A BRCA2 prostate cancer cluster region (PCCR) was recently proposed (c.7914 to 3') wherein pathogenic variants (PVs) are associated with higher prostate cancer (PCa) risk than PVs elsewhere in the BRCA2 gene. Using a prospective cohort study of 447 male BRCA2 PV carriers recruited in the UK and Ireland from 1998 to 2016, we estimated standardised incidence ratios (SIRs) compared with population incidences and assessed variation in risk by PV location. Carriers of PVs in the PCCR had a PCa SIR of 8.33 (95% confidence interval [CI] 4.46-15.6) and were at a higher risk of PCa than carriers of other BRCA2 PVs (SIR = 3.31, 95% CI 1.97-5.57; hazard ratio = 2.34, 95% CI 1.09-5.03). PCCR PV carriers had an estimated cumulative PCa risk of 44% (95% CI 23-72%) by the age of 75 yr and 78% (95% CI 54-94%) by the age of 85 yr. Our results corroborate the existence of a PCCR in BRCA2 in a prospective cohort. PATIENT SUMMARY: In this report, we investigated whether the risk of prostate cancer for men with a harmful mutation in the BRCA2 gene differs based on where in the gene the mutation is located. We found that men with mutations in one region of BRCA2 had a higher risk of prostate cancer than men with mutations elsewhere in the gene.
European urology. 2020 Jun 10 [Epub ahead of print]
Tommy Nyberg, Debra Frost, Daniel Barrowdale, D Gareth Evans, Elizabeth Bancroft, Julian Adlard, Munaza Ahmed, Julian Barwell, Angela F Brady, Carole Brewer, Jackie Cook, Rosemarie Davidson, Alan Donaldson, Jacqueline Eason, Helen Gregory, Alex Henderson, Louise Izatt, M John Kennedy, Claire Miller, Patrick J Morrison, Alex Murray, Kai-Ren Ong, Mary Porteous, Caroline Pottinger, Mark T Rogers, Lucy Side, Katie Snape, Vishakha Tripathi, Lisa Walker, Marc Tischkowitz, Rosalind Eeles, Douglas F Easton, Antonis C Antoniou
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. Electronic address: ., Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK., Manchester Regional Genetics Service, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK., Oncogenetics Team, Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK; Cancer Genetics Unit, Royal Marsden NHS Foundation Trust, London, UK., Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Leeds, UK., North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Trust, London, UK., Leicestershire Clinical Genetics Service, University Hospitals of Leicester NHS Trust, Leicester, UK., North West Thames Regional Genetics Service, London North West University Healthcare NHS Trust, London, UK., Peninsula Clinical Genetics Service, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK., North Trent Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK., West of Scotland Regional Genetics Service, NHS Greater Glasgow and Clyde, Glasgow, UK., South Western Regional Genetics Service, University Hospitals Bristol NHS Foundation Trust, Bristol, UK., Nottingham Centre for Medical Genetics, Nottingham University Hospitals NHS Trust, Nottingham, UK., North of Scotland Regional Genetics Service, NHS Grampian, Aberdeen, UK., Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK., South East Thames Regional Genetics Service, Guy's and St Thomas' NHS Foundation Trust, London, UK., St James's Hospital, Dublin, Republic of Ireland; National Centre for Medical Genetics, Dublin, Republic of Ireland., Merseyside and Cheshire Clinical Genetics Service, Liverpool Women's NHS Foundation Trust, Liverpool, UK., Northern Ireland Regional Genetics Service, Belfast Health and Social Care Trust, Belfast, UK., Medical Genetics Services for Wales, Abertawe Bro Morgannwg University Health Board, Swansea, UK., West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK., South East of Scotland Regional Genetics Service, NHS Lothian, Edinburgh, UK., Medical Genetics Services for Wales, Betsi Cadwaladr University Health Board, Bodelwyddan, UK., All Wales Medical Genetics Service, NHS Wales, Cardiff, UK., Wessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust, Southampton, UK., South West Thames Regional Genetics Service, St George's University Hospitals NHS Foundation Trust, London, UK., Oxford Regional Genetics Service, Oxford University Hospitals NHS Foundation Trust, Oxford, UK., Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK.