallopian tube epithelial ( FTE ) cells underwent premature cellular arrest and in ex vivo FTE culture , LKB1 loss and p53 mutant synergized to disrupt apical to basal polarity and decrease the number of ciliated cells .
6		Overexpression of cyclin E1 allowed for bypass of LKB1 -induced cellular arrest , and increased both proliferation and anchorage -independent growth of transformed FTE cells .
7		These data suggest that LKB1 loss early in ovarian serous tumorigenesis has an integral role in tumor promotion by disrupting apical to basal polarity in the presence of mutated p53 in fallopian tube cells .

PMID: 25738363 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Progression of naive intraepithelial neoplasia genome to aggressive squamous cell carcinoma genome of uterine cervix .
1		Although cervical intraepithelial neoplasia ( CIN ) is considered a neoplasia , its genomic alterations remain unknown .
2		For this , we performed whole-exome sequencing and copy number profiling of three CINs , a microinvasive carcinoma ( MIC ) and four cervical squamous cell carcinomas ( CSCC ) .
3		Both total mutation and driver mutation numbers of the CINs were significantly fewer than those of the MIC/CSCCs ( P = 0036 and P = 0018 , respectively ) .
4		Importantly , PIK3CA was altered in all MIC/CSCCs by either mutation or amplification , but not in CINs .
5	Μ	The CINs harbored significantly lower numbers of copy number alterations ( CNAs ) than the MIC/CSCCs as well ( P = 0036 ) .
6		Pathway analysis predicted that the MIC/CSCCs were enriched with cancer-related signalings such as cell adhesion , mTOR signaling pathway and cell migration that were depleted in the CINs .
7	Μ	The mutation-based estimation of evolutionary ages identified that CIN genomes were younger than MIC/CSCC genomes .
8		The data indicate that CIN genomes harbor unfixed mutations in addition to human papilloma virus infection but require additional driver hits such as PIK3CA , TP53 , STK11 and MAPK1 mutations for CSCC progression .
9		Taken together , our data may explain the long latency from CIN to CSCC progression and provide useful information for molecular diagnosis of CIN and CSCC .

PMID: 25734181 (None)   Terms: clinical trial
Sent#	Symbols	Sentence	Mnemonics
0		Drug repositioning for gynecologic tumors : a new therapeutic strategy for cancer .
1		The goals of drug repositioning are to find a new pharmacological effect of a drug for which human safety and pharmacokinetics are established and to expand the therapeutic range of the drug to another disease .
2		Such drug discovery can be performed at low cost and in the short term based on the results of previous clinical trials .
3		New drugs for gynecologic tumors may be found by drug repositioning .
4		For example , PPAR ligands may be effective against ovarian cancer , since PPAR activation eliminates COX-2 expression , arrests the cell cycle , and induces apoptosis .
5		Metformin , an antidiabetic drug , is effective for endometrial cancer through inhibition of the PI3K-Akt-mTOR pathway by activating LKB1-AMPK and reduction of insulin and insulin-like growth factor -1 due to AMPK activation .
6		COX-2 inhibitors for cervical cancer may also be examples of drug repositioning .
7		PGE2 is induced in the arachidonate cascade by COX-2 .
8		PGE2 maintains high expression of COX-2 and induces angiogenic factors including VEGF and bFGF , causing carcinogenesis .
9		COX-2 inhibitors suppress these actions and inhibit carcinogenesis .
10		Combination therapy using drugs found by drug repositioning and current anticancer drugs may increase efficacy and reduce adverse drug reactions .
11		Thus , drug repositioning may become a key approach for gynecologic cancer in drug discovery .

PMID: 25724520 (Patient)   Terms: phase II trial
Sent#	Symbols	Sentence	Mnemonics
0		PIK3CA Pathway Mutations Predictive of Poor Response Following Standard Radiochemotherapy +/- Cetuximab in Cervical Cancer Patients .
1		PURPOSE :
2		EGFR is frequently overexpressed in cervical cancer , suggesting EGFR blockade as a promising treatment approach .
3		Cetuximab , an anti EGFR antibody , used conjointly with radiochemotherapy , was feasible in first - line treatment of cervix carcinoma limited to the pelvis .
4		EXPERIMENTAL DESIGN :
5		This randomized phase II trial enrolled 78 FIGO stage IB2-IIIB cervical cancer patients to either cisplatin-based radiochemotherapy alone ( arm B , n = 38 ) or conjointly with a 6-week course of weekly cetuximab ( arm A , n = 40 ) .
6		Brachytherapy was given to the pelvic mass .
7		Primary endpoint was disease-free survival ( DFS ) at 2 years .
8		EGFR expression and targeted sequencing were performed in 54 of 78 patients .
9		RESULTS :
10		Cetuximab over a 6-week period did not improve DFS at 24 months .
11		At 31 months median follow-up , DFS was not significantly different ( P = 018 ) .
12		Complete response at 4 to 6 months was strongly predictive for excellent DFS ( log-rank test ; P <0001 ) .
13	Μ	PIK3CA , KRAS , and STK11 mutations were observed in 22% , 4% , and 2% of patients , respectively .
14	✓	No tumor with a PI3K pathway mutation showed complete response ( 0/8 in arm A and 0/6 in arm B ) , whereas 14 of 52 ( 27% ) tumors without mutations did ( P = 0021 ) .	GM-ASS-RO
15		PI3K pathway-mutated tumors showed a trend toward poorer DFS ( P = 006 ) following cetuximab ( 8/22 ) as compared with those following standard treatment only ( 6/18 ) .
16		CONCLUSIONS :
17		Similar to patients with head and neck cancer , patients with cervical cancer showed no gain in DFS at 2 years following a combined treatment of cetuximab with radiochemotherapy .
18		Although treatment tolerance and compliance were satisfactory , it remains to be demonstrated whether maintenance therapy with cetuximab could be beneficial in selected patient groups .

PMID: 25679014 (None)   Terms: This review
Sent#	Symbols	Sentence	Mnemonics
0		LKB1 Tumor Suppressor : Therapeutic Opportunities Knock when LKB1 Is Inactivated .
1	Μ	LKB1 is commonly thought of as a tumor suppressor gene because its hereditary mutation is responsible for a cancer syndrome , and somatic inactivation of LKB1 is found in non-small cell lung cancer , melanoma , and cervical cancers .
2		However , unlike other tumor suppressors whose main function is to either suppress cell proliferation or promote cell death , one of the functions of LKB1 -regulated AMPK signaling is to suppress cell proliferation in order to promote cell survival under energetic stress conditions .
3		This unique , pro-survival function of LKB1 has led to the discovery of reagents , such as phenformin , that specifically exploit the vulnerability of LKB1-null cells in their defect in sensing energetic stress .
4		Such targeted agents represent a novel treatment strategy because they induce cell killing when LKB1 is absent .
5		This review article summarizes various vulnerabilities of LKB1-mutant cells that have been reported in the literature and discusses the potential of using existing or developing novel reagents to target cancer cells with defective LKB1 .

PMID: 25530972 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Sex cord tumor with annular tubules : an incidental finding in an endometriotic cyst--the first known cooccurrence .
1		Sex cord tumor with annular tubules ( SCTATs ) is a relatively rare ovarian neoplasm often having a syndromic association with Peutz-Jeghers syndrome ( PJS ) .
2		Other associations described with this rare neoplasm include adenoma malignum of cervix , Turners syndrome , dysgerminoma , gonadoblastoma , endometrial carcinoma , and endometriosis of fallopian tube .
3		We describe for the first time to the best of our literature search the incidental detection of SCTAT coexisting with an endometriotic cyst of ovary .
4		Meticulous histological scanning and awareness is mandatory for detection of such unusual incidental lesions .

PMID: 25510663 (None)   Terms: in vitro, in vivo, Xenograft
Sent#	Symbols	Sentence	Mnemonics
0		MicroRNA-17 promotes normal ovarian cancer cells to cancer stem cells development via suppression of the LKB1-p53-p21/WAF1 pathway .
1		The mechanism underlying the development of human ovarian cancer is poorly understood .
2		The liver kinase protein , LKB1 , is hypothesized to play a pivotal role in tumor cell proliferation and invasion capacity through regulation of p53 and p21/WAF1 expression .
3		Previous studies suggest LKB1 may , in turn , be regulated by microRNA-17 .
4		Here , we examined the role of miR-17 in the expression of LKB1 and the downstream effects on proliferation and invasion capacity of normal ovarian cancer cells ( OCCs ) and ovarian stem cells .
5		In this study , both the mRNA and protein expression levels of LKB1 , p53 , and p21 decreased in OCCs following transfection with a miR-17 expression plasmid .
6		MiR-17 expression affected cell cycle regulation and stimulated the proliferation and invasion capacity of OCCs in vitro .
7		ChIP assays indicated that the binding efficiency of p53 to the p21/WAF1 gene promoter was much lower in miR-17 transfected OCCs than in OCCs transfected with a mutated miR-17 .
8		Co-immunoprecipitation and western blotting showed significantly lower levels of p53 and p53 Ser15-pho in the miR-17 transfected OCCs as compared to the mutant miR-17 transfected OCCs .
9		Xenograft experiments confirmed that suppression of tumor growth in vivo occurred in the absence of functional miR-17 .
10		These findings suggest that mature miR-17 expression may have an important role in the pathogenesis of human ovarian tumors through its interference with the LKB1-p53-p21/WAF1 pathway expression by epigenetic modification .
11		These findings are of potential importance in the identification of novel therapeutic targets in human ovarian cancer .

PMID: 25479140 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer .
1	Μ	BACKGROUND & ; AIMS : We investigated the prevalence of germline mutations in APC , ATM , BRCA1 , BRCA2 , CDKN2A , MLH1 , MSH2 , MSH6 , PALB2 , PMS2 , PRSS1 , STK11 , and TP53 in patients with pancreatic cancer .
2		METHODS :
3		The Ontario Pancreas Cancer Study enrolls consenting participants with pancreatic cancer from a province-wide electronic pathology database ; 708 probands were enrolled from April 2003 through August 2012 .
4		To improve the precision of BRCA2 prevalence estimates , 290 probands were selected from 3 strata , based on family history of breast and/or ovarian cancer , pancreatic cancer , or neither .
5		Germline DNA was analyzed by next-generation sequencing using a custom multiple - gene panel .
6		Mutation prevalence estimates were calculated from the sample for the entire cohort .
7		RESULTS :
8	Μ	Eleven pathogenic mutations were identified : 3 in ATM , 1 in BRCA1 , 2 in BRCA2 , 1 in MLH1 , 2 in MSH2 , 1 in MSH6 , and 1 in TP53 .
9	Μ	The prevalence of mutations in all 13 genes was 3.8% ( 95% confidence interval , 21%-56% ) .
10		Carrier status was associated significantly with breast cancer in the proband or first-degree relative ( P <01 ) , and with colorectal cancer in the proband or first-degree relative ( P <01 ) , but not family history of pancreatic cancer , age at diagnosis , or stage at diagnosis .
11		Of patients with a personal or family history of breast and colorectal cancer , 10.7% ( 95% confidence interval , 44%-170% ) and 11.1% ( 95% confidence interval , 30%-191% ) carried pathogenic mutations , respectively .
12		CONCLUSIONS :
13		A small but clinically important proportion of pancreatic cancer is associated with mutations in known predisposition genes .
14	Μ	The heterogeneity of mutations identified in this study shows the value of using a multiple - gene panel in pancreatic cancer .

PMID: 25420630 (None)   Terms: in vivo, in vitro, xenograft, tumor xenograft
Sent#	Symbols	Sentence	Mnemonics
0		Synergistic effects of eukaryotic co-expression plasmid-based STAT3-specific siRNA and LKB1 on ovarian cancer in vitro and in vivo .
1		The signal transducer and activator of transcription 3 ( STAT3 ) are ideal targets for ovarian cancer .
2		Previous studies showed that downregulation of STAT3 using specific short hairpin RNAs ( shRNA ) can significantly reduce ovarian tumor growth .
3		However , RNA interference does not fully ablate target gene expression due to idiosyncrasies associated with shRNAs and their targets .
4		To enhance the therapeutic efficacy of STAT3-specific shRNA , we employed a combinatorial expression of STAT3-specific shRNA and liver kinase B1 ( LKB1 ) , a tumor suppressor .
5		Thus , the LKB1 coding sequences and STAT3-specific shRNAs were constructed in a eukaryotic co-expression plasmid pCDNA3.1 , and then transfected into ovarian cancer cells to evaluate the synergistic effects of this combination on anticancer activity and explore the relevant molecular mechanisms .
6		Co-expression of STAT3specific siRNA and LKB1 ( pSi-STAT3-LKB1 ) synergistically inhibited ovarian cancer cell growth , invasion and migration , induced cell apoptosis and arrested the cell cycle in vitro when compared with monotherapy .
7	Μ	The results showed that the co-expression of plasmid pSi-STAT3-LKB1 inserted subcutaneously into ovarian tumor xenograft resulted in more significant inhibition of tumor growth .
8	Μ	Further study showed that the synergistic anti-ovarian cancer effects of the co-expression of STAT3-specific siRNA and LKB1 may be associated with the upregulation of p-p53 , p21 and downregulation of survivin , BCL-2 and cyclin D1 .
9		Results of the present study suggested that combined therapy with eukaryotic co-expression of the plasmidcarrying STAT3-specific siRNA and LKB1 is a novel and efficient treatment strategy for human ovarian cancer .

PMID: 25404506 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Molecular characterization of serous ovarian carcinoma using a multigene next generation sequencing cancer panel approach .
1		BACKGROUND :
2		High grade serous ovarian cancer is one of the poorly characterized malignancies .
3		This study aimed to elucidate the mutational events in Malaysian patients with high grade serous ovarian cancer by performing targeted sequencing on 50 cancer hotspot genes .
4		RESULTS :
5		Nine high grade serous ovarian carcinoma samples and ten normal ovarian tissues were obtained from Universiti Kebangsaan Malaysia Medical Center ( UKMMC ) and the Kajang Hospital .
6		The Ion AmpliSeq Cancer Hotspot Panel v2 targeting "mutation-hotspot region" in 50 most common cancer-associated genes was utilized .
7	Μ	A total of 20 variants were identified in 12 genes .
8		Eleven ( 55% ) were silent alterations and nine ( 45% ) were missense mutations .
9		Six of the nine missense mutations were predicted to be deleterious while the other three have low or neutral protein impact .
10		Eight genes were altered in both the tumor and normal groups ( APC , EGFR , FGFR3 , KDR , MET , PDGFRA , RET and SMO ) while four genes ( TP53 , PIK3CA , STK11 and KIT ) were exclusively altered in the tumor group .
11		TP53 alterations were present in all the tumors but not in the normal group .
12		Six deleterious mutations in TP53 ( pR175H , pH193R , pY220C , pY163C , pR282G and pY234H ) were identified in eight serous ovarian carcinoma samples and none in the normal group .
13		CONCLUSION :
14	Μ	TP53 remains as the most frequently altered gene in high grade serous ovarian cancer and Ion Torrent Personal Genome Machine ( PGM ) in combination with Ion Ampliseq Cancer Hotspot Panel v2 were proven to be instrumental in identifying a wide range of genetic alterations simultaneously from a minute amount of DNA .
15		However , larger series of validation targeting more genes are necessary in order to shed a light on the molecular events underlying pathogenesis of this cancer .

PMID: 25238946 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Society of Gynecologic Oncology statement on risk assessment for inherited gynecologic cancer predispositions .
1		Women with germline mutations in the cancer susceptibility genes , BRCA1 or BRCA2 , associated with Hereditary Breast & ; Ovarian Cancer syndrome , have up to an 85% lifetime risk of breast cancer and up to a 46% lifetime risk of ovarian , tubal , and peritoneal cancers .
2		Similarly , women with mutations in the DNA mismatch repair genes , MLH1 , MSH2 , MSH6 , or PMS2 , associated with the Lynch/Hereditary Non-Polyposis Colorectal Cancer ( HNPCC ) syndrome , have up to a 40-60% lifetime risk of both endometrial and colorectal cancers as well as a 9-12% lifetime risk of ovarian cancer .
3		Mutations in other genes including TP53 , PTEN , and STK11 are responsible for hereditary syndromes associated with gynecologic , breast , and other cancers .
4		Evaluation of the likelihood of a patient having one of these gynecologic cancer predisposition syndromes enables physicians to provide individualized assessments of cancer risk , as well as the opportunity to provide tailored screening and prevention strategies such as surveillance , chemoprevention , and prophylactic surgery that may reduce the morbidity and mortality associated with these syndromes .
5		Evaluation for the presence of a hereditary cancer syndrome is a process that includes assessment of clinical and tumor characteristics , education and counseling conducted by a provider with expertise in cancer genetics , and may include genetic testing after appropriate consent is obtained .
6		This commentary provides guidance on identification of patients who may benefit from assessment for the presence of a hereditary breast and/or gynecologic cancer syndrome .

PMID: 25155037 (Cell)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Mir-155 promotes cervical cancer cell proliferation through suppression of its target gene LKB1 .
1		MicroRNAs ( miRNAs ) are important regulators of many physiological and pathological processes , including cell proliferation , apoptosis , and cell cycle arrest .
2		In this study , we aimed to investigate the biological role of miR-155 in cervical cancer and the underlying molecular mechanism involved in tumorigenesis .
3	Μ	The expression of miR-155 in human cervical cancer tissues was detected by real-time PCR .
4		MTT assay and BrdU incorporation assay were used to measure the proliferation of cervical cancer cells .
5		Apoptosis cells and cell cycle distribution were analyzed by flow cytometry .
6	Μ	We found that the expression of miR-155 was upregulated in cervical cancer tissues compared to the adjacent non-cancer tissues .
7		Overexpression of miR-155 promoted the proliferation of Hela and SiHa cells .
8		By contrast , downregulation of miR-155 inhibited the growth of cervical cancer cells .
9	Μ	Flow cytometry analysis showed that low expression of miR-155 promoted apoptosis and induced cell cycle arrest in Hela and SiHa cells .
10		Moreover , the mRNA and protein expression of LKB1 was significantly reduced in cervical cancer tissues .
11		Luciferase reporter assay demonstrated that LKB1 was a target gene of miR-155 , suggesting that miRNA-155 promoted the proliferation of cervical cancer cells by regulating LKB1 expression .

PMID: 24792998 (Cell)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Expression and transcriptional profiling of the LKB1 tumor suppressor in cervical cancer cells .
1		OBJECTIVES :
2		To characterize the biological activities of LKB1 , examine LKB1 protein expression and identify LKB1 -regulated genes that may serve as therapeutic targets in cervical cancer .
3		METHODS :
4		Proliferation of cervical cancer HeLa cells expressing LKB1 was examined .
5		LKB1 expression in normal cervical tissues and cervical cancers was assessed by immunohistochemistry .
6		Gene expression profiles of cervical cancer HeLa cells stably expressing LKB1 were analyzed by microarray .
7		Differentially expressed genes were analyzed using Gene Ontology ( GO ) terms and the Kyoto Encyclopedia of Genes and Genomes ( KEGG ) PATHWAY database .
8		Quantitative RT-PCR was used to validate the microarray data .
9		The expression of lipid phosphatase inositol polyphosphate 4-phosphatase type II ( INPP4B ) was confirmed by western blotting .
10		RESULTS :
11		Expression of LKB1 inhibited HeLa cell proliferation , activated AMPK and was lost in more than 50% of cervical carcinomas .
12		More than 200 genes were differentially expressed between HeLa cells with and without LKB1 .
13		Bioinformatics analysis with GO annotation indicated that LKB1 plays a role in receiving diverse stimuli and converting them into molecular signals .
14		KEGG PATHWAY analysis showed that 8 pathways were significantly regulated .
15		These include arginine and proline metabolism and inositol phosphate metabolism .
16		The differential expression of 7 randomly selected genes was confirmed by quantitative RT-PCR .
17		Furthermore , the steady-state level of INPP4B protein was up-regulated in LKB1-overexpressing cells .
18		CONCLUSIONS :
19		This study establishes LKB1 as an important tumor suppressor in cervical cancer and sheds light on a novel signaling pathway regulated by LKB1 .

PMID: 24490603 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		A tumor of the uterine cervix with a complex histology in a Peutz-Jeghers syndrome patient with genomic deletion of the STK11 exon 1 region .
1		Patients with Peutz-Jeghers syndrome ( PJS ) have a risk of complicating malignant tumors , including cancer of the uterine cervix .
2	Μ	Mutations in the STK11 gene have been identified as being responsible for PJS .
3		However , the genotype-phenotype correlation in PJS is poorly understood , especially with respect to malignant tumors .
4		Here , we report a detailed analysis of a case of a cervical tumor in a PJS patient showing a large genomic deletion in exon 1 of STK11 without human papillomavirus infection .
5		Histological examination revealed a complex histology consisting of three components : lobular endocervical gland hyperplasia ( LEGH ) , minimal deviation adenocarcinoma ( MDA ) and mucinous adenocarcinoma .
6		Immunohistochemistry for STK11 was positive in the LEGH and MDA components , while that of the mucinous adenocarcinoma stained very faintly .
7		These findings support a close relationship among LEGH , MDA and mucinous adenocarcinoma and imply that inactivation of STK11 may occur during progression from MDA to mucinous adenocarcinoma .

PMID: 24390348 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Landscape of genomic alterations in cervical carcinomas .
1		Cervical cancer is responsible for 10-15% of cancer-related deaths in women worldwide .
2		The aetiological role of infection with high-risk human papilloma viruses ( HPVs ) in cervical carcinomas is well established .
3		Previous studies have also implicated somatic mutations in PIK3CA , PTEN , TP53 , STK11 and KRAS as well as several copy-number alterations in the pathogenesis of cervical carcinomas .
4		Here we report whole-exome sequencing analysis of 115 cervical carcinoma-normal paired samples , transcriptome sequencing of 79 cases and whole - genome sequencing of 14 tumour-normal pairs .
5		Previously unknown somatic mutations in 79 primary squamous cell carcinomas include recurrent E322K substitutions in the MAPK1 gene ( 8% ) , inactivating mutations in the HLA-B gene ( 9% ) , and mutations in EP300 ( 16% ) , FBXW7 ( 15% ) , NFE2L2 ( 4% ) , TP53 ( 5% ) and ERBB2 ( 6% ) .
6		We also observe somatic ELF3 ( 13% ) and CBFB ( 8% ) mutations in 24 adenocarcinomas .
7		Squamous cell carcinomas have higher frequencies of somatic nucleotide substitutions occurring at cytosines preceded by thymines ( Tp*C sites ) than adenocarcinomas .
8		Gene expression levels at HPV integration sites were statistically significantly higher in tumours with HPV integration compared with expression of the same genes in tumours without viral integration at the same site .
9		These data demonstrate several recurrent genomic alterations in cervical carcinomas that suggest new strategies to combat this disease .

PMID: 24306927 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Etiology of familial breast cancer with undetected BRCA1 and BRCA2 mutations : clinical implications .
1		BACKGROUND :
2		Familial breast cancer accounts for 20-30 % of all breast cancer cases .
3		Mutations in the BRCA1 and BRCA2 genes account for the majority of high risk families with both early onset breast cancer and ovarian cancer .
4	Μ	Most of the families with less than six breast cancer cases and no ovarian cancer do not carry BRCA1 or BRCA2 mutations that can be detected using routine sequencing protocols .
5		Here , we aimed to review the etiology of familial breast cancer in cases without BRCA1 and BRCA2 mutations .
6		RESULTS :
7		After excluding BRCA1 and BRCA2 mutations , factors proposed to contribute to familial breast cancer include : chance clustering of apparently sporadic cases , shared lifestyle , monogenic inheritance , i.e. , dominant gene mutations associated with a high risk ( TP53 , PTEN , STK11 ) , dominant gene mutations associated with a relatively low risk ( ATM , BRIP1 , RLB2 ) , recessive gene mutations associated with horizontal inheritance patterns ( sister-sister ) , and polygenic inheritance where susceptibility to familial breast cancer is thought to be conferred by a large number of low risk alleles .
8		CONCLUSIONS :
9		Current evidence suggests that in the majority of cases with BRCA1 and BRCA2 negative familial breast cancer the etiology is due to interactions of intermediate or low risk alleles with environmental and lifestyle factors .
10		Thus , a careful selection of patients submitted to genetic testing is needed .
11		Clearly , further research is required to fully elucidate the etiology of non-BRCA familial breast cancer .

PMID: 24285539 (Cell)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Liver kinase B1 expression promotes phosphatase activity and abrogation of receptor tyrosine kinase phosphorylation in human cancer cells .
1		Aberrant receptor tyrosine kinase phosphorylation ( pRTK ) has been associated with diverse pathological conditions , including human neoplasms .
2		In lung cancer , frequent liver kinase B1 ( LKB1 ) mutations correlate with tumor progression , but potential links with pRTK remain unknown .
3		Heightened and sustained receptor activation was demonstrated by LKB1-deficient A549 ( lung ) and HeLaS3 ( cervical ) cancer cell lines .
4		Depletion ( siRNA ) of endogenous LKB1 expression in H1792 lung cancer cells also correlated with increased pRTK .
5		However , ectopic LKB1 expression in A549 and HeLaS3 cell lines , as well as H1975 activating-EGF receptor mutant lung cancer cell resulted in dephosphorylation of several tumor-enhancing RTKs , including EGF receptor , ErbB2 , hepatocyte growth factor receptor ( c-Met ) , EphA2 , rearranged during transfection ( RET ) , and insulin-like growth factor I receptor .
6		Receptor abrogation correlated with attenuation of phospho-Akt and increased apoptosis .
7		Global phosphatase inhibition by orthovanadate or depletion of protein tyrosine phosphatases ( PTPs ) resulted in the recovery of receptor phosphorylation .
8		Specifically , the activity of SHP-2 , PTP-1beta , and PTP-PEST was enhanced by LKB1-expressing cells .
9		Our findings provide novel insight on how LKB1 loss of expression or function promotes aberrant RTK signaling and rapid growth of cancer cells .

PMID: 24170201 (Cell)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Loss of LKB1 and PTEN tumor suppressor genes in the ovarian surface epithelium induces papillary serous ovarian cancer .
1		Epithelial ovarian cancer presents mostly with serous , endometrioid or mucinous histology but is treated as a single disease .
2		The development of histotype-specific therapy has been challenging because of the relative lack of studies attributing disrupted pathways to a distinct histotype differentiation .
3		mTOR activation is frequently associated with poor prognosis in serous ovarian cancer , which is the most common and most deadly histotype .
4		However , the mechanisms dysregulating mTOR in the pathogenesis of ovarian cancer are unknown .
5	Μ	We detected copy number loss and correlated lower expression levels of LKB1 , TSC1 , TSC2 and PTEN tumor suppressor genes for upstream regulators of mTOR activity in up to 80% in primary ovarian serous tumor databases , with LKB1 allelic loss-predominant .
6		Reduced LKB1 protein was usually associated with increased mTOR activity in both serous ovarian cancer cell lines and primary tumors .
7		Conditional deletion of Lkb1 in murine ovarian surface epithelial ( OSE ) cells caused papillary hyperplasia and shedding but not tumors .
8		Simultaneous deletion of Lkb1 and Pten , however , led to development of high-grade ovarian serous histotype tumors with 100% penetrance that expressed WT1 , ERalpha , PAX8 , TP53 and cytokeratin 8 , typical markers used in the differential diagnosis of serous ovarian cancer .
9		Neither hysterectomy nor salpingectomy interfered with progression of ovarian tumorigenesis , suggesting that neither uterine nor Fallopian tube epithelial cells were contributing to tumorigenesis .
10		These results implicate LKB1 loss in the OSE in the pathogenesis of serous ovarian cancer and provide a compelling rationale for investigating the therapeutic potential of targeting LKB1 signaling in patients with this deadly disease .

PMID: 24145653 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Lobular endocervical glandular hyperplasia is a neoplastic entity with frequent activating GNAS mutations .
1	Μ	To clarify the significance of GNAS mutations in cervical tumorigenesis , we performed mutational analyses in a total of 154 lesions and in 22 normal tissues of the uterine cervix .
2	Μ	Activating GNAS mutations were found in 8 of the 19 lobular endocervical glandular hyperplasias ( LEGH ; 42% ) and 4 of the 79 endocervical-type mucinous adenocarcinomas ( 5% ) but were never seen in the normal endocervical tissue , minimal deviation adenocarcinomas , endometrioid adenocarcinomas , or squamous cell carcinomas .
3		We further examined the presence of human papillomavirus ( HPV ) DNA and p16 expression to probe the relationship between GNAS mutations and HPV infection in LEGHs and carcinomas .
4		All the GNAS-mutated LEGHs were negative for HPV DNA and p16 expression , whereas all the GNAS-mutated adenocarcinomas were positive for HPV DNA and/or p16 expression , implicating GNAS mutations in the development of LEGH and a minor subset of HPV-related cervical adenocarcinomas .
5	Μ	Additional mutational analyses of LEGH identified KRAS and STK11 mutations in 1 and 2 cases , respectively .
6		The GNAS , KRAS , and STK11 mutations were mutually exclusive ; thus , a total of 11 LEGHs ( 58% ) had 1 of these genetic alterations .
7		Although LEGH has been regarded as a metaplastic lesion , the frequent presence of genetic alterations suggests a neoplastic nature .

PMID: 24086281 (None)   Terms: , mouse, mouse models, rabbit
Sent#	Symbols	Sentence	Mnemonics
0		The LKB1 tumor suppressor as a biomarker in mouse and human tissues .
1		Germline mutations in the LKB1 gene ( also known as STK11 ) cause the Peutz-Jeghers Syndrome , and somatic loss of LKB1 has emerged as causal event in a wide range of human malignancies , including melanoma , lung cancer , and cervical cancer .
2		The LKB1 protein is a serine-threonine kinase that phosphorylates AMP-activated protein kinase ( AMPK ) and other downstream targets .
3		Conditional knockout studies in mouse models have consistently shown that LKB1 loss promotes a highly-metastatic phenotype in diverse tissues , and human studies have demonstrated a strong association between LKB1 inactivation and tumor recurrence .
4		Furthermore , LKB1 deficiency confers sensitivity to distinct classes of anticancer drugs .
5		The ability to reliably identify LKB1-deficient tumors is thus likely to have important prognostic and predictive implications .
6		Previous research studies have employed polyclonal antibodies with limited success , and there is no widely-employed immunohistochemical assay for LKB1 .
7		Here we report an assay based on a rabbit monoclonal antibody that can reliably detect endogenous LKB1 protein ( and its absence ) in mouse and human formalin-fixed , paraffin-embedded tissues .
8		LKB1 protein levels determined through this assay correlated strongly with AMPK phosphorylation both in mouse and human tumors , and with mRNA levels in human tumors .
9		Our studies fully validate this immunohistochemical assay for LKB1 in paraffin-embedded formalin tissue sections .
10		This assay should be broadly useful for research studies employing mouse models and also for the development of human tissue -based assays for LKB1 in diverse clinical settings .

PMID: 24082825 (None)   Terms: This review
Sent#	Symbols	Sentence	Mnemonics
0		Unravelling the connection between metabolism and tumorigenesis through studies of the liver kinase B1 tumour suppressor .
1	Μ	The liver kinase B1 ( LKB1 ) tumour suppressor functions as a master regulator of growth , metabolism and survival in cells , which is frequently mutated in sporadic human non-small cell lung and cervical cancers .
2		LKB1 functions as a key upstream activator of the AMP-activated protein kinase ( AMPK ) , a central metabolic switch found in all eukaryotes that govern glucose and lipid metabolism and autophagy in response to alterations in nutrients and intracellular energy levels .
3		The LKB1/AMPK signalling pathway suppresses mammalian target of rapamycin complex 1 ( mTORC1 ) , an essential regulator of cell growth in all eukaryotes that is deregulated in a majority of human cancers .
4		LKB1 inactivation in cancer leads to both tumorigenesis and metabolic deregulation through the AMPK and mTORC1 -signalling axis and there remain critical challenges to elucidate the direct role LKB1 inactivation plays in driving aberrant metabolism and tumour growth .
5		This review addresses past and current efforts to delineate the molecular mechanisms fueling metabolic deregulation and tumorigenesis following LKB1 inactivation as well as translational promise of therapeutic strategies aimed at targeting LKB1-deficient tumors .

PMID: 24074562 (Cell)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		The LKB1 tumor suppressor differentially affects anchorage independent growth of HPV positive cervical cancer cell lines .
1		Infection with high-risk human papillomaviruses is causally linked to cervical carcinogenesis .
2		However , most lesions caused by high-risk HPV infections do not progress to cancer .
3		Host cell mutations contribute to malignant progression but the molecular nature of such mutations is unknown .
4	✓	Based on a previous study that reported an association between liver kinase B1 ( LKB1 ) tumor suppressor loss and poor outcome in cervical cancer , we sought to determine the molecular basis for this observation .	GM-ASS-RO
5		LKB1-negative cervical and lung cancer cells were reconstituted with wild type or kinase defective LKB1 mutants and we examined the importance of LKB1 catalytic activity in known LKB1 -regulated processes including inhibition of cell proliferation and elevated resistance to energy stress .
6		Our studies revealed marked differences in the biological activities of two kinase defective LKB1 mutants in the various cell lines .
7		Thus , our results suggest that LKB1 may be a cell -type specific tumor suppressor .

PMID: 23415580 (Patient)   Terms: retrospective
Sent#	Symbols	Sentence	Mnemonics
0		Cancer risk associated with STK11/LKB1 germline mutations in Peutz-Jeghers syndrome patients : results of an Italian multicenter study .
1		BACKGROUND :
2		Germline mutations in the STK11/LKB1 gene cause Peutz-Jeghers syndrome , an autosomal-dominantly inherited condition characterized by mucocutaneous pigmentation , hamartomatous gastrointestinal polyposis , and an increased risk for various malignancies .
3		We here report the results of the first Italian collaborative study on Peutz-Jeghers syndrome .
4		AIMS :
5	Μ	To assess cancer risks in a large homogenous cohort of patients with Peutz-Jeghers syndrome , carrying , in large majority , an identified STK11/LKB1 mutation .
6		METHODS :
7		One-hundred and nineteen patients with Peutz-Jeghers syndrome , ascertained in sixteen different Italian centres , were enrolled in a retrospective cohort study .
8		Relative and cumulative cancer risks and genotype-phenotype correlations were evaluated .
9		RESULTS :
10	Μ	36 malignant tumours were found in 31/119 ( 29 STK11/LKB1 mutation carriers ) patients .
11		The mean age at first cancer diagnosis was 41 years .
12		The relative overall cancer risk was 15.1 with a significantly higher risk ( p <0001 ) in females ( 220 ) than in males ( 86 ) .
13		Highly increased relative risks were present for gastrointestinal ( 1262 ) and gynaecological cancers ( 277 ) , in particular for pancreatic ( 1397 ) and cervical cancer ( 556 ) .
14		The Kaplan-Meier estimates for overall cumulative cancer risks were 20% , 43% , 71% , and 89% , at age 40 , 50 , 60 and 65 years , respectively .
15		CONCLUSION :
16		Peutz-Jeghers syndrome entails markedly elevated cancer risks , mainly for pancreatic and cervical cancers .
17		This study provides a helpful reference for improving current surveillance protocols .

PMID: 22878090 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Peutz-Jeghers syndrome-associated atypical mucinous proliferation of the uterine cervix : a case of minimal deviation adenocarcinoma ( 'adenoma malignum' ) in situ .
1		Suppression of pancreatic and colon cancer cells by antisense K-ras RNA expression vectors .

PMID: 22846738 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Imatinib for the treatment of patients with unresectable or metastatic malignant KIT-positive gastrointestinal stromal tumours : an open-label Belgian trial .
1		Gastric cancer is a global public health concern , ranking as the fourth leading cause of cancer mortality , with a 5-year survival of only 20% .
2		Approximately 10% of gastric cancers appear to have a familial predisposition , and about half of these can be attributed to hereditary germline mutations .
3		We review the genetic syndromes and current standards for genetic counseling , testing , and medical management for screening and treatment of gastric cancer .
4	Μ	Recently , germline mutations in the E-cadherin/CDH1 gene have been identified in families with an autosomal dominant inherited predisposition to gastric cancer of the diffuse type .
5		The cumulative lifetime risk of developing gastric cancer in CDH1 mutation carriers is up to 80% , and women from these families also have an increased risk for developing lobular breast cancer .
6	Μ	Prophylactic gastrectomies are recommended in unaffected CDH1 mutation carriers , because screening endoscopic examinations and blind biopsies have proven inadequate for surveillance .
7		In addition to this syndrome , gastric cancer risk is elevated in Lynch syndrome associated with germline mutations in DNA mismatch repair genes and microsatellite instability , in hereditary breast and ovarian cancer syndrome due to germline BRCA1 and BRCA2 mutations , in familial adenomatous polyposis caused by germline APC mutations , in Li-Fraumeni syndrome due to germline p53 mutations , in Peutz-Jeghers syndrome associated with germline STK11 mutations , and in juvenile polyposis syndrome associated with germline mutations in the SMAD4 and BMPR1A genes .
8		Guidelines for genetic testing , counseling , and management of individuals with hereditary diffuse gastric cancer are suggested .
9		A raised awareness among the physician and genetic counseling communities regarding these syndromes may allow for increased detection and prevention of gastric cancers in these high-risk individuals .

PMID: 22735790 (Cell)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Metformin impairs the growth of liver kinase B1-intact cervical cancer cells .
1		A case of pancreatic adenocarcinoma with novel K-ras mutation and long term survival .

PMID: 21926085 (None)   Terms: , mouse models, mouse
Sent#	Symbols	Sentence	Mnemonics
0		The tumor suppressor kinase LKB1 : lessons from mouse models .
1		Cysteine-rich 61 ( CCN1 ) enhances chemotactic migration , transendothelial cell migration , and intravasation by concomitantly up-regulating chemokine receptor 1 and 2 .

PMID: 21860411 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Molecular chaperone complexes with antagonizing activities regulate stability and activity of the tumor suppressor LKB1 .
1		LKB1 is a tumor suppressor that is constitutionally mutated in a cancer-prone condition , called Peutz-Jeghers syndrome , as well as somatically inactivated in a sizeable fraction of lung and cervical neoplasms .
2		The LKB1 gene encodes a serine/threonine kinase that associates with the pseudokinase STRAD ( STE-20-related pseudokinase ) and the scaffolding protein MO25 , the formation of this heterotrimeric complex promotes allosteric activation of LKB1 .
3		We have previously reported that the molecular chaperone heat shock protein 90 ( Hsp90 ) binds to and stabilizes LKB1 .
4		Combining pharmacological studies and RNA interference approaches , we now provide evidence that the co-chaperone Cdc37 participates to the regulation of LKB1 stability .
5		It is known that the Hsp90-Cdc37 complex recognizes a surface within the N-terminal catalytic lobe of client protein kinases .
6		In agreement with this finding , we found that the chaperones Hsp90 and Cdc37 interact with an LKB1 isoform that differs in the C-terminal region , but not with a novel LKB1 variant that lacks a portion of the kinase N-terminal lobe domain .
7		Reconstitution of the two complexes LKB1-STRAD and LKB1-Hsp90-Cdc37 with recombinant proteins revealed that the former is catalytically active whereas the latter is inactive .
8		Furthermore , consistent with a documented repressor function of Hsp90 , LKB1 kinase activity was transiently stimulated upon dissociation of Hsp90 .
9		Finally , disruption of the LKB1-Hsp90 complex favors the recruitment of both Hsp/Hsc70 and the U - box dependent E3 ubiquitin ligase CHIP ( carboxyl terminus of Hsc70-interacting protein ) that triggers LKB1 degradation .
10		Taken together , our results establish that the Hsp90-Cdc37 complex controls both the stability and activity of the LKB1 kinase .
11		This study further shows that two chaperone complexes with antagonizing activities , Hsp90-Cdc37 and Hsp/Hsc70-CHIP , finely control the cellular level of LKB1 protein .

PMID: 21744334 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Selective gene expression profiling of mTOR-associated tumor suppressor and oncogenes in ovarian cancer .
1		The aim of this study was to selectively profile the activation status of mammalian target of rapamycin ( mTOR )- associated oncogenes and tumor suppressor genes ( TSGs ) in ovarian cancer specimens , healthy ovaries and benign ovarian tumors , including endometrial cysts .
2		We used a novel type of microfluidic gene array to examine the expression of 15 human tumor suppressors and oncogenes in ovarian cancer specimens of 53 patients , benign ovarian cysts of 29 women ( endometrial and simple ) and 11 healthy ovaries of individuals in whom the material was obtained during total hysterectomies performed because of fibroid changes .
3		The array was custom-designed to include the following genes : NF1 , RHEB , mTOR1 , AKT-1 , PTEN , TSC1 , TSC2 , KRAS , RPS6KB1 , 4EBP1 , TP53 , EIF4E , STK11 , PIK3CA and BECN1 .
4		Confirmatory immunohistochemical detection was performed for a group of selected proteins .
5	Μ	Particularly significant differences were observed as to the expression of PTEN ( p <00001 ) , TP53 ( p = 00003 ) , PIK3CA ( p = 00003 ) and BECN1 ( p = 00014 ) which were shown to be downregulated in cancer patients when compared to healthy ovaries and benign ovarian cysts ( endometrial and simple ) .
6		These markers did not show association with grade or stage of the tumor .
7		Immunohistochemistry showed that PTEN , TP53 , PIK3CA and BECN1 proteins are expressed in ovarian cancer .
8		Our results indicate that there are significant differences in the expression of some of the mTOR-related tumor suppressors and oncogenes which could be associated with the pathogenesis of ovarian cancer .

PMID: 21266715 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Genome -wide RNAi screen reveals disease-associated genes that are common to Hedgehog and Wnt signaling .
1		The Hedgehog ( Hh ) and Wnt signal transduction pathways are master regulators of embryogenesis and tissue renewal and represent anticancer therapeutic targets .
2		Using genome -wide RNA interference screening in murine cultured cells , we established previously unknown associations between these signaling pathways and genes linked to developmental malformations , diseases of premature tissue degeneration , and cancer .
3		We identified functions in both pathways for the multitasking kinase Stk11 ( also known as Lkb1 ) , a tumor suppressor implicated in lung and cervical cancers .
4		We found that Stk11 loss resulted in disassembly of the primary cilium , a cellular organizing center for Hh pathway components , thus dampening Hh signaling .
5		Loss of Stk11 also induced aberrant signaling through the Wnt pathway .
6		Chemicals that targeted the Wnt acyltransferase Porcupine or that restored primary cilia length by inhibiting the tubulin deacetylase HDAC6 ( histone deacetylase 6 ) countered deviant pathway activities driven by Stk11 loss .
7		Our study demonstrates that Stk11 is a critical mediator in both the Hh and the Wnt pathways , and our approach provides a platform to support the development of targeted therapeutic strategies .

PMID: 21192934 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Molecular mechanisms of tumor suppression by LKB1 .
1	Μ	The LKB1 tumor suppressor gene is frequently mutated in sporadic lung adenocarcinomas and cervical cancers and germline mutations are causative for Peutz-Jeghers syndrome characterized by gastrointestinal polyposis .
2		The intracellular LKB1 kinase is implicated in regulating polarity , metabolism , cell differentiation , and proliferation - all functions potentially contributing to tumor suppression .
3		LKB1 acts as an activating kinase of atleast 14 kinases mediating LKB1 functions in a complex signaling network with partial overlaps .
4		Regulation of the LKB1 signaling network is highly context dependent , and spatially organized in various cellular compartments .
5		Also the mechanisms by which LKB1 activity suppresses tumorigenesis is context dependent , where recent observations are providing hints on the molecular mechanisms involved .

PMID: 20193846 (Cell)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Homozygous deletion of the STK11/LKB1 locus and the generation of novel fusion transcripts in cervical cancer cells .
1	Μ	The STK11/LKB1 gene encodes a ubiquitously expressed serine/threonine kinase that is mutated in multiple sporadic cancers including non-small cell lung carcinomas , pancreatic cancers , and melanomas .
2		LKB1 plays a role in multiple cellular functions including cell growth , cell cycle progression , metabolism , cell polarity , and migration .
3		To date , only a limited number of studies have assessed the status of LKB1 in cervical cancers .
4		Herein , we investigate DNA methylation , DNA mutation , and transcription at the LKB1 locus in cervical cancer cell lines .
5	Μ	We identified homozygous deletions of 25-85kb in the HeLa and SiHa cell lines .
6	Μ	Deletion breakpoint analysis in HeLa cells revealed that the deletion resulted from an Alu-recombination-mediated deletion ( ARMD ) and generated a novel LKB1 fusion transcript driven by an uncharacterized CpG island promoter located approximately 11kb upstream of LKB1 .
7		Although the homozygous deletion in SiHa cells removes the entire LKB1 gene and portions of the neighboring genes SBNO2 and c19orf26 , this deletion also generates a fusion transcript driven by the c19orf26 promoter and composed of both c19orf26 and SBNO2 sequences .
8	Μ	Further analyses of public gene expression and mutation databases suggest that LKB1 and its neighboring genes are frequently dysregulated in primary cervical cancers .
9		Thus , homozygous deletions affecting LKB1 in cervical cancers may generate multiple fusion transcripts involving LKB1 , SBNO2 , and c19orf26 .

PMID: 19874425 (Cell)   Terms: , mouse
Sent#	Symbols	Sentence	Mnemonics
0		Metformin attenuates ovarian cancer cell growth in an AMP-kinase dispensable manner .
1		Metformin , the most widely used drug for type 2 diabetes activates 59 adenosine monophosphate ( AMP )- activated protein kinase ( AMPK ) , which regulates cellular energy metabolism .
2		Here , we report that ovarian cell lines VOSE , A2780 , CP70 , C200 , OV202 , OVCAR3 , SKOV3ip , PE01 and PE04 predominantly express -alpha(1) , -beta(1) , -gamma(1) and -gamma(2) isoforms of AMPK subunits .
3		Our studies show that metformin treatment (1) significantly inhibited proliferation of diverse chemo-responsive and -resistant ovarian cancer cell lines ( A2780 , CP70 , C200 , OV202 , OVCAR3 , SKVO3ip , PE01 and PE04 ) , (2) caused cell cycle arrest accompanied by decreased cyclin D1 and increased p21 protein expression , (3) activated AMPK in various ovarian cancer cell lines as evident from increased phosphorylation of AMPKalpha and its downstream substrate ; acetyl co-carboxylase ( ACC ) and enhanced beta-oxidation of fatty acid and (4) attenuated mTOR-S6RP phosphorylation , inhibited protein translational and lipid biosynthetic pathways , thus implicating metformin as a growth inhibitor of ovarian cancer cells .
4		We also show that metformin-mediated effect on AMPK is dependent on liver kinase B1 ( LKB1 ) as it failed to activate AMPK-ACC pathway and cell cycle arrest in LKB1 null mouse embryo fibroblasts ( mefs ) .
5		This observation was further supported by using siRNA approach to down-regulate LKB1 in ovarian cancer cells .
6		In contrast , met formin inhibited cell proliferation in both wild-type and AMPKalpha ( 1/2 ) null mefs as well as in AMPK silenced ovarian cancer cells .
7		Collectively , these results provide evidence on the role of metformin as an anti-proliferative therapeutic that can act through both AMPK -dependent as well as AMPK-independent pathways .

PMID: 19737912 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Reproductive disturbances in multiple neuroendocrine tumor syndromes .
1		In the context of multiple neuroendocrine tumor syndromes , reproductive abnormalities may occur via a number of different mechanisms , such as hyperprolactinemia , increased GH/IGF-1 levels , hypogonadotropic hypogonadism , hypercortisolism , hyperandrogenism , hyperthyroidism , gonadotropin hypersecretion , as well as , tumorigenesis or functional disturbances in gonads or other reproductive organs .
2		Precocious puberty and/or male feminization is a feature of McCune-Albright syndrome ( MAS ) , neurofibromatosis type 1 ( NF1 ) , Carney complex ( CNC ) , and Peutz-Jeghers syndrome ( PJS ) , while sperm maturation and ovulation defects have been described in MAS and CNC .
3		Although tumorigenesis of reproductive organs due to a multiple neuroendocrine tumor syndrome is very rare , certain lesions are characteristic and very unusual in the general population .
4		Awareness leading to their recognition is important especially when other endocrine abnormalities coexist , as occasionally they may even be the first manifestation of a syndrome .
5		Lesions such as certain types of ovarian cysts ( MAS , CNC ) , pseudogynecomastia due to neurofibromas of the nipple-areola area ( NF1 ) , breast disease ( CNC and Cowden disease ( CD ) ) , cysts and 'hypernephroid' tumors of the epididymis or bilateral papillary cystadenomas ( mesosalpinx cysts ) and endometrioid cystadenomas of the broad ligament ( von Hippel-Lindau disease ) , testicular Sertoli calcifying tumors ( CNC , PJS ) monolateral or bilateral macroochidism and microlithiasis ( MAS ) may offer diagnostic clues .
6		In addition , multiple neuroendocrine tumor syndromes may be complicated by reproductive malignancies including ovarian cancer in CNC , breast and endometrial cancer in CD , breast malignancies in NF1 , and malignant sex-cord stromal tumors in PJS .

PMID: 19724060 (None)   Terms: , mouse model, mouse
Sent#	Symbols	Sentence	Mnemonics
0		Tumor suppression by LKB1 : SIK-ness prevents metastasis .
1		The LKB1 serine-threonine kinase is a tumor suppressor that is inactivated in a large number of sporadic human lung non-small cell carcinomas ( NSCLCs ) and cervical cancers .
2	✓	Genetic deletion of LKB1 in various mouse tissues results in tumorigenesis , and loss of LKB1 increases metastasis in a mouse model of NSCLC .	GM-REG-RO
3		LKB1 directly activates a family of 14 kinases related to AMPK [adenosine monophosphate ( AMP )- activated protein kinase] to control cell metabolism , growth , and polarity , though which of these are critical to its tumor suppressor functions remain undefined .
4		The LKB1 -dependent kinase SIK1 ( salt-inducible kinase 1 ) has now been identified as a key modulator of anoikis ( apoptosis induced by cell detachment ) and transformation in culture , and its modulation of the tumor suppressor p53 controls metastasis in transplanted tumor cells .
5	✓	Reduced SIK1 expression is correlated with poor prognosis in two large human breast cancer data sets .	GE-ASS-RO
6		These findings suggest that SIK1 is a key upstream regulator of p53 -dependent anoikis that may be targeted in tumorigenesis .

PMID: 19407487 (Cell)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Inhibition of cervical cancer cell growth through activation of upstream kinases of AMP -activated protein kinase .
1		AMP-activated protein kinase ( AMPK ) is a critical energy-balancing sensor in the regulation of cellular metabolism in response to external stimuli .
2		Emerging evidence has suggested that AMPK is a potential therapeutic target for human cancers .
3		AICAR , one of the pharmacological AMPK activators , has been widely used to suppress cancer cell growth through activation of LKB1 , an upstream kinase of AMPK .
4	Μ	However , frequent mutations and deletions of LKB1 found in some cancer cells limit the application of AICAR as an efficient therapeutic drug .
5		Here we show that an alternative pharmacological AMPK activator , A23187 , was able to inhibit cervical cancer cell growth through activation of Ca(2+)/calmodulin -dependent protein kinase kinase beta , another upstream kinase of AMPK .
6		Using cervical cancer cell models , we found that HeLa (LKB1-deficient cell) responded less to the anti-proliferative effect exerted by AICAR treatment ( p <0001 ) compared with CaSki and C41 (LKB1-expressing cells) .
7		Conversely , the anti-proliferative effect was increased significantly in HeLa but not in CaSki and C41 cells under treatment by A23187 ( p <0001 ) .
8		Moreover , co-treatment of AICAR and A23187 was able to further enhance the inhibitory effect on cell growth of Hela , CaSki and C41 cells .
9		Notably , both AICAR and A23187 exerted the anti-proliferative effect on cervical cancer cells by suppressing AMPK/mTOR signalling activity .
10		These data suggest that A23187 could be an alternative potential therapeutic drug used for anti-proliferation in LKB1-deficient cancer cells .

PMID: 19340305 (Cell)   Terms: in vivo
Sent#	Symbols	Sentence	Mnemonics
0	✓	Somatic LKB1 mutations promote cervical cancer progression .	GM-REG-RO
1		Human Papilloma Virus ( HPV ) is the etiologic agent for cervical cancer .
2		Yet , infection with HPV is not sufficient to cause cervical cancer , because most infected women develop transient epithelial dysplasias that spontaneously regress .
3	Μ	Progression to invasive cancer has been attributed to diverse host factors such as immune or hormonal status , as no recurrent genetic alterations have been identified in cervical cancers .
4		Thus , the pressing question as to the biological basis of cervical cancer progression has remained unresolved , hampering the development of novel therapies and prognostic tests .
5		Here we show that atleast 20% of cervical cancers harbor somatically-acquired mutations in the LKB1 tumor suppressor .
6	Μ	Approximately one-half of tumors with mutations harbored single nucleotide substitutions or microdeletions identifiable by exon sequencing , while the other half harbored larger monoallelic or biallelic deletions detectable by multiplex ligation probe amplification ( MLPA ) .
7	Μ	Biallelic mutations were identified in most cervical cancer cell lines ; HeLa , the first human cell line , harbors a homozygous 25 kb deletion that occurred in vivo .
8	✓	LKB1 inactivation in primary tumors was associated with accelerated disease progression .	GE-ASS-RO
9		Median survival was only 13 months for patients with LKB1-deficient tumors , but >100 months for patients with LKB1-wild type tumors ( P = 0015 , log rank test ; hazard ratio = 025 , 95% CI = 0083 to 077 ) .
10		LKB1 is thus a major cervical tumor suppressor , demonstrating that acquired genetic alterations drive progression of HPV -induced dysplasias to invasive , lethal cancers .
11		Furthermore , LKB1 status can be exploited clinically to predict disease recurrence .

PMID: 19145097 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Different phenotypes including gynecological cancer in three female patients with Peutz-Jeghers syndrome and mutations in the STK11 gene .
1		BACKGROUND :
2		Peutz-Jeghers syndrome ( PJS ) , a rare hereditary disorder , is characterized by the occurrence of gastrointestinal hamartomatous polyps associated with mucocutaneous pigmentation .
3		Patients are at an increased cancer risk not only for gastrointestinal but also for extraintestinal neoplasms .
4		PATIENTS AND RESULTS :
5		We report on the clinical and molecular findings in 3 young female patients with PJS ; 2 of them suffered from severe gynecological cancer .
6		One patient died at the age of 29 years of an incurable mucin-producing cervical adenocarcinoma .
7		Another patient had a papillary serous carcinoma of the ovary .
8	Μ	In all patients , we identified corresponding mutations in the STK11 gene , 2 of them novel .
9		CONCLUSION :
10		PJS should be considered in differential diagnosis in young women with gynecological malignancies .
11		Identification of STK11 mutations in patients and their relatives can help to improve the clinical management .

PMID: 19109876 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Cellular origin of gastrointestinal stromal tumors : a study of 27 cases .
1		Site -dependent differential KIT and PDGFRA expression in gastric and intestinal gastrointestinal stromal tumors .

PMID: 18193442 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Breast cancer , ovarian gonadoblastoma and cervical cancer in a patient with Peutz-Jeghers Syndrome .
1		BACKGROUND :
2		Peutz-Jeghers Syndrome ( PJS ) is a rare autosomal dominant disorder characterized by gastrointestinal hamartomatous polyps and mucocutaneous pigmentation .
3		Patients with PJS have increased risk for gastrointestinal , breast , and female genital tract cancers .
4		CASE :
5		Multiple genital tract cancers in a 34-year-old woman with PJS are described .
6		The patient , who was admitted to our department with severe vaginal bleeding , was performed right salpingo-oophorectomy because of pure gonadoblastoma in 1996 .
7		In 2003 , concomitant to cervical carcinoma , breast cancer was diagnosed .
8		Patient underwent left modified radical mastectomy due to the invasive papillary carcinoma .
9		The patient received six cycles combination chemotherapy and radiation therapy because of stage IIIB cervical cancer .
10		CONCLUSION(S) :
11		This is the first case report presenting PJS associated with multiple genital tract tumors including ovarian gonadoblastoma in literature .
12		The clinical significance of these tumors in PJS patients has been reviewed .

PMID: 17761947 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Tumor suppressor LKB1 inhibits activation of signal transducer and activator of transcription 3 ( STAT3 ) by thyroid oncogenic tyrosine kinase rearranged in transformation ( RET )/papillary thyroid carcinoma ( PTC ) .
1		Clinicopathologic characteristics of the EGFR gene mutation in non-small cell lung cancer .

PMID: 17212587 (Cell)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Interference with energy metabolism by 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside induces HPV suppression in cervical carcinoma cells and apoptosis in the absence of LKB1 .
1		Carcinogenesis is a dynamic and stepwise process , which is accompanied by a variety of somatic and epigenetic alterations in response to a changing microenvironment .
2		Hypoxic conditions will select for cells that have adjusted their metabolic profile and can maintain proliferation by successfully competing for scarce nutritional and oxygen resources .
3		In the present study we have investigated the effects of energy depletion in the context of HPV ( human papillomavirus )- induced pathogenesis .
4		We show that cervical carcinoma cell lines are susceptible to undergoing either growth arrest or cell death under conditions of metabolic stress induced by AICAR ( 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside ) , a known activator of the AMPK ( AMP-activated protein kinase ) .
5		Our results reveal that AICAR treatment leads to a reduced binding affinity of the transcription factor AP-1 ( activator protein-1 ) and in turn to a selective suppression of HPV transcription .
6	✓	Moreover , the outcome of AICAR on proliferation and survival was dependent on p53 activation and the presence of LKB1 , the major upstream kinase of AMPK .	RO-ASS-GE
7		Using non-malignant LKB1-expressing somatic cell hybrids , which lose expression after tumorigenic segregation , as well as small interfering RNA LKB1 knockdown approaches , we could further demonstrate that expression of LKB1 protects cells from cytotoxicity induced by agents which modulate the ATP/AMP ratio .
8		Since simulation of low energy status can selectively eradicate LKB1-negative cervical carcinoma cells , AICAR may represent a novel drug in the treatment of cervical cancer .

PMID: 16891826 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Peutz-Jeghers Syndrome with multiple genital tract tumors and breast cancer : a case report with a review of literatures .
1		We report here on the multiple genital tract neoplasms in a 41-yr-old Korean woman with Peutz-Jeghers Syndrome ( PJS ) .
2		The patient presented with lower abdominal pain .
3		Her previous medical history was PJS and breast cancer .
4		Pelvic ultrasound showed a multilocular cyst at the right adnexal region , diagnosed as bilateral ovarian mucinous borderline tumors .
5		An ovarian sex cord tumor with annular tubules was incidentally diagnosed together with a minimal deviation adenocarcinoma of the uterine cervix and mucinous metaplasia of both the Fallopian tubal mucosa and the endometrium .
6		Although the cases of multiple genital tract tumors with PJS has rarely been reported , the present case appears to be the first in Korea in which the PJS syndrome was complicated by multiple genital tract tumors and infiltrating carcinoma of the breast .
7		The clinical significance of the multiple genital tract tumors and breast cancer associated with PJS is reviewed .

PMID: 15516847 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Familial pancreatic carcinoma in Jews .
1		Pancreatic cancer ( PC ) is the most fatal of all gastrointestinal cancers , wherein its mortality compares strikingly with its incidence .
2		Unfortunately , 80-90% of PCs are diagnosed in the nonresectable stage .
3		While the lifetime risk of PC in developed countries is approximately 1-3% , it is the fifth most common cause of cancer deaths among both males and females in Western countries .
4		It occurs in excess in Jews .
5		Approximately 5-10% of PC shows familial clustering .
6		Examination of such familial clusters must take into consideration cancers of diverse anatomic sites , such as malignant melanoma in the familial atypical multiple melanoma ( FAMMM ) syndrome due to the CDKN2A ( p16 ) germline mutation , and combinations of colorectal and endometrial carcinoma , ovarian carcinoma , and several other cancers in hereditary nonpolyposis colorectal cancer ( HNPCC ) , which are due to mismatch repair germline mutations , the most common of which are MSH2 and MLH1 .
7		Other hereditary disorders predisposing to PC include Peutz-Jeghers syndrome , due to the STK11 mutation , familial pancreatitis due to the cationic trypsinogen gene , site -specific familial pancreatic cancer which may be due to the 4q32-34 mutation , hereditary breast-ovarian cancer ( HBOC ) syndrome that is due to BRCA2 and possibly some families with HBOC that is due to BRCA1 , familial adenomatous polyposis due to the ATP gene , and ataxia telangiectasia due to the ATM germline mutation .
8		This extant heterogeneity mandates that the physician be knowledgeable about these PC-prone syndromes which play such an important role when considering the differential diagnosis of hereditary PC .
9		Unfortunately , there are no PC screening programs with acceptable sensitivity and specificity .
10		However , the gold standard for screening at this time is endoscopic ultrasound .
11		Clearly , there is a great need for the development of novel screening approaches with acceptable sensitivity and specificity .
12		Further research is needed to elucidate those etiologic factors that contribute to the apparent excess of PC in Ashkenazi Jews .
13		Attention should also be given to the search for mutations predisposing to PC in Jews so that opportunities to learn more about the disease's pathogenesis , as well as screening and control , may take place .

PMID: 15280181 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Genetic alterations in hereditary breast cancer .
1		Genetic linkage studies have led to the identification of highly penetrant genes as the possible cause of inherited cancer risk in many cancer-prone families .
2		Most women with a family history of breast/ovarian cancer have tumors characterized by alterations in particular genes , mainly BRCA1 and BRCA2 , but also CHK2 , ATM , STK11 and others .
3		This paper examines the BRCA1 and BRCA2 genes , focusing on the Italian pattern of mutations .
4		The function of these two genes , classified as tumor suppressors , is linked with key metabolic mechanisms such as DNA damage repair , regulation of gene expression and cell cycle control .
5		The pathological BRCA allelic variants may cause alteration of protein function , transcriptional activity and DNA repair ; accumulation of the defects leads to widespread chromosome instability that may be directly responsible for cancer formation .
6		In fact , mutations in BRCA1 and BRCA2 , conferring a highly increased susceptibility to breast and ovarian cancer , do not lead to cancer by themselves .
7		The current consensus is that these are 'caretaker' genes , which , when inactivated , allow other genetic defects to accumulate .
8		The nature of these other molecular events may define the pathway through which BRCA1 and BRCA2 act .
9		The BRCA mutation spectrum is complex , and the significance of most nucleotide alterations is difficult to understand .
10		Moreover , the mutation pattern seems to be related to ethnicity .
11	Μ	The Italian Consortium of Hereditary Breast and Ovarian Cancer has reviewed 1758 families ; 23% have been found to be carriers of pathogenetic mutations in BRCA1 or BRCA2 .
12	Μ	Founder mutations have been described in geographically restricted areas of Italy ; a regional founder effect has been demonstrated in Italy for the mutations BRCA1 5083del19 and BRCA2 8765delAG , and a probable new founder mutation has been characterized in Tuscany .
13		The presence of founder mutations has practical implications for genetic testing .

PMID: 14751181 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		An unusual admixture of neoplastic and metaplastic lesions of the female genital tract in the Peutz-Jeghers Syndrome .
1		BACKGROUND :
2		Peutz-Jeghers Syndrome ( PJS ) is a rare autosomal dominant condition with variable penetrance characterized by gastrointestinal hamartomatous polyps and mucocutaneous pigmentation .
3		Patients with PJS have an increased risk for breast , gastrointestinal and female genital tract cancers .
4		CASE :
5		Multiple genital tract neoplasms in a 41-year-old Italian woman with PJS are described .
6		The patient presented with abdominal pain due to intussusception .
7		A CT scan of the abdomen also showed a left adnexal mass , diagnosed as ovarian mixed serous and mucinous borderline tumor .
8		An ovarian microscopic sex cord tumor with annular tubules ( SCTAT ) was incidentally diagnosed together with a minimal deviation mucinous adenocarcinoma of the uterine cervix .
9		Also areas of typical hyperplasia of the tubal mucosa with mucinous metaplasia were found .
10		CONCLUSION :
11		This appears to be one of the rare cases reported in literature in which PJS is complicated by multiple and contemporaneous genital tract tumors and rare histological findings .
12		The clinical significance of recurrence of these unusual genital tract tumors and histological alterations in PJS patients is reviewed .

PMID: 14530500 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Genetics and the management of women at high risk for breast cancer .
1		It is estimated that 5%-10% of all breast cancers in women are associated with hereditary susceptibility due to mutations in autosomal dominant genes , such as BRCA1 and BRCA2 , p53 , pTEN , and STK11/LKB1 .
2		Another 15%-20% of female breast cancers occur in women with a family history but without an apparent autosomal dominant inheritance pattern , and are probably due to other genetic factors with environmental influence .
3		Approximately 7%-10% of ovarian cancers occur in women with hereditary susceptibility , primarily secondary to mutations in BRCA1 and BRCA2 , with smaller contributions from mutations in mismatch repair genes associated with the hereditary nonpolyposis colorectal cancer and other , as yet undiscovered , genes .

PMID: 12575811 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Peutz-Jeghers syndrome associated with intestinal intussusception : a case report .
1		A 12-year-old boy visited our hospital with complaints of severe upper abdominal pain and vomiting .
2		Marked tenderness was present in the upper abdomen , and a movable hard tumor the size of a fist was felt there .
3		Because abdominal computed tomography scans revealed invagination , an emergency laparotomy was performed .
4		The small intestine was invaginated over an area measuring 30 cm in length .
5		After the invaginated intestine was restored , a mass was felt in the small intestine , which was resected over an area measuring approximately 10 cm in length .
6		The extracted mass was histopathologically found to be a hamartoma .
7		The patient was diagnosed to have Peutz-Jeghers syndrome ( PJS ) based on the presence of pigmented spots detected on the oral cavity , lips , and toes of both feet .
8		PJS is an autosomal dominant genetic disease associated with melanin pigment spots on the oral mucosa , lips , nasal alae , palm , and soles , as well as hamartomatous polyposis in the alimentary canal .
9		Polyps are often a cause of invagination and ileus in affected patients .
10		Gastrointestinal cancer , uterine cancer , and breast cancer are also seen in patients with PJS .
11		A long-term follow-up is required to prevent invagination and ileus in children and cancer in adults .

PMID: 12533684 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Mutations in the STK11 gene characterize minimal deviation adenocarcinoma of the uterine cervix .
1		Enhancement of paclitaxel-mediated cytotoxicity in lung cancer cells by 17-allylamino geldanamycin : in vitro and in vivo analysis .

PMID: 12144681 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Ovarian tumors associated with multiple endocrine neoplasias and related syndromes ( Carney complex , Peutz-Jeghers syndrome , von Hippel-Lindau disease , Cowden's disease ) .
1		Despite the relatively high prevalence of ovarian cancer ( 1% of American women will develop this disease in their lifetime ) and recent developments in its molecular genetic understanding ( several proto-oncogenes , such as AKT2 and cKRAS , and tumor suppressor genes , such as BRCA1 and BRCA2 , have been implicated ) , little is known about the presence of ovarian tumors and cancer in women already diagnosed with other familial multiple tumor syndromes .
2		In this review , we focus on the possible association of ovarian tumors with multiple endocrine neoplasias ( MENs ) and their related syndromes , such as Carney complex ( CNC ) , Peutz-Jeghers syndrome ( PJS ) , von Hippel-Lindau disease ( VHLD ) , and Cowden's disease ( CD ) .
3		These conditions recently have been molecularly elucidated , and some of the genes responsible for them ( including STK11/LKB1 and PTEN , the genes responsible for PJS and CD , respectively ) have already been investigated in series of sporadic ovarian lesions , mostly carcinomas .
4		A brief description of each disease is followed by a literature search for affected patients with ovarian tumors ; we review our own experience with CNC patients and ovarian tumors .
5		An association between PJS and CNC and ovarian neoplasms seems likely ; carcinoids of the ovary may occur in patients with MEN 1 .
6		Only few patients with CD and VHLD have any ovarian pathology , but PTEN , the CD gene has been investigated in sporadic ovarian tumors .
7		The aim of the present report is to alert clinicians who care for patients with MENs , CNC , PJS , VHLD , CD , and other syndromes for possible associations between various types of ovarian tumors and these conditions .

PMID: 11561603 (Patient)   Terms: prospective
Sent#	Symbols	Sentence	Mnemonics
0		Familial pancreatic cancer .
1		Pancreatic cancer is the fourth leading cause of cancer death in both men and women in the United States and will be responsible for an estimated 28,900 deaths in 2001 .
2		Relatively little is known of its etiology , and the only well-established risk factor is cigarette smoking .
3		Studies over the past 3 decades have shown that 4%-16% of patients with pancreatic cancer have a family history of the disease .
4		A small fraction of this aggregation can be accounted for in inherited cancer syndromes , including familial atypical multiple-mole melanoma , Peutz-Jeghers syndrome , hereditary breast-ovarian cancer , hereditary pancreatitis , and hereditary nonpolyposis colorectal cancer .
5		These syndromes arise as a result of germline mutations in the BRCA2 , pl6 ( familial atypical multiple-mole melanoma ) , mismatch repair ( hereditary nonpolyposis colorectal cancer ) , and STK11 ( Peutz-Jeghers syndrome ) genes .
6		In addition , hereditary plays a role in predisposing certain patients with apparently sporadic pancreatic cancer .
7		Many patients with pancreatic cancers caused by a germline mutation in a cancer-causing gene do not have a pedigree that is suggestive of a familial cancer syndrome .
8		A recent prospective analysis of the pedigrees in the National Familial Pancreatic Tumor Registry found that individuals with a family history of pancreatic cancer in multiple first-degree relatives have a high risk of pancreatic cancer themselves .
9		The identification of such high-risk individuals will help clinicians target screening programs and develop preventive interventions with the hope of reducing the mortality of pancreatic cancer in these families .

PMID: 11352305 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Hamartomatous polyposis syndromes : molecular genetics , neoplastic risk , and surveillance recommendations .
1		UNLABELLED :
2		Hamartomatous polyposis syndromes are characterized by an overgrowth of cells or tissues native to the area in which they normally occur .
3		Juvenile polyposis syndrome ( JPS ) results from germ - line mutations in the SMAD-4 gene ( 18q211 ) that encodes for an enzyme involved in transforming growth factor beta ( TGF-beta ) signal transduction .
4		The increased neoplastic risk may result from SMAD-4 mutations in the stromal component , which stimulate epithelial dysplasia and progression to invasive malignancy .
5		Peutz-Jeghers syndrome ( PJS ) is associated with germ - line mutations in the LKB1 gene ( 19p133 ) that encodes a multifunctional serine-threonine kinase .
6		These mutations occur in the epithelial component , suggesting a direct tumor suppressor effect .
7		Patients are at an increased risk of intestinal and extraintestinal malignancies , including breast , pancreatic , ovarian , testicular , and cervical cancer .
8		Cowden's disease is associated with germ - line mutations in the PTEN gene ( 10q22-23 ) and an increased risk of breast and thyroid malignancies .
9		Ruvalcaba-Myhre-Smith syndrome is less common ; controversy suggests that it may represent a variant of Cowden's disease .
10		CONCLUSIONS :
11		Genetic alterations underlying hamartomatous polyposis syndromes are diverse .
12		Carcinogenesis may result from either germ - line mutations in the stroma ( JPS ) or as a direct result of functional deletion of tumor suppressor genes (PJS) .
13		Diagnosis depends on clinical presentation and patterns of inheritance within families .
14		Suggested surveillance guidelines for the proband and first-degree relatives are outlined .

PMID: 10389980 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Allele loss and mutation screen at the Peutz-Jeghers ( LKB1 ) locus ( 19p13.3 ) in sporadic ovarian tumours .
1		Germline mutations in the LKB1 (STK11) gene ( chromosome sub-band 19p133 ) cause characteristic hamartomas and pigmentation to develop in patients with Peutz-Jeghers syndrome .
2		Peutz-Jeghers syndrome carries an overall risk of cancer that may be up to 20 times that of the general population and Peutz-Jeghers patients are at increased risk of benign and malignant ovarian tumours , particularly granulosa cell tumours .
3		Loss of heterozygosity ( allele loss , LOH ) has been reported in about 50% of ovarian cancers on 19p13.3 .
4		LKB1 is therefore a candidate tumour suppressor gene for sporadic ovarian tumours .
5	Μ	We found allele loss at the marker D19S886 ( 19p133 ) in 12 of 49 ( 24% ) sporadic ovarian adenocarcinomas .
6		Using SSCP analysis , we screened ten ovarian cancers with LOH , 35 other ovarian cancers and 12 granulosa cell tumours of the ovary for somatic mutations in LKB1 .
7	Μ	No variants were detected in any of the adenocarcinomas .
8	Μ	Two mutations were detected in one of the granulosa cell tumours : a mis-sense mutation affecting the putative 'start' codon ( ATG -->ACG , M1T ) ; and a silent change in exon 7 ( CTT -->CTA , leucine ) .
9		Like BRCA1 and BRCA2 , therefore , it appears that LKB1 mutations can cause ovarian tumours when present in the germline , but occur rarely in the soma .
10		The allele loss on 19p13.3 in ovarian cancers almost certainly targets a different gene from LKB1 .

PMID: 10379360 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		The molecular basis and clinical aspects of Peutz-Jeghers syndrome .
1		Peutz-Jeghers syndrome ( PJS ) is a classic , but not widely known hereditary trait [1,2] .
2		Its clinical hallmarks are intestinal hamartomatous polyposis and melanin pigmentation of the skin and mucous membranes .
3		In addition , PJS predisposes to cancer [3,4] .
4		The most common malignancies are small intestinal , colorectal , stomach and pancreatic adenocarcinomas .
5		Other cancer types that probably occur in excess in PJS families include breast and uterine cervical cancer , as well as testicular and ovarian sex cord tumors .
6		The relative risk of cancer may be as high as 18 times that of the general population , and the cancer patients' prognosis is reduced .
7		Recently , the predisposing locus was mapped to 19p13.3 using a novel method [5] .
8		Subsequently , the causative gene was shown to be LKB1 (aka STK11) , a serine/threonine kinase of unknown function [6] .
9	✓	Although preliminary reports seem to suggest a minor role for LKB1 in sporadic tumorigenesis [7-12] , further investigations are needed .	GE-INV-RO

PMID: 10079245 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		LKB1 somatic mutations in sporadic tumors .
1		Germline mutations of LKB1/Peutz-Jeghers syndrome gene predispose carriers to hamartomatous polyposis of the gastrointestinal tract as well as to cancer of different organ systems .
2		Although Peutz-Jeghers syndrome patients frequently present with neoplasms of the colon , stomach , small intestine , pancreas , breast , ovaries , and cervix , somatic mutations appear to be rare in the sporadic tumor types thus far studied ( colorectal , gastric , testicular , and breast cancers ) .
3	Μ	To evaluate whether somatic mutations of LKB1 contribute to the tumorigenesis of yet unstudied tumor types , we screened 14 cell lines and 129 tumor specimens from different cancers for a genetic defect in LKB1 .
4		Six melanoma and eight myeloma cell lines were scrutinized for LKB1 somatic mutations by genomic sequencing .
5	Μ	No changes were found in the coding LKB1 sequence and exon/intron boundaries .
6	Μ	Next , we analyzed 12 pancreatic , 8 gastric , 12 ovarian granulosa cell , 26 cervical , 28 lung , 24 soft tissue , and 19 renal tumors by single - strand conformational polymorphism analysis .
7	Μ	Three changes in LKB1 coding nucleotide sequence were identified .
8	Μ	One base pair deletion at A957 and G958 substitution by T occurred in a cervical adenocarcinoma sample , resulting in a frameshift and premature stop codon at position 335 .
9	Μ	Substitution of A581 by T occurred in a lung adenocarcinoma sample , resulting in the change of aspartic acid at position 194 to valine .
10	Μ	A loss of another allele was detected in this sample .
11		One silent change , C1257T , was found in a pancreatic carcinoma sample .
12		The changes were not present in the matched normal tissue DNA samples .
13		Our results suggest that mutational inactivation of LKB1 is a rare event in most sporadic tumor types .

PMID: 7523322 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Oxyphilic Sertoli cell tumor of the ovary : a report of three cases , two in patients with the Peutz-Jeghers syndrome .
1		Three women , aged 19 , 21 , and 30 years , two with the Peutz-Jeghers syndrome ( PJS ) , had unilateral ovarian tumors composed of Sertoli cells with abundant eosinophilic cytoplasm .
2		Electron microscopical and immunohistochemical examinations in one case supported the diagnosis of a sex cord tumor .
3		Two patients are well 3 and 20 months postoperatively ; the third was well for 15 years when recurrent tumor involving multiple intraabdominal sites was discovered .
4		The occurrence of two of these tumors in patients with PJS and the known increased frequency of sex cord tumors in patients with this syndrome indicate an association .
5		Sertoli cell tumor should be included in the differential diagnosis of oxyphilic ovarian tumors , particularly if there is a tubular pattern .