Prostate cancer (PCa) is a highly heterogeneous disease with studies suggesting a degree of heritability greater than other cancers. It has been found that as much as 58% of disease risk can be explained by heritable factors. While more than 150 common genetic risk variants have been identified, these variants still only explain a minor portion of risk, are largely of low to moderate effect size, and are functionally ambiguous. There has recently been significant success in the discovery of rare genetic variants contributing to complex disease, through next-generation sequencing of large families, where rare variants are enriched and there is reduced genetic complexity. Here, we have applied whole-genome sequencing (WGS) to several large Tasmanian PCa pedigrees with the aim of identifying rare genetic variants contributing to the development of PCa.
Thirty-seven individuals from six PCa pedigrees were WGS on the Illumina HiSeq X™ Ten platform. Variants were prioritised on a per-family basis by frequency (<1% in 1KGP, UK10K, ExAC and ESP), segregation with disease, mutation type (missense, nonsense or splice) and predicted functional consequence (CADD, PolyPhen and SIFT). Unaffected older male relatives and population controls were also WGS and used to prioritise variants based on non-sharing. After additional genotyping in our larger familial and population datasets, familial-based association testing found two variants to be significantly associated with PCa risk. A rare variant in the non-coding region of the EZH2 gene was identified in two Tasmanian families, and has the potential to effect splicing. EZH2 is constitutively overexpressed in many cancer, including PCa, and therefore, functional studies are currently underway to determine the effect of the mutation on gene and protein expression.
This study was designed to identify new biological pathways involved in the pathogenesis of familial PCa and may lead to novel diagnostic and therapeutic targets for PCa patients.