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Prostate Cancer Methylation Levels Linked to Regulatory Variants in Germline

NEW YORK – Cancer-related alterations found in the germline of individuals with prostate cancer seem to impact epigenetic profiles that appear in their prostate tumor tissue, new research suggests.

Members of an international team led by investigators in Canada, the US, and the UK brought together new and already available whole-genome or exome sequence data for nearly 600 individuals with localized prostate cancer to tally germline variants across the genome. They then looked at how these alterations lined up with somatic mutations and array-based DNA methylation features in the patients' tumor tissue.

The team's findings, which appeared online today in Nature Medicine, highlighted thousands of germline variants that appeared to influence methylation levels, including a subset of variants with ties to methylation levels in prostate tumors but not in cancer-free tissue.

"These data reveal intricate crosstalk between the germline and the epigenome of primary tumors, which may help identify germline biomarkers of aggressive disease to aid patient triage and optimize the use of more invasive or expensive diagnostic assays," co-senior and co-corresponding authors Paul Boutros and Robert Bristow, along with their colleagues, wrote.

Boutros is a researcher at the University of California, Los Angeles. He also directs cancer data science at UCLA's Jonsson Comprehensive Cancer Center and he was affiliated with the Ontario Institute for Cancer Research, the University of Toronto, and the Vector institute when the study was initiated.

Bristow was named director of the University of Manchester's Manchester Cancer Research Centre in 2017. Prior to that, his affiliations were with the University of Toronto's medical biophysics and radiation oncology departments, as well as the Princess Margaret Cancer Centre.

"Since single nucleotide polymorphisms can confer susceptibility by modulating DNA methylation, we reasoned that interrogating the more direct link between the germline and methylation would yield associations with larger effect sizes than germline survival analyses," the authors explained.

For the discovery stage of the study, the team generated new whole-genome germline sequence data for 80 individuals with untreated prostate cancer, analyzing them alongside 161 germline genomes for treatment-naïve prostate cancer patients sequenced for past studies.

After validation testing with data from the Cancer Genome Atlas (TGCA) project — which included tumor methylation profiles and exome sequence or SNP array data generated from blood samples of prostate cancer patient — the researchers settled on a set of almost 7,600 quantitative trait loci in the germline that appeared to influence methylation levels. From those, they narrowed in on 1,178 methylation quantitative trait loci (meQTL) in the genome that seemed to specifically influence DNA methylation levels in tumor tissue.

"MeQTLs detected in reference tissue may facilitate tumor initiation … while tumor meQTLs may facilitate tumor progression," the authors suggested.

With chromatin immunoprecipitation sequencing and other analyses on prostate cancer cell lines or tumor samples, the team went on to explore the relationships between tumor meQTLs and other genomic features in the tumor — from histone modifications and chromatin structure to RNA and protein expression levels.

The researchers also searched for tumor meQTLs with potential ties to prostate cancer aggressiveness, identifying a suspicious germline locus in the TCERG1L gene as well as a chromosome 14 haplotype that appeared to influence methylation and expression of AKT1.

Since altered AKT1 levels have been implicated in prostate cancer relapse risk, they went on to look for potential links to survival in another 101 individuals with prostate cancer, uncovering an apparent rise in relapse risk in those carrying the alternative allele at the AKT1 locus. 

"Taken together, these data highlight how germline genotypes can modulate the tumor epigenome to contribute to the tumorigenesis of aggressive prostate cancers," the authors wrote. "This phenomenon may apply to other tumor types, providing a strategy to create robust, minimally invasive biomarkers for the early detection of aggressive disease."

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