Germline Mutations in ATM and BRCA1/2 Are Associated with Grade Reclassification in Men on Active Surveillance for Prostate Cancer |
| |
Authors: | H Ballentine Carter Brian Helfand Mufaddal Mamawala Yishuo Wu Patricia Landis Hongjie Yu Kathleen Wiley Rong Na Zhuqing Shi Jacqueline Petkewicz Sameep Shah Richard J Fantus Kristian Novakovic Charles B Brendler S Lilly Zheng William B Isaacs Jianfeng Xu |
| |
Institution: | 1. Department of Urology and the James Buchanan Brady Urologic Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA;2. Program for Personalized Cancer Care, North Shore University Health System, Evanston, IL, USA;3. Department of Surgery, North Shore University Health System, Evanston, IL, USA;4. Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China;5. Department of Urology, Ruijin Hospital, Jiaotong University, Shanghai, China;6. State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University, Shanghai, China;7. University of Chicago, Evanston, IL, USA |
| |
Abstract: | BackgroundMutations in DNA repair genes are associated with aggressive prostate cancer (PCa).ObjectiveTo assess whether germline mutations are associated with grade reclassification (GR) in patients undergoing active surveillance (AS).Design, setting, and participantsTwo independent cohorts of PCa patients undergoing AS; 882 and 329 patients from Johns Hopkins and North Shore, respectively.Outcome measurements and statistical analysisGermline 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 limitationsOf 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.ConclusionsMutation status of BRCA1/2 and ATM is associated with GR among men undergoing AS.Patient summaryMen on active surveillance with inherited mutations in BRCA1/2 and ATM are more likely to harbor aggressive prostate cancer. |
| |
Keywords: | Active surveillance Germline mutations |
本文献已被 ScienceDirect 等数据库收录! |
|