1. ¹Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA
2. ²Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, 50 South Drive, MSC 8000, Building 50, Bethesda, MD 20892, USA
3. ³Edinburgh Molecular Genetics Service, Molecular Medicine Centre, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK
4. ⁴Department of Epidemiology, School of Public Health and Community Medicine, University of Washington, Mail Box 357236, Seattle, WA 98195, USA

Correspondence: Dr JL Stanford, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, M4-B874, Seattle, WA 98109, USA. E-mail: jstanfor@fhcrc.org

Received 3 May 2007; Revised 16 July 2007; Accepted 16 July 2007; Published online 14 August 2007.

Abstract

Studies of families who segregate BRCA2 mutations have found that men who carry disease-associated mutations have an increased risk of prostate cancer, particularly early-onset disease. A study of sporadic prostate cancer in the UK reported a prevalence of 2.3% for protein-truncating BRCA2 mutations among patients diagnosed at ages 55 years, highlighting the potential importance of this gene in prostate cancer susceptibility. To examine the role of protein-truncating BRCA2 mutations in relation to early-onset prostate cancer in a US population, 290 population-based patients from King County, Washington, diagnosed at ages <55 years were screened for germline BRCA2 mutations. The coding regions, intron–exon boundaries, and potential regulatory elements of the BRCA2 gene were sequenced. Two distinct protein-truncating BRCA2 mutations were identified in exon 11 in two patients. Both cases were Caucasian, yielding a mutation prevalence of 0.78% (95% confidence interval (95%CI) 0.09–2.81%) and a relative risk (RR) of 7.8 (95%CI 1.8–9.4) for early-onset prostate cancer in white men carrying a protein-truncating BRCA2 mutation. Results suggest that protein-truncating BRCA2 mutations confer an elevated RR of early-onset prostate cancer. However, we estimate that <1% of early-onset prostate cancers in the general US Caucasian population can be attributed to these rare disease-associated BRCA2 mutations.