Germline mutations in ATM and BRCA1/2 distinguish risk for lethal and indolent prostate cancer and are associated with early age at death
Autor: | Donald L. Helseth, Sarah D. Isaacs, Liti Zhang, Mario A. Eisenberger, Xu Liu, Margo Quinn, Michael McGuire, Brian T. Helfand, Sameep Shah, Kristian Novakovic, Patrick C. Walsh, Charles M. Ewing, Elizabeth Humphries, Alan W. Partin, Charles B. Brendler, Michael A. Carducci, Peter J. Hulick, S. Lilly Zheng, Qiang Ding, Janardan D. Khandekar, Daniel H. Shevrin, Kathleen E. Wiley, Kamalakar Gulukota, Chi Hsiung Wang, Hongjie Yu, Kathleen A. Cooney, Zhoujun Shen, Rong Na, Samuel R. Denmeade, Misop Han, Deke Jiang, Jacqueline Petkewicz, Yishuo Wu, William B. Isaacs, Ning Zhang, H. Ballentine Carter, Jianfeng Xu |
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Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Male Pathology medicine.medical_specialty DNA Repair endocrine system diseases DNA repair Urology Black People Ataxia Telangiectasia Mutated Proteins urologic and male genital diseases medicine.disease_cause Article Germline White People 03 medical and health sciences Prostate cancer 0302 clinical medicine Germline mutation Asian People Medicine Humans skin and connective tissue diseases Survival analysis Germ-Line Mutation Aged Proportional Hazards Models Retrospective Studies BRCA2 Protein Mutation business.industry BRCA1 Protein Case-control study Age Factors Prostatic Neoplasms Sequence Analysis DNA Middle Aged medicine.disease Prognosis Survival Analysis 030104 developmental biology 030220 oncology & carcinogenesis Case-Control Studies Cancer research Neoplasm Grading business |
Zdroj: | European Urology Supplements. 16:e832-e833 |
ISSN: | 1569-9056 |
DOI: | 10.1016/s1569-9056(17)30541-9 |
Popis: | Germline mutations in BRCA1/2 and ATM have been associated with prostate cancer (PCa) risk.To directly assess whether germline mutations in these three genes distinguish lethal from indolent PCa and whether they confer any effect on age at death.A retrospective case-case study of 313 patients who died of PCa and 486 patients with low-risk localized PCa of European, African, and Chinese descent. Germline DNA of each of the 799 patients was sequenced for these three genes.Mutation carrier rates and their effect on lethal PCa were analyzed using the Fisher's exact test and Cox regression analysis, respectively.The combined BRCA1/2 and ATM mutation carrier rate was significantly higher in lethal PCa patients (6.07%) than localized PCa patients (1.44%), p=0.0007. The rate also differed significantly among lethal PCa patients as a function of age at death (10.00%, 9.08%, 8.33%, 4.94%, and 2.97% in patients who died ≤ 60 yr, 61-65 yr, 66-70 yr, 71-75 yr, and over 75 yr, respectively, p=0.046) and time to death after diagnosis (12.26%, 4.76%, and 0.98% in patients who died ≤ 5 yr, 6-10 yr, and10 yr after a PCa diagnosis, respectively, p=0.0006). Survival analysis in the entire cohort revealed mutation carriers remained an independent predictor of lethal PCa after adjusting for race and age, prostate-specific antigen, and Gleason score at the time of diagnosis (hazard ratio=2.13, 95% confidence interval: 1.24-3.66, p=0.004). A limitation of this study is that other DNA repair genes were not analyzed.Mutation status of BRCA1/2 and ATM distinguishes risk for lethal and indolent PCa and is associated with earlier age at death and shorter survival time.Prostate cancer patients with inherited mutations in BRCA1/2 and ATM are more likely to die of prostate cancer and do so at an earlier age. |
Databáze: | OpenAIRE |
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