Cis-regulatory drivers in colorectal cancer. H. Ongen1, C. L. Andersen2, J. B. Bramsen2, B. Oster2, M. H. Rasmussen2, P. G. Ferreira1, J. Sandoval3, E. Vidal3, N. Whiffin4, I. Tomlinson5, R. S. Houlson4, M. Esteller3, T. F. Orntoft2, E. T. Dermitzakis1 1) Department of Genetics and Development, CMU, University of Geneva, Geneva., Switzerland; 2) Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; 3) Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Catalonia, Spain; 4) Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK; 5) Nuffield Department of Clinical Medicine and Oxford NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK.
The cis-regulatory effects responsible for cancer development have not been as extensively studied as the perturbations of the protein coding genome in tumorigenesis. In order to better characterise colorectal cancer (CRC) development we are conducting an RNA-seq experiment of 300 matched tumour and adjacent normal colon mucosa samples from CRC patients of Danish origin, which are also germline genotyped. Preliminary analysis with 103 matched samples show that there are 1626 differentially expressed genes (FDR = 5%, fold change 2) between normal colon and cancer. We identify multiple regions on nearly all chromosomes where the correlation of expression for proximal genes is significantly increased in the tumours when compared to normals. On average there are 688 significant allele-specific expression (ASE) signals (FDR = 1%) per sample. The proportion of sites that have an ASE effect is significantly more in tumours. By investigating ASE we show that the germline genotypes remain important determinants of allelic gene expression in tumours. Utilizing the changes in ASE in 103 matched pairs of samples we discover 71 genes with excess of somatic cis-regulatory effect in CRC, suggesting a cancer driver role. We correlated genotypes and gene expression to identify expression quantitative trait loci (eQTLs) in 103 normal and tumour tissues and find 1693 and 948 cis-eQTLs in normals 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 find tumour-specific eQTLs are more enriched for low CRC genome-wide association study (GWAS) p-values than shared eQTLs, which suggests some of the variants discovered in GWAS are cis-regulatory variants active specifically in the tumour. 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 drivers.
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