H Ballentine Carter1, Brian Helfand2, Mufaddal Mamawala3, Yishuo Wu4, Patricia Landis3, Hongjie Yu5, Kathleen Wiley3, Rong Na6, Zhuqing Shi7, Jacqueline Petkewicz8, Sameep Shah5, Richard J Fantus9, Kristian Novakovic8, Charles B Brendler5, S Lilly Zheng5, William B Isaacs3, Jianfeng Xu10. 1. Department of Urology and the James Buchanan Brady Urologic Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: hcarter@jhmi.edu. 2. Program for Personalized Cancer Care, North Shore University Health System, Evanston, IL, USA; Department of Surgery, North Shore University Health System, Evanston, IL, USA. 3. Department of Urology and the James Buchanan Brady Urologic Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 4. Program for Personalized Cancer Care, North Shore University Health System, Evanston, IL, USA; Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China. 5. Program for Personalized Cancer Care, North Shore University Health System, Evanston, IL, USA. 6. Program for Personalized Cancer Care, North Shore University Health System, Evanston, IL, USA; Department of Urology, Ruijin Hospital, Jiaotong University, Shanghai, China. 7. Program for Personalized Cancer Care, North Shore University Health System, Evanston, IL, USA; State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University, Shanghai, China. 8. Department of Surgery, North Shore University Health System, Evanston, IL, USA. 9. Program for Personalized Cancer Care, North Shore University Health System, Evanston, IL, USA; University of Chicago, Evanston, IL, USA. 10. Program for Personalized Cancer Care, North Shore University Health System, Evanston, IL, USA; Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China; State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University, Shanghai, China.
Abstract
BACKGROUND: Mutations in DNA repair genes are associated with aggressive prostate cancer (PCa). OBJECTIVE: To assess whether germline mutations are associated with grade reclassification (GR) in patients undergoing active surveillance (AS). DESIGN, SETTING, AND PARTICIPANTS: Two independent cohorts of PCa patients undergoing AS; 882 and 329 patients from Johns Hopkins and North Shore, respectively. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Germline DNA was sequenced for DNA repair genes, including BRCA1/2 and ATM (three-gene panel). Pathogenicity of mutations was defined according to the American College of Medical Genetics guidelines. Association of mutation carrier status and GR was evaluated by a competing risk analysis. RESULTS AND LIMITATIONS: Of 1211, 289 patients experienced GR; 11 of 26 with mutations in a three-gene panel and 278 of 1185 noncarriers; adjusted hazard ratio (HR)=1.96 (95% confidence interval [CI]=1.004-3.84, p=0.04). Reclassification occurred in six of 11 carriers of BRCA2 mutations and 283 of 1200 noncarriers; adjusted HR=2.74 (95% CI=1.26-5.96, p=0.01). The carrier rates of pathogenic mutations in the three-gene panel, and BRCA2 alone, were significantly higher in those reclassified (3.8% and 2.1%, respectively) than in those not reclassified (1.6% and 0.5%, respectively; p=0.04 and 0.03, respectively). Carrier rates for BRCA2 were greater for those reclassified from Gleason score (GS) 3+3 at diagnosis to GS ≥4+3 (4.1% vs 0.7%, p=0.01) versus GS 3+4 (2.1% vs 0.6%; p=0.03). Results are limited by the small number of mutation carriers and an intermediate end point. CONCLUSIONS: Mutation status of BRCA1/2 and ATM is associated with GR among men undergoing AS. PATIENT SUMMARY: Men on active surveillance with inherited mutations in BRCA1/2 and ATM are more likely to harbor aggressive prostate cancer.
BACKGROUND: Mutations in DNA repair genes are associated with aggressive prostate cancer (PCa). OBJECTIVE: To assess whether germline mutations are associated with grade reclassification (GR) in patients undergoing active surveillance (AS). DESIGN, SETTING, AND PARTICIPANTS: Two independent cohorts of PCa patients undergoing AS; 882 and 329 patients from Johns Hopkins and North Shore, respectively. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Germline DNA was sequenced for DNA repair genes, including BRCA1/2 and ATM (three-gene panel). Pathogenicity of mutations was defined according to the American College of Medical Genetics guidelines. Association of mutation carrier status and GR was evaluated by a competing risk analysis. RESULTS AND LIMITATIONS: Of 1211, 289 patients experienced GR; 11 of 26 with mutations in a three-gene panel and 278 of 1185 noncarriers; adjusted hazard ratio (HR)=1.96 (95% confidence interval [CI]=1.004-3.84, p=0.04). Reclassification occurred in six of 11 carriers of BRCA2 mutations and 283 of 1200 noncarriers; adjusted HR=2.74 (95% CI=1.26-5.96, p=0.01). The carrier rates of pathogenic mutations in the three-gene panel, and BRCA2 alone, were significantly higher in those reclassified (3.8% and 2.1%, respectively) than in those not reclassified (1.6% and 0.5%, respectively; p=0.04 and 0.03, respectively). Carrier rates for BRCA2 were greater for those reclassified from Gleason score (GS) 3+3 at diagnosis to GS ≥4+3 (4.1% vs 0.7%, p=0.01) versus GS 3+4 (2.1% vs 0.6%; p=0.03). Results are limited by the small number of mutation carriers and an intermediate end point. CONCLUSIONS: Mutation status of BRCA1/2 and ATM is associated with GR among men undergoing AS. PATIENT SUMMARY:Men on active surveillance with inherited mutations in BRCA1/2 and ATM are more likely to harbor aggressive prostate cancer.
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