The genetic prediction of risk for gynecologic cancers.

Salient to the intent of personalized medicine, hereditary cancer syndromes present significant opportunities in the treatment and prevention of some gynecologic cancers. Mutations in BRCA1, BRCA2, and DNA mismatch repair genes: MLH1, MSH2, MSH6, and PMS2 are important causal agents in hereditary breast and ovarian cancer (HBOC) and Lynch syndromes. Though they only account for an estimated 10-18% of ovarian, tubal, peritoneal, and endometrial cancer cases, inherited cancers are imminently preventable if mutation carriers are identified in a timely manner. Population level screening is currently impractical due to low prevalence of disease, cost of testing, and ethical issues associated with testing, so diagnosis of these mutations is limited. Being affected by one of the heritable gynecologic malignancies is a logical entry point into the genetic counseling and testing pipeline for the patient and her family members. Thus, gynecologic cancer providers are uniquely positioned to diagnose germline mutations that can inform prognosis and treatment for their patients in addition to enabling prevention for patients' cancer-unaffected blood relatives, or "previvors". The purpose of this review is to describe our current perspective on testing for and implications of heritable cancer syndromes in the women with ovarian, tubal, peritoneal, and endometrial cancers.

Randall LM ，Pothuri B 《-》

Identification of germline genetic mutations in patients with pancreatic cancer.

Pancreatic adenocarcinoma (PAC) is part of several cancer predisposition syndromes; however, indications for genetic counseling/testing are not well-defined. In the current study, the authors sought to determine mutation prevalence and characteristics that are predictive of an inherited predisposition for PAC. A total of 175 consecutive patients with PAC who underwent clinical genetics assessment at Memorial Sloan Kettering Cancer Center between 2011 and 2014 were identified. Clinical data, family history, and germline results were evaluated. Among 159 patients with PAC who pursued genetic testing, 24 pathogenic mutations were identified (15.1%; 95% confidence interval, 9.5%-20.7%), including BRCA2 (13 mutations), BRCA1 (4 mutations), p16 (2 mutations), PALB2 (1 mutation), and Lynch syndrome (4 mutations). BRCA1/BRCA2 prevalence was 13.7% in Ashkenazi Jewish (AJ) patients (95 patients) and 7.1% in non-AJ patients (56 patients). In AJ patients with a strong, weak, or absent family history of BRCA-associated cancers, the mutation prevalence was 16.7%, 15.8%, and 7.4%, respectively. The mean age at the time of diagnosis in all mutation carriers was 58.5 years (range, 45-75 years) compared with 64 years (range, 27-87 years) in those not carrying a mutation (P = .02). Although BRCA2 was the most common mutation identified, no patients with early-onset PAC (diagnosed at age ≤ 50 years) harbored a BRCA2 mutation and the mean age at diagnosis in BRCA2 carriers was equivalent to that of individuals who were not mutation carriers (P = .34). Mutation prevalence in patients with early-onset disease (21 patients) was 28.6%, including BRCA1 (2 mutations), p16 (2 mutations), MSH2 (1 mutation), and MLH1 (1 mutation). Mutations in BRCA2 account for > 50% of patients with PAC with an identified susceptibility syndrome. AJ patients were found to have high BRCA1/BRCA2 prevalence regardless of personal/family history, suggesting that ancestry alone indicates a need for genetic evaluation. With the exception of BRCA2-associated PAC, an inherited predisposition for PAC is associated with an earlier age at PAC diagnosis, suggesting that this subset of patients may also represent a population warranting further evaluation.

Salo-Mullen EE ，O'Reilly EM ，Kelsen DP ，Ashraf AM ，Lowery MA ，Yu KH ，Reidy DL ，Epstein AS ，Lincoln A ，Saldia A ，Jacobs LM ，Rau-Murthy R ，Zhang L ，Kurtz RC ，Saltz L ，Offit K ，Robson ME ，Stadler ZK ... -  《-》

Lack of referral for genetic counseling and testing in BRCA1/2 and Lynch syndromes: a nationwide study based on 240,134 consultations and 134,652 genetic tests.

Pujol P ，Lyonnet DS ，Frebourg T ，Blin J ，Picot MC ，Lasset C ，Dugast C ，Berthet P ，de Paillerets BB ，Sobol H ，Grandjouan S ，Soubrier F ，Buecher B ，Guimbaud R ，Lidereau R ，Jonveaux P ，Houdayer C ，Giraud S ，Olschwang S ，Nogue E ，Galibert V ，Bara C ，Nowak F ，Khayat D ，Nogues C ... -  《-》

Consideration of hereditary nonpolyposis colorectal cancer in BRCA mutation-negative familial ovarian cancers.

Inherited mutations account for approximately 10% of all epithelial ovarian cancers. Breast cancer (BRCA1 and BRACA2) gene mutations are responsible for up to 85% of inherited breast and/or ovarian cancer. Another condition that has been associated with ovarian cancer is hereditary nonpolyposis colorectal cancer syndrome (HNPCC), which carries a lifetime risk of up to 13% for ovarian cancer. The objective of this study was to determine the incidence of HNPCC-related gene mutations in patients with familial ovarian cancer who previously tested negative for BRCA1 and BRCA2 gene mutations. Seventy-seven probands were identified who had familial ovarian cancer and negative BRCA gene mutation testing. Their pedigrees were analyzed for HNPCC syndrome. DNA samples underwent gene sequencing and Southern blot analysis for mutations in the 3 most common HNPCC-associated genes: mutL homolog 1 (MLH1) and mutS homolog 2 (MSH2) with reflex testing for MSH6 if tests for the first 2 genes were negative. None of the probands met Amsterdam criteria for the clinical diagnosis of HNPCC. DNA testing revealed 2 patients (2.6%) with deleterious mutations in the MSH2 gene. An additional 8 patients (10.4%) had substitutions in either the MLH1 gene or the MSH2 gene that were classified as variants of uncertain significance. If Amsterdam criteria were expanded to include ovarian cancer, then 15 of 77 patients (19.5%) would have met these expanded criteria. One deleterious mutation was noted in this group, yielding a mutation incidence of 6.7%. This percentage may be even higher if any of the identified variants of uncertain significance are confirmed to be deleterious. HNPCC should be considered when evaluating patients with suspected hereditary ovarian cancer who have had negative BRCA mutation testing.

South SA ，Vance H ，Farrell C ，DiCioccio RA ，Fahey C ，Piver MS ，Rodabaugh KJ ... -  《CANCER》

Prevalence of mutations in BRCA and MMR genes in patients affected with hereditary endometrial cancer.

Vietri MT ，D'Elia G ，Caliendo G ，Casamassimi A ，Federico A ，Passariello L ，Cioffi M ，Molinari AM ... -  《-》