Elsevier

European Urology

Volume 71, Issue 5, May 2017, Pages 740-747
European Urology

Platinum Priority – Prostate Cancer
Editorial by Declan G. Murphy, Gail P. Risbridger, Robert G. Bristow and Shahneen Sandhu on pp. 748–749 of this issue
Germline Mutations in ATM and BRCA1/2 Distinguish Risk for Lethal and Indolent Prostate Cancer and are Associated with Early Age at Death

https://doi.org/10.1016/j.eururo.2016.11.033Get rights and content

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.

Introduction

While over 1 111 700 men are diagnosed with prostate cancer (PCa) each year worldwide, a much smaller number (307 500) eventually die from this disease [1]. Understanding the inherited factors contributing to the progression of PCa to a lethal disease could have an important translational impact on the detection, diagnosis, and prognosis of this common cancer. Specifically, a currently unmet clinical need is to be able to predict which men are more likely to develop a lethal PCa versus an indolent one.

The past 10 yr have seen substantial progress in elucidating molecular factors affecting PCa susceptibility with the identification of over 100 common genetic variants associated with an increased risk of PCa [2]. Although these factors provide robust markers of PCa risk overall, they are limited in distinguishing the risk for lethal versus indolent PCa [3], [4].

One gene has emerged as a potentially specific driver of more aggressive PCa. In 1997, Sigurdsson et al [5] described the association of a deleterious founder mutation in BRCA2 with aggressive PCa in Icelandic families. Subsequently, multiple studies confirmed the link between PCa and BRCA2 emphasizing BRCA2 as a strong risk factor [6], [7], [8], [9]. Castro et al and others have described and characterized BRCA2 as an important prognostic factor for aggressive PCa [10], [11], [12], [13], [14], [15], [16], [17], [18], [19]; however, the mutation frequency was low and most estimates suggested that BRCA2 accounted for a very small fraction of PCa (1–2%), even when early-onset family history-positive cases were examined [20], [21], [22], [23]. In a seminal paper, Robinson et al [24] identified mutations in three DNA repair genes, BRCA1/2, and ATM, at a surprisingly high rate in men unselected for age at diagnosis or family history, but rather for aggressive disease.

More recently, Pritchard et al [25] demonstrated an elevated rate of mutations in a number of DNA repair genes in men with metastatic PCa. Importantly, the combined frequency of pathogenic mutations in a set of genes including BRCA1/2 and ATM was higher than that reported in either the Exome Aggregation Consortium database of 53 000 unselected individuals or in the Cancer Genome Atlas database of men with clinically localized PCa. However, mixed racial populations and different sequencing technologies among study populations emphasize the need for confirmation of these findings.

In this study, we directly compared germline pathogenic mutations in BRCA1/2 and ATM among lethal and indolent (low risk localized) PCa patients from three racial groups and assessed the effect mutational status on age at death in a large case-case PCa cohort.

Section snippets

Study participants

This is a retrospective case-case study including 313 independent patients with lethal PCa and 486 independent patients with low risk localized PCa of European American, African American, and Chinese ancestry. Study participants were ascertained from patients undergoing PCa treatment in both the Brady Urological Institute and the Sidney Kimmel Comprehensive Cancer Center of the Johns Hopkins Medical Center, Baltimore, MD, USA (Hopkins), patients undergoing active surveillance at the John and

Results

A total of 313 men who died from PCa and 486 low risk localized PCa patients were included in the study. Among them, 613, 119, and 67 were European American, African American, and Chinese men, respectively. Germline pathogenic and likely pathogenic mutations in ATM and BRCA1/2 detected in these study participants are described in Figure 1 and Supplementary Table 1. The frequency of mutations was 6.07% in lethal PCa patients, significantly higher than that observed in localized PCa patients

Discussion

In addition to confirming the major findings from previous studies on association of germline mutations of BRCA2 and risk/progression of PCa, results from this study provide novel findings that further substantiate roles of germline mutations in these three DNA repair genes (BRCA2, ATM, and BRCA1) in distinguishing lethal from indolent PCa and predicting age of PCa-specific death. Our study is novel in several respects. Firstly, it is the first report analyzing germline mutations in these three

Conclusions

In summary, our study provides additional evidence that the mutation status of ATM and BRCA1/2 distinguishes the risk for lethal and indolent PCa and is associated with earlier age at death and shorter survival time. Together with previous studies, the consistent findings to date may have important clinical implications in genetic testing and decision making for PCa screening and treatment.

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    These authors contribute equally to the study.

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