Putative cis-regulatory drivers in colorectal cancer.

Nature 2014 Aug 23;512(7512):87-90. Epub 2014 Jul 23.

1] Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland [2] Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, 1211 Geneva, Switzerland [3] Swiss Institute of Bioinformatics, 1211 Geneva, Switzerland.

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.

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature13602DOI Listing
August 2014
40 Reads

Publication Analysis

Top Keywords

eqtl genes
8
cis-regulatory effects
8
gene expression
8
colorectal cancer
8
cancer
6
eqtls
5
crc
5
expression
5
genes raising
4
trait loci
4
raising possibility
4
expression quantitative
4
expression identify
4
identify expression
4
quantitative trait
4
shared eqtl
4
948 eqtls
4
eqtls normal
4
normal samples
4
samples tumours
4

References

(Supplied by CrossRef)

FW Huang et al.
Science 2013

H Dvinge et al.
Nature 2013

E Grundberg et al.
Nature Genet. 2012

T Lappalainen et al.
Am. J. Hum. Genet. 2011

The Cancer Genome Atlas et al.
Nature 2012

C Perez-Llamas et al.
PLoS ONE 2011

D Tamborero et al.
Scientific Rep. 2013

C Ma et al.
Genes Dev. 2008

D Sun et al.
J. Biol. Chem. 2013

CW Schweinfest et al.
Proc. Natl Acad. Sci. USA 1993

Similar Publications