Genomic basis for RNA alterations in cancer

Date 06 February 2020   Categories News, Featured

The paper “Genomic basis for RNA alterations in cancer” of the collaborative research efforts of the international cancer genome consortium subgroup “PCAWG” is out - together with 22 other papers published in Nature and its affiliated journals.

Cancer is a disease that is caused by DNA-sequence changes that are accumulating in the cells of a human body. In addition to such changes in the genome, changes in RNA have also been observed. Given our current knowledge of such RNA alterations, it is difficult to link the changes occurring in the DNA to observable differences in the RNA. This is mainly due to a lack of samples being available that measure both RNA and DNA as well as the large differences between individual types of cancer. In our study, we collected and analysed the most comprehensive catalogue of cancer-associated gene alterations to date. This catalogue is based on DNA and RNA sequencing samples  from 1,188 donors of the Pan-Cancer Analysis of Whole Genomes (PCAWG) consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). Using this collection of DNA/RNA sample pairs, we were able to study several categories of RNA alterations and link them to both heritable and non-heritable changes within the genome. This also allowed us to suggest probable genetic mechanisms underlying these links. Lastly, the compendium of RNA changes provided in a genomic context will serve as a valuable resource for future research and can help identify additional genes and mechanisms that play a role in the formation of cancer and its progression.

Abstract Transcript alterations often result from somatic changes in cancer genomes1. Various forms of RNA alterations have been described in cancer, including overexpression2, altered splicing3 and gene fusions4; however, it is difficult to attribute these to underlying genomic changes owing to heterogeneity among patients and tumour types, and the relatively small cohorts of patients for whom samples have been analysed by both transcriptome and whole-genome sequencing. Here we present, to our knowledge, the most comprehensive catalogue of cancer-associated gene alterations to date, obtained by characterizing tumour transcriptomes from 1,188 donors of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA)5. Using matched whole-genome sequencing data, we associated several categories of RNA alterations with germline and somatic DNA alterations, and identified probable genetic mechanisms. Somatic copy-number alterations were the major drivers of variations in total gene and allele-specific expression. We identified 649 associations of somatic single-nucleotide variants with gene expression in cis, of which 68.4% involved associations with flanking non-coding regions of the gene. We found 1,900 splicing alterations associated with somatic mutations, including the formation of exons within introns in proximity to Alu elements. In addition, 82% of gene fusions were associated with structural variants, including 75 of a new class, termed ‘bridged’ fusions, in which a third genomic location bridges two genes. We observed transcriptomic alteration signatures that differ between cancer types and have associations with variations in DNA mutational signatures. This compendium of RNA alterations in the genomic context provides a rich resource for identifying genes and mechanisms that are functionally implicated in cancer.

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