Epigenomic annotation of noncoding mutations identifies mutated pathways in primary liver cancer

Abstract

Evidence that noncoding mutation can result in cancer driver events is mounting. However, it is more difficult to assign molecular biological consequences to noncoding mutations than to coding mutations, and a typical cancer genome contains many more noncoding mutations than protein-coding mutations. Accordingly, parsing functional noncoding mutation signal from noise remains an important challenge. Here we use an empirical approach to identify putatively functional noncoding somatic single nucleotide variants (SNVs) from liver cancer genomes. Annotation of candidate variants by publicly available epigenome datasets finds that 40.5% of SNVs fall in regulatory elements. When assigned to specific regulatory elements, we find that the distribution of regulatory element mutation mirrors that of nonsynonymous coding mutation, where few regulatory elements are recurrently mutated in a patient population but many are singly mutated. We find potential gain-of-binding site events among candidate SNVs, suggesting a mechanism of action for these variants. When aggregating noncoding somatic mutation in promoters, we find that genes in the ERBB signaling and MAPK signaling pathways are significantly enriched for promoter mutations. Altogether, our results suggest that functional somatic SNVs in cancer are sporadic, but occasionally occur in regulatory elements and may affect phenotype by creating binding sites for transcriptional regulators. Accordingly, we propose that noncoding mutation should be formally accounted for when determining gene- and pathway-mutation burden in cancer.

Genome‐wide DNA methylation profiling of primary colorectal laterally spreading tumors identifies disease‐specific epimutations on common pathways

“…Consistent with previous discovery, 25 we found elevated observed/expected values across most tissues analyzed in repressed ChromHMM states, including heterochromatin (13_Het), repressed Polycomb states (17_ReprPCWk) and Quies (18_Quies) (Fig. 4a).…”

Deep‐targeted sequencing of endothelial nitric oxide synthase gene exons uncovers exercise intensity and ethnicity‐dependent associations with post‐exercise hypotension

“…In instances where there was insufficient power, for example, rs77325852 with a power of 30.5% for DBP and CADD score of 7.62 in Table , the CADD score indicated that this variant was likely to have causal variation effects. Evidence is mounting that noncoding variants located in DNA regulatory elements, as are all the NOS3 variants that passed multiple testing thresholds in our analyses (Table ), may have functional consequences by creating, deleting, or altering binding sites for transcriptional regulators (Lowdon and Wang ). Indeed, Chip‐seq annotations of NOS3 rs373009, rs867225, and rs77325852 from ENCODE‐based datasets provide strong evidence supporting regulatory effects, however, linking a specific regulatory effect to these polymorphisms is beyond the scope of our investigation.…”

Pathogenic noncoding variants in the neurofibromatosis and schwannomatosis predisposition genes

“…An increasing number of studies have reported variants located in intronic and regulatory regions as causative of rare disorders (Johnston et al, 2019; Vuckovic et al, 2020; Whiffin et al, 2020). Moreover, disruption of regulatory mechanisms of gene expression is recognized as an important factor in carcinogenesis (K. Li et al, 2020; Lowdon & Wang, 2017; Orlando et al, 2018; Weinhold et al, 2014). Furthermore, some studies have been able to define tumor subtypes by the recurrent noncoding variants they carry, suggesting the possibility of the use of epigenetic signatures in diagnosis and treatment (Hayward et al, 2017; Torchia et al, 2016; Wellenreuther et al, 1995)…”