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.
Highlights
Cancer genomics suffers from a dramatic signal to noise problem, where the majority of somatic mutations are not expected to cause cancer phenotypes, but to be passenger mutations that do not contribute to selective growth advantage [1,2,3]
After isolating noncoding single nucleotide variants (SNVs) from primary liver cancer (PLC) samples, we removed variants at positions of known population variants and kept only variants that were confirmed somatic and that were discovered from whole genome resequencing (WGS) (Methods)
We focused our analysis on WGS-derived variants because we wanted an unbiased interrogation of somatically mutated genome-wide regulatory elements
Summary
Cancer genomics suffers from a dramatic signal to noise problem, where the majority of somatic mutations are not expected to cause cancer phenotypes, but to be passenger mutations that do not contribute to selective growth advantage [1,2,3]. The challenge of identifying mutations that change cancer phenotype is especially difficult in the noncoding genome: whereas over 50 years of molecular genetics research has given cancer investigators a toolkit for understanding the deleteriousness of coding mutation, the same code book does not exist for noncoding mutations. Annotation of somatic mutations in primary liver cancer. National Cancer Institute [http://www.cancer.gov] U01CA200060 (TW); American Cancer Society [http://cancer.org] Research Scholar grant RSG14-049-01-DMC (TW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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