Heritable methylation marks associated with prostate cancer risk

Abstract

DNA methylation marks that are inherited from parents to offspring are known to play a role in cancer risk and could explain part of the familial risk for cancer. We therefore conducted a genome-wide search for heritable methylation marks associated with prostate cancer risk. Peripheral blood DNA methylation was measured for 133 of the 469 members of 25 multiple-case prostate cancer families, using the EPIC array. We used these families to systematically search the genome for methylation marks with Mendelian patterns of inheritance, then we tested the 1,000 most heritable marks for association with prostate cancer risk. After correcting for multiple testing, 41 heritable methylation marks were associated with prostate cancer risk. Separate analyses, based on 869 incident cases and 869 controls from a prospective cohort study, showed that 9 of these marks near the metastable epiallele VTRNA2-1 were also nominally associated with aggressive prostate cancer risk in the population.

SAM-DNMT3A, a strategy for induction of genome-wide DNA methylation, identifies DNA methylation as a vulnerability in ER-positive breast cancers

“…Pooled genetic screens enable high throughput investigation of genetic perturbations and how they regulate biological processes 21, 22 . We have previously reported that some methylation sites are heritable and some of these heritable methylation sites are associated with increased risk of breast 7, 8 and prostate 8, 9 cancer. Increased cell proliferation is a hallmark of cancer 23 and is associated with many cancer risk associated genes 24 .…”

“…Mendelian-like inheritance of DNA methylation has been shown in various organisms 6 . We have shown that in some cases heritable DNA methylation is associated with susceptibility to different cancer types 7,8,9 . Although DNA methylation is a fundamental cellular process that is involved in almost every aspect of life, due to the limited available toolkit to study DNA methylation, we still lack comprehensive understanding of how DNA methylation mediates biological processes.…”

Non-coding 886 ( nc886 / vtRNA2-1 ), the epigenetic odd duck – implications for future studies

“…In studies where the original methylation pattern has been considered, both hyper- and hypomethylation have been reported [ 43 , 55 , 115 ], with both also reported to have predicted poorer survival [ 37 , 115 ]. Also, the innate DNA methylation status of the nc886 locus has been shown to predict the future risk of prostate [ 4 , 5 ], breast [ 5 , 42 ] and pancreatic cancer [ 116 ], although the study by Wang et al treats nc886 methylation as a continuous variable and reports rather inconsistent results [ 116 ]. These studies suggest that individuals with non-methylated nc886 might be at an increased risk of developing cancer, which would, at least in theory, be in line with the suggested growth-promoting role of maternally imprinted genes, such as nc886 , during foetal development [ 117 ].…”

Non-coding 886 (nc886/vtRNA2-1), the epigenetic odd duck – implications for future studies

“…Non-coding 886 (nc886, HGNC symbol vtRNA2-1, previously referred to also as pre-miR-886, CBL3 and hvg-5) is the only known polymorphically imprinted gene in humans, the variation of which is not caused by genetic factors [1][2][3][4][5] . In population cohorts consisting mainly of Caucasians, 75% of individuals have been reported to present a maternally imprinted region in this locus (chr5:136078784-136080957, GRCh38 2 ), while approximately 25% of individuals present two non-methylated alleles 1,[6][7][8] (Figure 1A).…”

“…In those studies, where the original methylation pattern has been considered, both hyper- and hypomethylation have been reported 42,53,113 , with hypermethylation being associated with poorer survival and increased risk of tumour recurrence 113 . Also, the innate DNA methylation status of nc886 locus has been shown to predict the future risk of prostate 4,5 , breast 5,41 and pancreatic cancer 114 , although the study by Wang et al treats nc886 methylation as a continuous variable and reports rather inconsistent results 114 . These studies suggest that individuals with non-methylated nc886 might be at increased risk of developing cancer, which would, at least in theory, be in line with the suggested growth promoting role of maternally imprinted genes, such as nc886 , during foetal development 115 .…”