Germline Mutations in ATM and BRCA1/2 Distinguish Risk for Lethal and Indolent Prostate Cancer and are Associated with Early Age at Death

Abstract

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.

Keywords: DNA repair genes; Germline; Lethal prostate cancer; Mutation.

Fig. 1

Germline pathogenic and likely pathogenic mutations in BRCA1/2 and ATM. Each mutation (complementary DNA position and resulting amino acid change) found in these three genes is presented by a lollipop plot. Mutations found in lethal and localized prostate cancer patients are coded in red and green, respectively. The y axis represents the total number of mutations identified. AA = African Americans; BRCT = BRCA1 C-Terminal domain; CHN = Chinese; EA = European Americans; FAT = focal adhesion targeting; FATC = FRAP, ATM, TRRAP C-terminal; PCa = prostate cancer.

Fig. 2

Kaplan-Meier survival curves for mutation carriers and noncarriers (A) in the entire study cohort, (B) in patients diagnosed with localized prostate cancer at time of diagnosis, and (C) in the patients diagnosed with metastatic prostate cancer at time of diagnosis. PCa = prostate cancer.