Evidence of linkage in MSH6-associated region exclusive to high-risk African-American families with prostate cancer.

Abstract

180 Background: The significance of germline variants and their implications for prostate cancer (PCa) patients has gained prominence. Mismatch repair (MMR) genes such as MSH6 and MSH2, along with DNA repair genes, may be more important in PCa than previously appreciated. In the present study, we compared linkage results between African American (AA) and Caucasian (CA) PCa families with multiple affected family members. Methods: Study subjects were from 15 large, high-risk, clinically homogenous AA families and 4 CA families from Southern Louisiana. All families had at least ≥ 3 members with family member diagnosed with PCa. Genotyping for linkage analyses was done using Illumina Infinium II SNP HumanLinkage-12 panel. 6,068 SNPs were released for linkage analyses. Parametric linkage analyses were performed using Merlin software, version 1.1.2. An HLOD score > 1.86 was considered suggestive of linkage. Results: A total of 129 individuals from 15 AA families were genotyped including 45 affected men, 44 unaffected men, and 40 women. The average age at diagnosis was 61; 8 of 15 families had more than 4 affected individuals. 50 CA individuals from similar families were genotyped including 12 affected men, 26 presently unaffected men, and 12 women. For CA families, the average age of onset was 66, with at least 5 affected individuals in each family. In AAs, we identified a peak of suggestive linkage at chromosome 2p16 (HLOD = 1.97). Similarly, in CA families, the strongest linkage signal was observed on chromosome 2q14.1 with an HLOD score of 1.94. At the2 q14 linkage region, there was no linkage in AA PCa families (HLOD = 0.0004). Similarly, on 2p16, there was no linkage in the CA cohort (HLOD = 0). Conclusions: The MSH6 gene is located in 2p16 region. MMR gene mutations have been shown to have evidence of microsatellite instability in PCa as well as hereditary nonpolyposis colorectal cancer. MSH6 gene may represent a genetic variant contributing to risk of PCa in high risk AA families. This potentially has therapeutic implications for use of PD1 inhibitors in this population.