Format

Send to

Choose Destination
Eur Urol. 2019 Sep 5. pii: S0302-2838(19)30675-X. doi: 10.1016/j.eururo.2019.08.025. [Epub ahead of print]

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

Author information

1
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. Electronic address: ten25@medschl.cam.ac.uk.
2
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
3
Manchester Regional Genetics Service, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
4
Oncogenetics Team, Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
5
Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
6
North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Trust, London, UK.
7
Leicestershire Clinical Genetics Service, University Hospitals of Leicester NHS Trust, Leicester, UK.
8
North West Thames Regional Genetics Service, London North West University Healthcare NHS Trust, London, UK.
9
Peninsula Clinical Genetics Service, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
10
North Trent Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK.
11
West of Scotland Regional Genetics Service, NHS Greater Glasgow and Clyde, Glasgow, UK.
12
South Western Regional Genetics Service, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.
13
Nottingham Centre for Medical Genetics, Nottingham University Hospitals NHS Trust, Nottingham, UK.
14
North of Scotland Regional Genetics Service, NHS Grampian, Aberdeen, UK.
15
Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK.
16
South East Thames Regional Genetics Service, Guy's and St Thomas' NHS Foundation Trust, London, UK.
17
St. James's Hospital, Dublin, Ireland; National Centre for Medical Genetics, Dublin, Ireland.
18
Merseyside and Cheshire Clinical Genetics Service, Liverpool Women's NHS Foundation Trust, Liverpool, UK.
19
Northern Ireland Regional Genetics Service, Belfast Health and Social Care Trust, Belfast, UK.
20
Medical Genetics Services for Wales, Abertawe Bro Morgannwg University Health Board, Swansea, UK.
21
West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.
22
South East of Scotland Regional Genetics Service, NHS Lothian, Edinburgh, UK.
23
Medical Genetics Services for Wales, Betsi Cadwaladr University Health Board, Bodelwyddan, UK.
24
All Wales Medical Genetics Service, NHS Wales, Cardiff, UK.
25
Wessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
26
South West Thames Regional Genetics Service, St George's University Hospitals NHS Foundation Trust, London, UK.
27
Oxford Regional Genetics Service, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
28
Department of Medical Genetics, University of Cambridge, Cambridge, UK; East Anglian Regional Genetics Service, Cambridge University Hospitals NHS Trust, Cambridge, UK.
29
Oncogenetics Team, Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK; Cancer Genetics Unit, Royal Marsden NHS Foundation Trust, London, UK.

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.

KEYWORDS:

BRCA1; BRCA2; Genetic risk; Prospective cohort study; Prostate cancer

PMID:
31495749
DOI:
10.1016/j.eururo.2019.08.025
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center