AUA 2017: Germline Mutations in DNA Repair Genes are Significantly Enriched in Lethal Prostate Cancer and are Associated with Disease Survival

Boston, MA ( Recently, an association was found between germline mutations in several DNA repair genes and metastatic prostate cancer (PCa). This study systematically investigated whether the range of pathological germline mutations found in lethal PCa are specifically enriched in DNA repair genes and if these mutations are a distinguishable factor between lethal and indolent PCa.

This was a retrospective case-case study of 313 patients who died of PCa and 486 patients with presented with localized PCa of European, African, and Chinese descent. Whole exome sequencing (WES) or target sequencing was performed to sequence germline DNA from each of the subjects for DNA repair genes and cancer-related genes. Pathogenicity of mutations was classified by the American College of Medical Genetics guidelines. Using a chi-square test, enrichment pathway analysis was performed. The log-rank test and chi-square trend test were sued to analyze mutation carrier rates and their effects on PCA-specific survival.

Pathogenic or supposed pathogenic mutations in 178 DNA repair genes (Wood RD, et al., 2001) were significantly enriched in patients with lethal PCa in both European Americans (p=1.58e-6) and African Americans after WES. (p=0.0028) (WES was not performed in Chinese samples). Former literature suggests that lethal PCa will be developed among men who tend to have an increased burden of inherited DNA repair mutations when compared to genetic mutations in other cellular pathways.

This study particularly found that carrier rates differed significantly among the lethal PCa patients when assessing age at death (p=0.028) and time to death after diagnosis (p=0.0007). In the survival analysis, DNA repair gene mutation carriers had a significantly shorter median survival time (14 years; interval 11.5-16.5 years) than non-carriers (16 years; interval 14.9-17.1 years, log rank p=0.021).

Ultimately, stemming from past findings that germline mutations in DNA repair genes are significantly enriched in patients with lethal PCa, this study further determined that carrier mutation status was associated with both earlier age at death and shorter survival time.

Presented By: Rong Na

Authors: Rong Na*, Shanghai, China, People’s Republic of; S. Lilly S. Lilly, Evanston, IL; Misop Han, Baltimore, MD; Hongjie Yu, Deke Jiang, Sameep Shah, Evanston, IL; Charles Ewing, Liti Zhang, Baltimore, MD; Kristian Novakovic, Jacqueline Petkewicz, Kamalakar Gulukota, Donald Helseth Jr, Margo Quinn, Evanston, IL; Elizabeth Humphries, Kathleen Wiley, Sarah Isaacs, Baltimore, MD; Yishuo Wu, Shanghai, China, People’s Republic of; Xu Liu, Evanston, IL; Ning Zhang, Shanghai, China, People’s Republic of; Chi-Hsiung Wang, Janardan Khandekar, Peter Hulick, Daniel Shevrin, Evanston, IL; Kathleen Cooney, Salt Lake City, UT; Zhoujun Shen, Shanghai, China, People’s Republic of; Alan Alan, H. B. Carter, Michael Carducci, Mario Eisenberger, Sam Denmeade, Baltimore, MD; Michael McGuire, Evanston, IL; Patrick Walsh, Baltimore, MD; Brian Helfand, Charles Brendler, Evanston, IL; Qiang Ding, Shanghai, China, People’s Republic of; Jianfeng Xu, Evanston, IL; William Isaacs, Baltimore, MD

Affiliation: NorthShore University HealthSystem

Written By: Rita Derderian, University of California, Irvine for

at the 2017 AUA Annual Meeting - May 12 - 16, 2017 – Boston, Massachusetts, USA