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