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Segev Y.,Womens College Research Institute | Segev Y.,University of Toronto | Pal T.,Womens College Research Institute | Rosen B.,University of Toronto | And 8 more authors.
International Journal of Gynecological Cancer

Objective: The objective of this study was to evaluate the association between microsatellite instability (MSI) status and (1) ovarian cancer risk factors and (2) the distribution of the specific histologic subtypes in a population-based sample of epithelial ovarian cancers. Methods: Participants were drawn from 3 population-based studies of primary epithelial ovarian cancer. Tumor DNA was analyzed using 5 standardized microsatellite markers to assess MSI status. Patients were divided into 3 groups (MSI-high, MSI-low, and MSIstable) according to National Cancer Institute criteria. We compared the prevalence of specific known risk and protective factors among the 3 subgroups, including body mass index, smoking history, parity, BRCA1 and BRCA2 mutation status, past oral contraceptive use, and tubal ligation. Similarly, we compared the distribution of the histologic subtypes among the 3 subgroups. Results: A total of 917 ovarian cancer patients were included. One hundred twenty-seven (13.8%) cancers were MSI-high. Subgroup analyses according to smoking, body mass index, parity, past oral contraceptive use, and past tubal ligation did not reveal any statistically significant differences among the groups. Among the 29 patients with BRCA1 mutations, 20.7% had MSI-high cancers compared with 5.9% among 17 BRCA2-mutation patients. The proportions of different ovarian cancer histologic findings among the variousMSI subgroups were similar. Conclusions: The prevalence of risk and protective factors among ovarian cancer patients is similar for cancers with and withoutMSI. The distributions ofMSI do not differ significantly among ovarian cancers with different histologic findings.Ovarian cancer patients with BRCA1 mutations had a 21%rate ofMSI-high tumors, comparedwith 6%among patients with BRCA2 mutations, but this difference was not statistically significant. © 2013 by IGCS and ESGO. Source

Background:Germline mutations in BRCA1 and BRCA2 increase the susceptibility to develop breast and ovarian cancers as well as increase the risk of some other cancers. Primary objective was to estimate the risk of leukaemia in BRCA1 and BRCA2 mutation carriers.Methods:We followed 7243 women with a BRCA1 or a BRCA2 mutation for incident cases of leukaemia. We used the standardised incidence ratio (SIR) to estimate the relative risk of leukaemia, according to mutation and history of breast cancer.Results:We identified five incident cases of leukaemia (two BRCA1, three BRCA2). All five women had a prior history of breast cancer and four had received chemotherapy. The mean time from breast cancer diagnosis to the development of leukaemia was 10.2 years (range 3–18 years). The SIR for BRCA1 carriers was 0.66 (95% CI: 0.11–2.19, P=0.61) and the SIR for BRCA2 carriers was 2.42 (95% CI: 0.61–6.58, P=0.17). The SIR was significantly higher than expected for women with a BRCA2 mutation and breast cancer (SIR=4.76, 95% CI:1.21–12.96, P=0.03), in particular for women who received chemotherapy (SIR=8.11, 2.06–22.07, P=0.007).Conclusions:We observed an increased risk of leukaemia in women with a BRCA2 mutation who receive chemotherapy for breast cancer.British Journal of Cancer advance online publication 17 March 2016; doi:10.1038/bjc.2016.58 www.bjcancer.com. © 2016 Cancer Research UK Source

Phelan C.M.,Moffitt Cancer Center | Iqbal J.,Familial Breast Cancer Research | Lynch H.T.,Creighton University | Lubinski J.,Pomeranian Medical University | And 16 more authors.
British Journal of Cancer

Background:The BRCA1 and BRCA2 genes confer increased susceptibility to breast and ovarian cancer and to a spectrum of other cancers. There is controversy regarding the risk of colorectal cancer conferred by germline mutations in these two genes.Methods:We followed 7015 women with a BRCA mutation for new cases of colorectal cancer. Incidence rates in carriers were compared with population-specific incidence rates, and standardised incidence ratios (SIRs) were estimated. The expected numbers of cancers were computed by multiplying person-years at risk by the appropriate age-, sex-and country-specific incidence rates from the five countries.Results:Twenty-one incident colorectal cancer cases were observed among all mutation carriers, compared with 23.6 cases expected. The SIR for BRCA1 carriers was 0.92 (95% confidence interval (CI), 0.54-1.40, P=0.7) and for BRCA2 carriers was 0.82 (95% CI, 0.30-1.81, P=0.7). The SIR for colon cancer was 3.81 (95% CI 1.77-7.23) for women below the age of 50 years (both genes combined) and was 0.60 (95% CI 0.33-1.00) for women aged 50 years and above.Conclusion:The risk of colorectal cancer is increased in female carriers of BRCA1 mutations below the age of 50 years but not in women with BRCA2 mutations or in older women. © 2014 Cancer Research UK. Source

Iqbal J.,Familial Breast Cancer Research | Ragone A.,Pomeranian Medical University | Lubinski J.,Creighton University | Lynch H.T.,Norwegian Radium Hospital | And 15 more authors.
British Journal of Cancer

Background:Germline mutations in BRCA1 and BRCA2 predispose to pancreatic cancer. We estimated the incidence of pancreatic cancer in a cohort of female carriers of BRCA1 and BRCA2 mutation. We also estimated survival rates in pancreatic cancer cases from families with a BRCA mutation.Methods:We followed 5149 women with a mutation for new cases of pancreatic cancer. The standardised incidence ratios (SIR) for pancreatic cancer were calculated based on age group and country of residence. We also reviewed the pedigrees of 8140 pedigrees with a BRCA1 or a BRCA2 mutation for those with a case of pancreatic cancer. We recorded the year of diagnosis and the year of death for 351 identified cases.Results:Eight incident pancreatic cancer cases were identified among all mutation carriers. The SIR for BRCA1 carriers was 2.55 (95% CI=1.03-5.31, P=0.04) and for BRCA2 carriers was 2.13 (95% CI=0.36-7.03, P=0.3). The 5-year survival rate was 5% for cases from a BRCA1 family and 4% for cases from a BRCA2 family.Conclusion:The risk of pancreatic cancer is approximately doubled in female BRCA carriers. The poor survival in familial pancreatic cancer underscores the need for novel anti-tumoural strategies. © 2012 Cancer Research UK All rights reserved. Source

Sopik V.,Familial Breast Cancer Research | Phelan C.,Moffitt Cancer Center | Cybulski C.,Pomeranian Medical University | Narod S.A.,Familial Breast Cancer Research
Clinical Genetics

Women who carry a BRCA1 or BRCA2 mutation are at high risk of breast and ovarian cancer, and may be at moderately increased risk of other cancer types. This review examines studies to date that have evaluated the risk of BRCA1 and BRCA2 mutations for colorectal cancer. Accurate knowledge of colorectal cancer risk in BRCA1/2 carriers is important, because colonoscopy screening can prevent colorectal cancer through the removal of adenomatous polyps. Most studies that have identified an increased risk for colorectal cancer in BRCA1/2 mutation carriers were in high-risk cancer families, while studies that found no association were conducted in specific populations and involved the analysis of founder mutations. A recent prospective study of 7015 women with a BRCA1 or BRCA2 mutation identified significant fivefold increased risk of colorectal cancer among BRCA1 mutation carriers younger than 50 years [standardized incidence ratio (SIR): 4.8; 95% CI: 2.2-9], but not in women with a BRCA2 mutation or in older women. Based on this evidence, women with BRCA1 mutations should be counseled about their increased risk for early-onset colorectal cancer, and offered colonoscopy at 3- to 5-year intervals between the ages of 40 and 50 years, and should follow population guidelines thereafter. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Source

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