New variations uncovered in the silent parts of the genome with a relevance in cancer

Eduardo Eyras – Universitat Pompeu Fabra (UPF)

Cancer genomics has highlighted the prevalence of sequence variants of unknown significance. In our publication we hypothesized that a fraction of these mutations may reflect RNA-related selection processes, thereby impacting RNA metabolism and contributing to oncogenic processes. Analyzing whole genome sequencing data from multiple cancers we uncovered frequent mutations in binding sites for RNA binding proteins and splicing regulators. Furthermore, using RNA sequencing from the same samples validated a change in RNA processing in association to these mutations. We described new alterations in cancer that impact RNA processing and proposed a systematic method for the interpretation of noncoding variants in cancer genomes.

Reference

Singh B, Trincado JL, Tatlow PJ, Piccolo SR & Eyras E 2018, ‘Genome Sequencing and RNA-Motif Analysis Reveal Novel Damaging Noncoding Mutations in Human Tumors’, Molecular Cancer Research, 16(7):1112-1124.

Feaured in the journal highlights and in the cover of July issue.

In this article we studied the recurrence of cancer mutations on potential RNA-binding protein (RBP) binding sites using whole genome sequencing data from 14 different tumor types. Our study defined new alterations in non-coding regions that impact RNA processing and proposes a systematic method for aiding the interpretation of noncoding variants in cancer genomes. The cover image is based on the representation of the proportion of patient samples that show a mutated RBP binding site in each of the tumor types analyzed, coded in different colors. Colorectal tumors (cyan) and melanoma (brown) are the cancer types with the highest proportion of mutated RBP motifs.