TY - JOUR
T1 - Germline Mutations in ATM and BRCA1/2 Distinguish Risk for Lethal and Indolent Prostate Cancer and are Associated with Early Age at Death [figure presented]
AU - Na, Rong
AU - Zheng, S. Lilly
AU - Han, Misop
AU - Yu, Hongjie
AU - Jiang, Deke
AU - Shah, Sameep
AU - Ewing, Charles M.
AU - Zhang, Liti
AU - Novakovic, Kristian
AU - Petkewicz, Jacqueline
AU - Gulukota, Kamalakar
AU - Helseth, Donald L.
AU - Quinn, Margo
AU - Humphries, Elizabeth
AU - Wiley, Kathleen E.
AU - Isaacs, Sarah D.
AU - Wu, Yishuo
AU - Liu, Xu
AU - Zhang, Ning
AU - Wang, Chi Hsiung
AU - Khandekar, Janardan
AU - Hulick, Peter J.
AU - Shevrin, Daniel H.
AU - Cooney, Kathleen A.
AU - Shen, Zhoujun
AU - Partin, Alan W.
AU - Carter, H. Ballentine
AU - Carducci, Michael A.
AU - Eisenberger, Mario A.
AU - Denmeade, Sam R.
AU - McGuire, Michael
AU - Walsh, Patrick C.
AU - Helfand, Brian T.
AU - Brendler, Charles B.
AU - Ding, Qiang
AU - Xu, Jianfeng
AU - Isaacs, William B.
N1 - Publisher Copyright:
© 2016 European Association of Urology
PY - 2017/5/1
Y1 - 2017/5/1
N2 - Background Germline mutations in BRCA1/2 and ATM have been associated with prostate cancer (PCa) risk. Objective 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. Design, setting, and participants 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. Outcome measurements and statistical analysis Mutation carrier rates and their effect on lethal PCa were analyzed using the Fisher's exact test and Cox regression analysis, respectively. Results and limitations 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, and > 10 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. Conclusions 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. Patient summary 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.
AB - Background Germline mutations in BRCA1/2 and ATM have been associated with prostate cancer (PCa) risk. Objective 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. Design, setting, and participants 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. Outcome measurements and statistical analysis Mutation carrier rates and their effect on lethal PCa were analyzed using the Fisher's exact test and Cox regression analysis, respectively. Results and limitations 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, and > 10 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. Conclusions 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. Patient summary 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.
KW - DNA repair genes
KW - Germline
KW - Lethal prostate cancer
KW - Mutation
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U2 - 10.1016/j.eururo.2016.11.033
DO - 10.1016/j.eururo.2016.11.033
M3 - Article
C2 - 27989354
AN - SCOPUS:85008418077
SN - 0302-2838
VL - 71
SP - 740
EP - 747
JO - European Urology
JF - European Urology
IS - 5
ER -