Dataset Information

BRCA Mutations Increase Fertility in Families at Hereditary Breast/Ovarian Cancer Risk.

ABSTRACT:

Background

Deleterious mutations in the BRCA genes are responsible for a small, but significant, proportion of breast and ovarian cancers (5 - 10 %). Proof of de novo mutations in hereditary breast/ovarian cancer (HBOC) families is rare, in contrast to founder mutations, thousands of years old, that may be carried by as much as 1 % of a population. Thus, if mutations favoring cancer survive selection pressure through time, they must provide advantages that compensate for the loss of life expectancy.

Method

This hypothesis was tested within 2,150 HBOC families encompassing 96,325 individuals. Parameters included counts of breast/ovarian cancer, age at diagnosis, male breast cancer and other cancer locations. As expected, well-known clinical parameters discriminated between BRCA-mutated families and others: young age at breast cancer, ovarian cancer, pancreatic cancer and male breast cancer. The major fertility differences concerned men in BRCA-mutated families: they had lower first and mean age at paternity, and fewer remained childless. For women in BRCA families, the miscarriage rate was lower. In a logistic regression including clinical factors, the different miscarriage rate and men's mean age at paternity remained significant.

Results

Fertility advantages were confirmed in a subgroup of 746 BRCA mutation carriers and 483 non-carriers from BRCA mutated families. In particular, female carriers were less often nulliparous (9.1 % of carriers versus 16.0 %, p = 0.003) and had more children (1.8 ± 1.4 SD versus 1.5 ± 1.3, p = 0.002) as well as male carriers (1.7 ± 1.3 versus 1.4 ± 1.3, p = 0.024).

Conclusion

Although BRCA mutations shorten the reproductive period due to cancer mortality, they compensate by improving fertility both in male and female carriers.

SUBMITTER: Kwiatkowski F

PROVIDER: S-EPMC4457526 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Publications

BRCA Mutations Increase Fertility in Families at Hereditary Breast/Ovarian Cancer Risk.

Kwiatkowski Fabrice F Arbre Marie M Bidet Yannick Y Laquet Claire C Uhrhammer Nancy N Bignon Yves-Jean YJ

PloS one 20150605 6

<h4>Background</h4>Deleterious mutations in the BRCA genes are responsible for a small, but significant, proportion of breast and ovarian cancers (5 - 10 %). Proof of de novo mutations in hereditary breast/ovarian cancer (HBOC) families is rare, in contrast to founder mutations, thousands of years old, that may be carried by as much as 1 % of a population. Thus, if mutations favoring cancer survive selection pressure through time, they must provide advantages that compensate for the loss of life ...[more]

PMID: 26047126

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Project description:BACKGROUND:BRCA1 and BRCA2 mutations explain approximately one-fifth of the inherited susceptibility in high-risk Finnish hereditary breast and ovarian cancer (HBOC) families. EMSY is located in the breast cancer-associated chromosomal region 11q13. The EMSY gene encodes a BRCA2-interacting protein that has been implicated in DNA damage repair and genomic instability. We analysed the role of germline EMSY variation in breast/ovarian cancer predisposition. The present study describes the first EMSY screening in patients with high familial risk for this disease. METHODS:Index individuals from 71 high-risk, BRCA1/2-negative HBOC families were screened for germline EMSY sequence alterations in protein coding regions and exon-intron boundaries using Sanger sequencing and TaqMan assays. The identified variants were further screened in 36 Finnish HBOC patients and 904 controls. Moreover, one novel intronic deletion was screened in a cohort of 404 breast cancer patients unselected for family history. Haplotype block structure and the association of haplotypes with breast/ovarian cancer were analysed using Haploview. The functionality of the identified variants was predicted using Haploreg, RegulomeDB, Human Splicing Finder, and Pathogenic-or-Not-Pipeline 2. RESULTS:Altogether, 12 germline EMSY variants were observed. Two alterations were located in the coding region, five alterations were intronic, and five alterations were located in the 3'untranslated region (UTR). Variant frequencies did not significantly differ between cases and controls. The novel variant, c.2709 + 122delT, was detected in 1 out of 107 (0.9%) breast cancer patients, and the carrier showed a bilateral form of the disease. The deletion was absent in 897 controls (OR = 25.28; P = 0.1) and in 404 breast cancer patients unselected for family history. No haplotype was identified to increase the risk of breast/ovarian cancer. Functional analyses suggested that variants, particularly in the 3'UTR, were located within regulatory elements. The novel deletion was predicted to affect splicing regulatory elements. CONCLUSIONS:These results suggest that the identified EMSY variants are likely neutral at the population level. However, these variants may contribute to breast/ovarian cancer risk in single families. Additional analyses are warranted for rare novel intronic deletions and the 3'UTR variants predicted to have functional roles.

Project description:BACKGROUND:Genetic testing for BRCA1/2 genes is widely used as a strategy to reduce incidence and morbidity of hereditary breast and ovarian cancer (HBOC). The purpose of this study is to analyse the demographic and molecular characteristics of BRCA germline mutations in Navarra, Spain, and to investigate the clinical profile of hereditary and sporadic breast cancer (BC) and ovarian cancer (OC) in the Community. METHODS:The study includes 1246 individuals assessed for BRCA1/2 genetic testing in Navarra, during 2000-2016, and a cohort of BC (n?=?4384) and OC (n?=?561) from the population-based Navarra Cancer Registry. Distribution and molecular characteristics of BRCA1/2 mutations, as well as, comparative analysis of the clinical course, pathologic features and overall survival (OS) of patients in different risk groups were investigated. RESULTS:BRCA mutation detection rate was 16%, with higher proportion (63%) of BRCA2 families. Nineteen per cent of mutations were recurrent, one of which, BRCA2 c.6024dupG, showed high association to OC. BRCA carriers had double risk (95% CI?=?1.04-4.33) of developing multiple malignancies than low risk families and were diagnosed at a much earlier age (16.6 and 11.7?years difference for BC and OC, respectively) when compared to the general population. For BC, BRCA carriers showed a more advanced histological stage, higher risk of bilateral neoplasms (OR?=?4.3; 95% CI?=?1.3-11.4, for BRCA2 carriers) and worse OS rate at 5-, 10- and 15- years, than women with sporadic tumors. For OC, over 70% of patients of all risk groups showed advanced stages at diagnosis, with the highest among BRCA1 carriers (91%). Furthermore, they also had higher probability of developing ovarian bilateral tumors (OR?=?7.8, 95% CI?=?1.7-55.7, for BRCA1 carriers) than the general population. Five-year OS rate was worse among women with sporadic OC than BRCA carriers, but it levelled out over the 15-year period. CONCLUSIONS:In addition to national similarities in the HBOC-BRCA1/2 associated mutational spectrum, we identified a recurrent BRCA2 pathogenic variant (c.6024dupG), highly associated to OC in Navarra. Carriers of BRCA1/2 mutations showed a more severe BC and OC phenotype and had a worse overall prognosis when compared to a large cohort of women with sporadic counterpart tumors.

Dataset Information

BRCA Mutations Increase Fertility in Families at Hereditary Breast/Ovarian Cancer Risk.

Background

Method

Results

Conclusion

Publications

BRCA Mutations Increase Fertility in Families at Hereditary Breast/Ovarian Cancer Risk.

Similar Datasets

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