Germline DNA-Repair Genes and HOXB13 Mutations in Korean Men with Metastatic Prostate Cancer: Data from a Large Korean Cohort.

Abstract

Germline mutations in DNA damage repair (DDR) genes such as BRCA2 have been associated with prostate cancer (PC) risk but has not been thoroughly evaluated for metastatic prostate cancer (mPC) in Asian men. This study attempts to evaluate frequency of DDR mutations in the largest cohort of Koreans. We recruited 340 patients with mPC unselected for family history of cancer and compared to 495 controls. Whole genome sequencing was applied to assess germline pathogenic/likely pathogenic variants (PV/LPVs) in 26 DDR genes and HOXB13, including 7 genes (ATM, BRCA1/2, CHEK2, BRIP1, PALB2, and NBN) associated with hereditary PC. Comparisons to published Caucasian and Japanese cohorts were performed. Total of 28 PV/LPVs were identified in 30 (8.8%) patients; mutations were found in 13 genes, including BRCA2 (15 men [4.41%]), ATM (2 men [0.59%]), NBN (2 men [0.59%], and BRIP1 (2 men [0.59%]). Only one patient had HOXB13 mutation (0.29%). A lower rate of overall germline variant frequency was observed in Korean mPC compared to Caucasians (8.8% vs. 11.8%), but individual variants notably differed from Caucasian and geographically similar Japanese cohorts. PV/LPVs in DDR genes tended to increase gradually with higher Gleason scores (GS 7, 7.1%; GS 8, 7.5%; GS 9-10, 9.9%). BRCA2 was the most frequently mutated gene common to different cohorts supporting its importance, but differences in variant distribution in Korean mPC underscore the need for ethnic-specific genetic models. Future ethnic-specific analyses are warranted to verify our findings.