Whole-genome sequencing in a Finnish high-risk prostate cancer family to identify a novel cancer predisposition gene

Abstract

The etiology of prostate cancer (PCa) is significantly associated with hereditary genetic predisposition. However, a large portion of PCa with hereditary predisposition lacks the knowledge of the causative genetic factors. The primary aim of this thesis was to identify novel pathogenic PCa-associated germline variants from a Finnish high-risk PCa family, that could be utilized as prognostic markers for PCa risk. Twenty-five deleterious germline variants were selected from whole-genome sequencing (WGS) data from the index patient and were genotyped by Sanger sequencing in the affected patients of the family (n=6). The four most carried variants among the affected patients were genotyped in healthy individuals within the family (n=10) but none of the variants segregated fully with PCa phenotype. The most segregated HGH1 variant localized to a previously identified PCa risk locus at 8q24. The second most segregated HPSE variant was predicted in silico as the most pathogenic variant, and the gene had a connection to PCa in previous literature. However, the variants were not associated with PCa in FinnGen dataset. Although no definitive variant was identified in this study, the hereditary mutational burden of the variants can increase the risk for PCa. To address the unmet need in separating clinically significant and non-significant PCa cases, the HGH1 and HPSE variants could be potential polygenic risk score (PRS) candidates in PCa risk prediction, which could improve PCa risk assessment, treatment strategies, and patient outcomes. However, additional research and functional studies are warranted to validate the role of the variants in PCa predisposition.