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Lookup NU author(s): Dr Paul Brennan
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2025.Background: Carriers of germline pathogenic variants (PVs) in the BRCA1 and BRCA2 genes are at higher risk of developing breast and ovarian cancer than the general population. It is unclear if these PVs influence other breast or ovarian cancer risk factors, including age at menopause (ANM), age at menarche (AAM), menstrual cycle length, BMI or height. There is a biological rationale for associations between BRCA1 and BRCA2 PVs and reproductive traits, for example involving DNA damage and repair mechanisms. The evidence for or against such associations is limited. Methods: We used data on 3,046 BRCA1 and 3,264 BRCA2 PV carriers, and 2,857 non-carrier female relatives of PV carriers from the Epidemiological Study of Familial Breast Cancer (EMBRACE). Associations between ANM and PV carrier status was evaluated using linear regression models allowing for censoring. AAM, menstrual cycle length, BMI, and height in carriers and non-carriers were compared using linear and multinomial logistic regression. Analyses were adjusted for potential confounders, and weighted analyses carried out to account for non-random sampling with respect to cancer status. Results: No statistically significant difference in ANM between carriers and non-carriers was observed in analyses accounting for censoring. Linear regression effect sizes for ANM were -0.002 (95%CI: -0.401, 0.397) and -0.172 (95%CI: -0.531, 0.188), for BRCA1 and BRCA2 PV carriers respectively, compared with non-carrier women. The distributions of AAM, menstrual cycle length and BMI were similar between PV carriers and non-carriers, but BRCA1 PV carriers were slightly taller on average than non-carriers (0.5 cm difference, p = 0.003). Conclusion: Information on the distribution of cancer risk factors in PV carriers is needed for incorporating these factors into multifactorial cancer risk prediction algorithms. Contrary to previous reports, we found no evidence that BRCA1 or BRCA2 PV are associated with hormonal or anthropometric factors, except for a weak association with height. We highlight methodological considerations and data limitations inherent in studies aiming to address this question.
Author(s): Mavaddat N, Frost D, Zhao E, Barnes DR, Ahmed M, Barwell J, Brady AF, Brennan P, Conti H, Cook J, Copeland H, Davidson R, Donaldson A, Douglas E, Gallagher D, Hart R, Izatt L, Kemp Z, Lalloo F, Miedzybrodzka Z, Morrison PJ, Murray JE, Murray A, Musgrave H, Searle C, Side L, Snape K, Tripathi V, Walker L, Archer S, Evans DG, Tischkowitz M, Antoniou AC, Easton DF
Publication type: Article
Publication status: Published
Journal: Breast Cancer Research
Year: 2025
Volume: 27
Issue: 1
Online publication date: 21/05/2025
Acceptance date: 20/04/2025
Date deposited: 03/06/2025
ISSN (print): 1465-5411
ISSN (electronic): 1465-542X
Publisher: BioMed Central Ltd
URL: https://doi.org/10.1186/s13058-025-02030-9
DOI: 10.1186/s13058-025-02030-9
Data Access Statement: The datasets generated and/or analysed during the current study are not publicly available, as they potentially include personal data. However, they can be accessed upon reasonable request made to the EMBRACE study Data Access Coordination Committee (embrace@medschl.cam.ac.uk) and the completion of a data sharing agreement
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