Genome-wide germline correlates of the epigenetic landscape of prostate cancer

Abstract

Cancer initiation and progression are driven by germline, environmental and stochastic factors. How these interact to produce the molecular phenotypes of primary human tumours remains unknown. To better understand the role germline variation plays, we quantified the influence of germline single nucleotide polymorphisms (SNPs) on the somatic methylome of 589 primary localized prostate tumours with genome-wide DNA and methylation sequencing. We show that known risk loci influence a tumour’s epigenetic landscape, uncovering a mechanism for cancer susceptibility. We then identify and validate 1,178 loci associated with altered methylation levels in tumour tissue but not in non-malignant tissue. These tumour methylation quantitative trait loci (tumour meQTLs) influence chromatin structure, RNA abundance and protein abundance and recapitulate previously reported risk loci. One prominent tumour meQTL is associated with tumour-specific methylation and expression of TCERG1L, a transcription elongation factor predictive of rapid biochemical relapse following definitive local management. Another tumour meQTL is associated with expression of the oncogene AKT1 and is predictive of relapse in both our discovery cohort and an independent 101-patient validation cohort. Taken together, these data reveal a strong interplay between the germline mutational profile and the epigenomic features of primary tumours which can be exploited to understand the role of germline genetics in the heritability of aggressive prostate cancer.