Abstract: PD37-11
Sources of 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.

Introduction

A recent study published in the New England Journal of Medicine found that CHEK2 germline pathogenic mutations are associated with metastatic prostate cancer (PCa) risk. The objective of this study is to assess whether CHEK2 germline mutations differentiate risk of lethal from indolent PCa.

Methods

A retrospective case-case study of 261 patients who died of PCa and 352 patients with localized PCa of European American descent was conducted. Germline DNA from each of the 613 subjects was sequenced for DNA repair genes and cancer-related genes through whole exome sequencing (WES) or targeted sequencing. Mutations were annotated according to the American College of Medical Genetics guidelines.

Results

Among the 613 PCa patients in the study, 11 (1.79%) carried CHEK2 germline pathogenic mutations, which was significantly higher than the estimate from the general population (ExAC database: 0.61%, P<0.0001). However, the mutation carrier rate in lethal PCa patients (5/261=1.92%) was not significantly higher than either the localized cases in our study (6/352=1.70%, P=1.00) or in The Cancer Genome Atlas (2/406=0.49%, P=0.12). Among lethal cases, CHEK2 mutation carriers and non-carriers had similar mean age of death (77.0 and 73.0 years, respectively, P=0.72) and mean time to death (10.0 and 8.0 years, respectively, P=0.96). In the survival analysis of the entire study, CHEK2 mutations did not predict PCa-specific survival (Figure, log-rank P=0.86, comparing with non-carriers). In contrast, germline mutations of BRCA1/2 and ATM predicted worse PCa specific survival (all log-rank P<0.05, comparing with CHEK2 carriers and non-carriers).

Conclusions

CHEK2 germline mutations increase risk for PCa, but do not differentiate risk of lethal from indolent disease or PCa-specific survival.

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.