title: Putative cis-regulatory drivers in colorectal cancer.
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.
authors: 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.
authors: Halit
authors: H
authors: Ongen
authors: Department of Molecular Medicine, Aarhus University Hospital, 8000 Aarhus, Denmark.
authors: Claus L
authors: CL
authors: Andersen
authors: Department of Molecular Medicine, Aarhus University Hospital, 8000 Aarhus, Denmark.
authors: Jesper B
authors: JB
authors: Bramsen
authors: Department of Molecular Medicine, Aarhus University Hospital, 8000 Aarhus, Denmark.
authors: Bodil
authors: B
authors: Oster
authors: Department of Molecular Medicine, Aarhus University Hospital, 8000 Aarhus, Denmark.
authors: Mads H
authors: MH
authors: Rasmussen
authors: 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.
authors: Pedro G
authors: PG
authors: Ferreira
authors: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Catalonia, Spain.
authors: Juan
authors: J
authors: Sandoval
authors: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Catalonia, Spain.
authors: Enrique
authors: E
authors: Vidal
authors: Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.
authors: Nicola
authors: N
authors: Whiffin
authors: 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.
authors: Alexandra
authors: A
authors: Planchon
authors: 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.
authors: Ismael
authors: I
authors: Padioleau
authors: 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.
authors: Deborah
authors: D
authors: Bielser
authors: 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.
authors: Luciana
authors: L
authors: Romano
authors: Nuffield Department of Clinical Medicine and Oxford NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK.
authors: Ian
authors: I
authors: Tomlinson
authors: Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.
authors: Richard S
authors: RS
authors: Houlston
authors: 1] Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Catalonia, Spain [2] Department of Physiological Sciences II, School of Medicine, University of Barcelona, 08007 Barcelona, Barcelona, Spain [3] Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain.
authors: Manel
authors: M
authors: Esteller
authors: Department of Molecular Medicine, Aarhus University Hospital, 8000 Aarhus, Denmark.
authors: Torben F
authors: TF
authors: Orntoft
authors: 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.
authors: Emmanouil T
authors: ET
authors: Dermitzakis
mesh_terms: D000483:Alleles; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D052138:Genes, Neoplasm; D055106:Genome-Wide Association Study; D005838:Genotype; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D040641:Quantitative Trait Loci / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D017423:Sequence Analysis, RNA; D014157:Transcription Factors / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics
chemical_list: D014157:Transcription Factors