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Prostate Cancer Risks for Male BRCA1 and BRCA2 Mutation Carriers: A Prospective Cohort Study.

Nyberg, T; Frost, D; Barrowdale, D; Evans, DG; Bancroft, E; Adlard, J; Ahmed, M; Barwell, J; Brady, AF; Brewer, C; et al. Nyberg, T; Frost, D; Barrowdale, D; Evans, DG; Bancroft, E; Adlard, J; Ahmed, M; Barwell, J; Brady, AF; Brewer, C; Cook, J; Davidson, R; Donaldson, A; Eason, J; Gregory, H; Henderson, A; Izatt, L; Kennedy, MJ; Miller, C; Morrison, PJ; Murray, A; Ong, K-R; Porteous, M; Pottinger, C; Rogers, MT; Side, L; Snape, K; Walker, L; Tischkowitz, M; Eeles, R; Easton, DF; Antoniou, AC (2020) Prostate Cancer Risks for Male BRCA1 and BRCA2 Mutation Carriers: A Prospective Cohort Study. Eur Urol, 77 (1). pp. 24-35. ISSN 1873-7560 https://doi.org/10.1016/j.eururo.2019.08.025
SGUL Authors: Snape, Katie Mairwen Greenwood

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Abstract

BACKGROUND: BRCA1 and BRCA2 mutations have been associated with prostate cancer (PCa) risk but a wide range of risk estimates have been reported that are based on retrospective studies. OBJECTIVE: To estimate relative and absolute PCa risks associated with BRCA1/2 mutations and to assess risk modification by age, family history, and mutation location. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective cohort study of male BRCA1 (n = 376) and BRCA2 carriers (n = 447) identified in clinical genetics centres in the UK and Ireland (median follow-up 5.9 and 5.3 yr, respectively). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Standardised incidence/mortality ratios (SIRs/SMRs) relative to population incidences or mortality rates, absolute risks, and hazard ratios (HRs) were estimated using cohort and survival analysis methods. RESULTS AND LIMITATIONS: Sixteen BRCA1 and 26 BRCA2 carriers were diagnosed with PCa during follow-up. BRCA2 carriers had an SIR of 4.45 (95% confidence interval [CI] 2.99-6.61) and absolute PCa risk of 27% (95% CI 17-41%) and 60% (95% CI 43-78%) by ages 75 and 85 yr, respectively. For BRCA1 carriers, the overall SIR was 2.35 (95% CI 1.43-3.88); the corresponding SIR at age <65 yr was 3.57 (95% CI 1.68-7.58). However, the BRCA1 SIR varied between 0.74 and 2.83 in sensitivity analyses to assess potential screening effects. PCa risk for BRCA2 carriers increased with family history (HR per affected relative 1.68, 95% CI 0.99-2.85). BRCA2 mutations in the region bounded by positions c.2831 and c.6401 were associated with an SIR of 2.46 (95% CI 1.07-5.64) compared to population incidences, corresponding to lower PCa risk (HR 0.37, 95% CI 0.14-0.96) than for mutations outside the region. BRCA2 carriers had a stronger association with Gleason score ≥7 (SIR 5.07, 95% CI 3.20-8.02) than Gleason score ≤6 PCa (SIR 3.03, 95% CI 1.24-7.44), and a higher risk of death from PCa (SMR 3.85, 95% CI 1.44-10.3). Limitations include potential screening effects for these known mutation carriers; however, the BRCA2 results were robust to multiple sensitivity analyses. CONCLUSIONS: The results substantiate PCa risk patterns indicated by retrospective analyses for BRCA2 carriers, including further evidence of association with aggressive PCa, and give some support for a weaker association in BRCA1 carriers. PATIENT SUMMARY: In this study we followed unaffected men known to carry mutations in the BRCA1 and BRCA2 genes to investigate whether they are at higher risk of developing prostate cancer compared to the general population. We found that carriers of BRCA2 mutations have a high risk of developing prostate cancer, particularly more aggressive prostate cancer, and that this risk varies by family history of prostate cancer and the location of the mutation within the gene.

Item Type: Article
Additional Information: © 2019 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: BRCA1, BRCA2, Genetic risk, Prospective cohort study, Prostate cancer, BRCA1, BRCA2, Genetic risk, Prospective cohort study, Prostate cancer, 1103 Clinical Sciences, Urology & Nephrology
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cell Sciences (INCCCS)
Journal or Publication Title: Eur Urol
ISSN: 1873-7560
Language: eng
Dates:
DateEvent
January 2020Published
6 September 2019Published Online
15 August 2019Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
C12292/A20861Cancer Research UKhttp://dx.doi.org/10.13039/501100000289
C12292/A22820Cancer Research UKhttp://dx.doi.org/10.13039/501100000289
C1287/A23382Cancer Research UKhttp://dx.doi.org/10.13039/501100000289
C1287/A26886Cancer Research UKhttp://dx.doi.org/10.13039/501100000289
IS-BRC-1215-20007National Institute for Health Researchhttp://dx.doi.org/10.13039/501100000272
C5047/A8385Cancer Research UKhttp://dx.doi.org/10.13039/501100000289
PubMed ID: 31495749
Go to PubMed abstract
URI: http://openaccess.sgul.ac.uk/id/eprint/111344
Publisher's version: https://doi.org/10.1016/j.eururo.2019.08.025

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