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Spontaneous and therapeutic abortions and the risk of breast cancer among BRCA mutation carriers.

ABSTRACT: INTRODUCTION: BRCA1 and BRCA2 mutation carriers are at increased risk for developing both breast and ovarian cancer. It has been suggested that carriers of BRCA1/2 mutations may also be at increased risk of having recurrent (three or more) miscarriages. Several reproductive factors have been shown to influence the risk of breast cancer in mutation carriers, but the effects of spontaneous and therapeutic abortions on the risk of hereditary breast cancer risk have not been well studied to date. METHODS: In a matched case-control study, the frequencies of spontaneous abortions were compared among 1,878 BRCA1 mutation carriers, 950 BRCA2 mutation carriers and 657 related non-carrier controls. The rates of spontaneous and therapeutic abortions were compared for carriers with and without breast cancer. RESULTS: There was no difference in the rate of spontaneous abortions between carriers of BRCA1 or BRCA2 mutations and non-carriers. The number of spontaneous abortions was not associated with breast cancer risk among BRCA1 or BRCA2 mutation carriers. However, BRCA2 carriers who had two or more therapeutic abortions faced a 64% decrease in the risk of breast cancer (odds ratio = 0.36; 95% confidence interval 0.16-0.83; p = 0.02). CONCLUSION: Carrying a BRCA1 or BRCA2 mutation is not a risk factor for spontaneous abortions and spontaneous abortions do not appear to influence the risk of breast cancer in carriers of BRCA1 or BRCA2 mutations. However, having two or more therapeutic abortions may be associated with a lowered risk of breast cancer among BRCA2 carriers.

SUBMITTER: Friedman E

PROVIDER: S-EPMC1557713 | biostudies-literature | 2006

REPOSITORIES: biostudies-literature

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Spontaneous and therapeutic abortions and the risk of breast cancer among BRCA mutation carriers.

Friedman Eitan E Kotsopoulos Joanne J Lubinski Jan J Lynch Henry T HT Ghadirian Parviz P Neuhausen Susan L SL Isaacs Claudine C Weber Barbara B Foulkes William D WD Moller Pal P Rosen Barry B Kim-Sing Charmaine C Gershoni-Baruch Ruth R Ainsworth Peter P Daly Mary M Tung Nadine N Eisen Andrea A Olopade Olufunmilayo I OI Karlan Beth B Saal Howard M HM Garber Judy E JE Rennert Gad G Gilchrist Dawna D Eng Charis C Offit Kenneth K Osborne Michael M Sun Ping P Narod Steven A SA

Breast cancer research : BCR 20060321 2

<h4>Introduction</h4>BRCA1 and BRCA2 mutation carriers are at increased risk for developing both breast and ovarian cancer. It has been suggested that carriers of BRCA1/2 mutations may also be at increased risk of having recurrent (three or more) miscarriages. Several reproductive factors have been shown to influence the risk of breast cancer in mutation carriers, but the effects of spontaneous and therapeutic abortions on the risk of hereditary breast cancer risk have not been well studied to d ...[more]

PMID: 16563180

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Project description:Identification of BRCA mutations in breast cancer (BC) patients influences treatment and survival and may be of importance for their relatives. Testing is often restricted to women fulfilling high-risk criteria. However, there is limited knowledge of the sensitivity of such a strategy, and of the clinical aspects of BC caused by BRCA mutations in less selected BC cohorts. The aim of this report was to address these issues by evaluating the results of BRCA testing of BC patients in South-Eastern Norway.1371 newly diagnosed BC patients were tested with sequencing and Multi Ligation Probe Amplification (MLPA). Prevalence of mutations was calculated, and BC characteristics among carriers and non-carriers compared. Sensitivity and specificity of common guidelines for BRCA testing to identify carriers was analyzed. Number of identified female mutation positive relatives was evaluated.A pathogenic BRCA mutation was identified in 3.1%. Carriers differed from non-carriers in terms of age at diagnosis, family history, grade, ER/PR-status, triple negativity (TNBC) and Ki67, but not in HER2 and TNM status. One mutation positive female relative was identified per mutation positive BC patient. Using age of onset below 40 or TNBC as criteria for testing identified 32-34% of carriers. Common guidelines for testing identified 45-90%, and testing all below 60 years identified 90%. Thirty-seven percent of carriers had a family history of cancer that would have qualified for predictive BRCA testing. A Variant of Uncertain Significance (VUS) was identified in 4.9%.Mutation positive BC patients differed as a group from mutation negative. However, the commonly used guidelines for testing were insufficient to detect all mutation carriers in the BC cohort. Thirty-seven percent had a family history of cancer that would have qualified for predictive testing before they were diagnosed with BC. Based on our combined observations, we suggest it is time to discuss whether all BC patients should be offered BRCA testing, both to optimize treatment and improve survival for these women, but also to enable identification of healthy mutation carriers within their families. Health services need to be aware of referral possibility for healthy women with cancer in their family.

Project description:Ku80 is a subunit of the Ku heterodimer that binds to DNA double-strand break ends as part of the non-homologous end joining (NHEJ) pathway. Ku80 is also involved in homologous recombination (HR) via its interaction with BRCA1. Ku80 is encoded by the XRCC5 gene that contains a variable number tandem repeat (VNTR) insertion in its promoter region. Different VNTR genotypes can alter XRCC5 expression and affect Ku80 production, thereby affecting NHEJ and HR pathways. VNTR polymorphism is associated with multiple types of sporadic cancer. In this study, we investigated its potential association with familial breast cancer at the germline level. Using PCR, PAGE, Sanger sequencing, and statistical analyses, we compared VNTR genotypes in the XRCC5 promoter between healthy individuals and three types of familial breast cancer cases: mutated BRCA1 (BRCA1 (+)), mutated BRCA2 (BRCA2 (+)), and wild-type BRCA1/BRCA2 (BRCAx). We observed significant differences of VNTR genotypes between control and BRCA1 (+) group (P?<?0.0001) and BRCA2 (+) group (P?=?0.0042) but not BRCAx group (P?=?0.2185), and the differences were significant between control and cancer-affected BRCA1 (+) cases (P?<?0.0001) and BRCA2 (+) cases (P?=?0.0092) but not cancer-affected BRCAx cases (P?=?0.4251). Further analysis indicated that 2R/2R (OR?=?1.94, 95%CI?=?1.26-2.95, P?=?0.0096) and 2R/1R (OR?=?1.58, 95%CI?=?1.11-2.26, P?=?0.0388) were associated with increased risk but 1R/1R (OR?=?0.55, 95%CI?=?0.35-0.84, P?=?0.0196) and 1R/0R (OR?=?0, 95%CI?=?0-0.29, P?=?0.0012) were associated with decreased risk in cancer-affected BRCA1 (+) group; 2R/1R (OR?=?1.94, 95%CI?=?1.14-3.32, P?=?0.0242) was associated with increased risk in cancer-affected BRCA2 (+) group. No correlation was observed for the altered risk between cancer-affected or -unaffected carriers and between different age of cancer diagnosis in cancer-affected carriers. The frequently observed VNTR association with in BRCA1 (+) and BRCA2 (+) breast cancer group indicates that VNTR polymorphism in the XRCC5 promoter is associated with altered risk of breast cancer in BRCA1 (+) and BRCA2 (+) carriers.

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Spontaneous and therapeutic abortions and the risk of breast cancer among BRCA mutation carriers.

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Spontaneous and therapeutic abortions and the risk of breast cancer among BRCA mutation carriers.

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