Germline BRCA mutations denote a clinicopathologic subset of prostate cancer.
OBJECTIVE
Increased prostate cancer risk has been reported for BRCA mutation carriers, but BRCA-associated clinicopathologic features have not been clearly defined.


METHODS
We determined BRCA mutation prevalence in 832 Ashkenazi Jewish men diagnosed with localized prostate cancer between 1988 and 2007 and 454 Ashkenazi Jewish controls and compared clinical outcome measures among 26 BRCA mutation carriers and 806 noncarriers. Kruskal-Wallis tests were used to compare age of diagnosis and Gleason score, and logistic regression models were used to determine associations between carrier status, prostate cancer risk, and Gleason score. Hazard ratios (HR) for clinical end points were estimated using Cox proportional hazards models.


RESULTS
BRCA2 mutations were associated with a 3-fold risk of prostate cancer [odds ratio, 3.18; 95% confidence interval (95% CI), 1.52-6.66; P = 0.002] and presented with more poorly differentiated (Gleason score > or =7) tumors (85% versus 57%; P = 0.0002) compared with non-BRCA-associated prostate cancer. BRCA1 mutations conferred no increased risk. After 7,254 person-years of follow-up, and adjusting for clinical stage, prostate-specific antigen, Gleason score, and treatment, BRCA2 and BRCA1 mutation carriers had a higher risk of recurrence [HR (95% CI), 2.41 (1.23-4.75) and 4.32 (1.31-13.62), respectively] and prostate cancer-specific death [HR (95% CI), 5.48 (2.03-14.79) and 5.16 (1.09-24.53), respectively] than noncarriers.


CONCLUSIONS
BRCA2 mutation carriers had an increased risk of prostate cancer and a higher histologic grade, and BRCA1 or BRCA2 mutations were associated with a more aggressive clinical course. These results may have implications for tailoring clinical management of this subset of hereditary prostate cancer.
Gallagher
David J
DJ
Clinical Genetics Service, Department of Medicine, Urology Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Gaudet
Mia M
MM
Pal
Prodipto
P
Kirchhoff
Tomas
T
Balistreri
Lisa
L
Vora
Kinjal
K
Bhatia
Jasmine
J
Stadler
Zsofia
Z
Fine
Samson W
SW
Reuter
Victor
V
Zelefsky
Michael
M
Morris
Michael J
MJ
Scher
Howard I
HI
Klein
Robert J
RJ
Norton
Larry
L
Eastham
James A
JA
Scardino
Peter T
PT
Robson
Mark E
ME
Offit
Kenneth
K
D000230:Adenocarcinoma / Q000145:classification / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D005787:Gene Frequency; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011471:Prostatic Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology; D012307:Risk Factors