en
Scientific article
English

Putative cis-regulatory drivers in colorectal cancer

Published inNature, vol. 512, no. 7512, p. 87-90
Publication date2014
Abstract

The cis-regulatory effects responsible for cancer development have not been as extensively studied as the perturbations of the protein coding genome in tumorigenesis. To better characterize colorectal cancer (CRC) development we conducted an RNA-sequencing experiment of 103 matched tumour and normal colon mucosa samples from Danish CRC patients, 90 of which were germline-genotyped. By investigating allele-specific expression (ASE) we show that the germline genotypes remain important determinants of allelic gene expression in tumours. Using the changes in ASE in matched pairs of samples we discover 71 genes with excess of somatic cis-regulatory effects in CRC, suggesting a cancer driver role. We correlate genotypes and gene expression to identify expression quantitative trait loci (eQTLs) and find 1,693 and 948 eQTLs in normal samples and tumours, respectively. We estimate that 36% of the tumour eQTLs are exclusive to CRC and show that this specificity is partially driven by increased expression of specific transcription factors and changes in methylation patterns. We show that tumour-specific eQTLs are more enriched for low CRC genome-wide association study (GWAS) P values than shared eQTLs, which suggests that some of the GWAS variants are tumour specific regulatory variants. Importantly, tumour-specific eQTL genes also accumulate more somatic mutations when compared to the shared eQTL genes, raising the possibility that they constitute germline-derived cancer regulatory drivers. Collectively the integration of genome and the transcriptome reveals a substantial number of putative somatic and germline cis-regulatory cancer changes that may have a role in tumorigenesis.

Keywords
  • Alleles
  • Cell Transformation, Neoplastic/genetics/pathology
  • Colorectal Neoplasms/genetics/pathology
  • DNA Methylation
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic/genetics
  • Genes, Neoplasm
  • Genome-Wide Association Study
  • Genotype
  • Germ-Line Mutation/genetics
  • Humans
  • Intestinal Mucosa/cytology/metabolism/pathology
  • Quantitative Trait Loci/genetics
  • Regulatory Sequences, Nucleic Acid/genetics
  • Sequence Analysis, RNA
  • Transcription Factors/metabolism
  • Transcriptome/genetics
Citation (ISO format)
ONGEN, Halit et al. Putative cis-regulatory drivers in colorectal cancer. In: Nature, 2014, vol. 512, n° 7512, p. 87–90. doi: 10.1038/nature13602
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Article (Published version)
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ISSN of the journal0028-0836
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