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.

A comprehensive evaluation of CHEK2 germline mutations in men with prostate cancer

“…Among these patients, 313 lethal cases and 486 low-risk localized cases were reported in a previous manuscript that evaluated ATM and BRCA1/2. 4 The demographic characteristics of the men in each series are summarized in Table 1. The protocols of this study were approved by Institutional Review Boards at four participating medical centers and written informed consent was obtained from all patients at local sites.…”

“…PCa is also one of the most heritable cancers and recent studies have been focused on genetic markers capable of distinguishing the risk for lethal versus indolent PCa. [2][3][4] CHEK2 encodes a cell-cycle checkpoint regulator, which is activated by DNA damage and results in cell apoptosis or arrest of cell cycle until the DNA is repaired. [5][6][7] Mutations in CHEK2 gene have been associated with increased risk of prostate, breast and other cancers.…”

Germline mutations in DNA repair genes are associated with bladder cancer risk and unfavourable prognosis

“…A customized next-generation sequencing panel that targeted 222 cancer-related genes was used to sequence the germline DNA samples, including 54 DNA repair genes and 168 cancerrelated genes in other biological pathways. The pipelines used for sequencing and bioinformatics analysis were described in our previous study [19]. Notably, more stringent criteria were used to identify the pathogenicity of variants in addition to the American College of Medical Genetics and Genomics criteria [20,21].…”

A multiparametric approach to improve upon existing prostate cancer screening and biopsy recommendations

“…The mutation carrier rate of BRCA1/2 and ATM is highest among lethal PCa patients who died before 60 years old (10.00%) or who died within 5 years after a diagnosis of PCa (12.26%), and it is lowest among patients who died of PCa after 75 years old (2.97%) or died more than 10 years after a diagnosis of PCa (0.98%). These results suggest that not all lethal PCa patients have a similar genetic basis and that mutations in these three genes increase one’s risk of developing the most lethal form of PCa, dying younger, and/or dying sooner after diagnosis [31▪▪]. …”

“…Among patients with lethal PCa, 60% of pathogenic mutation carriers of BRCA1/2 and ATM reported a negative family history of PCa [31▪▪]. Therefore, all asymptomatic patients, regardless of family history, should consider including HPGs in cancer risk assessment.…”