Genomic basis for RNA alterations in cancer

By C. Calabrese, Natalie R. Davidson, Deniz Demircioğlu, Nuno A. Fonseca, Yao He, A. Kahles, Kjong-Van Lehmann, Fenglin Liu, Y. Shiraishi, C. Soulette and 64 more. Nature, 2020

354 citations recorded by the source corpus.

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. Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/ca8e6e44b7b0530cdb9313108aab6eee7915aee5

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

In Molecular Biology

Citations in the corpus

A systematic benchmark of Nanopore long read RNA sequencing for transcript level analysis in human cell lines (2021, background): “(5) Long read data improves over short read data for transcript abundance estimation While gene expression analysis is highly robust, the estimation of transcript expression abundance is more challenging as distinct transcripts from the same genes are often largely similar 16–19.”