Introduction

Germline mutations in several DNA repair genes were recently found to be associated with metastatic prostate cancer (PCa). The objective of this study was to systematically assess whether the spectrum of pathogenic germline mutations found in lethal PCa is enriched in DNA repair genes and whether these mutations distinguish lethal PCa from indolent PCa.

Methods

A retrospective case-case study of 313 patients who died of PCa and 486 patients with localized PCa of European, African, and Chinese descent. Germline DNA from each of the subjects was sequenced for DNA repair genes and cancer-related genes through whole exome sequencing (WES) or targeted sequencing. Pathogenicity of mutations was called according to the American College of Medical Genetics guidelines. Enrichment pathway analysis was performed using Chi-square test. Mutation carrier rates and their effects on PCa-specific survival were analyzed using log-rank test and Chi-square trend test.

Results

Based on WES results, pathogenic or likely pathogenic mutations in 178 DNA repair genes (Wood RD, et al., 2001) were significantly enriched in lethal PCa in both European Americans (P=1.58e-6) and African Americans (P=0.0028) (WES was not performed in Chinese samples). This suggests that men who will develop lethal PCa tend to have an increased burden of inherited DNA repair mutations when compared with genes in other cellular pathways. In the entire study population, the carrier rates differed significantly among lethal PCa patients as a function of age at death (P-trend=0.028) and time to death after diagnosis (P-trend=0.0007) (Table). In the survival analysis, DNA repair gene mutation carriers had a significantly shorter median survival time (14.0 years, 95%Confidence Interval: 11.5-16.5 years) than non-carriers (16.0 years, 95%Confidence Interval: 14.9-17.1 years, log-rank P=0.021).

Conclusions

Germline mutations in DNA repair genes are significantly enriched in patients with lethal PCa. DNA repair gene mutation status was associated with both earlier age at death and shorter survival time.

Funding

The study is partially supported by the National Key Basic Research Program Grant 973 of China (2012CB518301), the Key Project of the National Natural Science Foundation of China (81130047), PCW Fund,and the Rob Brooks Fund for Personalized Cancer Care at NorthShore University HealthSystem.