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
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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