Identification of candidate susceptibility genes for colorectal cancer through eQTL analysis.
In this study, we aim to identify the genes responsible for colorectal cancer risk behind the loci identified in genome-wide association studies (GWAS). These genes may be candidate targets for developing new strategies for prevention or therapy. We analyzed the association of genotypes for 26 GWAS single nucleotide polymorphisms (SNPs) with the expression of genes within a 2 Mb region (cis-eQTLs). Affymetrix Human Genome U219 expression arrays were used to assess gene expression in two series of samples, one of healthy colonic mucosa (n = 47) and other of normal mucosa adjacent to colon cancer (n = 97, total 144). Paired tumor tissues (n = 97) were also analyzed but did not provide additional findings. Partial Pearson correlation (r), adjusted for sample type, was used for the analysis. We have found Bonferroni-significant cis-eQTLs in three loci: rs3802842 in 11q23.1 associated to C11orf53, COLCA1 (C11orf92) and COLCA2 (C11orf93; r = 0.60); rs7136702 in 12q13.12 associated to DIP2B (r = 0.63) and rs5934683 in Xp22.3 associated to SHROOM2 and GPR143 (r = 0.47). For loci in chromosomes 11 and 12, we have found other SNPs in linkage disequilibrium that are more strongly associated with the expression of the identified genes and are better functional candidates: rs7130173 for 11q23.1 (r = 0.66) and rs61927768 for 12q13.12 (r = 0.86). These SNPs are located in DNA regions that may harbor enhancers or transcription factor binding sites. The analysis of trans-eQTLs has identified additional genes in these loci that may have common regulatory mechanisms as shown by the analysis of protein-protein interaction networks.
Cancer Prevention and Control Program, Catalan Institute of Oncology, and Consortium for Biomedical Research on Epidemiology and Public Health (CIBERESP), Barcelona E08907, Spain, Colorectal Cancer Group, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona E08907, Spain.
Adria
A
Closa
Cancer Prevention and Control Program, Catalan Institute of Oncology, and Consortium for Biomedical Research on Epidemiology and Public Health (CIBERESP), Barcelona E08907, Spain, Colorectal Cancer Group, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona E08907, Spain.
David
D
Cordero
Cancer Prevention and Control Program, Catalan Institute of Oncology, and Consortium for Biomedical Research on Epidemiology and Public Health (CIBERESP), Barcelona E08907, Spain, Colorectal Cancer Group, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona E08907, Spain.
Rebeca
R
Sanz-Pamplona
Cancer Prevention and Control Program, Catalan Institute of Oncology, and Consortium for Biomedical Research on Epidemiology and Public Health (CIBERESP), Barcelona E08907, Spain, Colorectal Cancer Group, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona E08907, Spain.
Xavier
X
Solé
Cancer Prevention and Control Program, Catalan Institute of Oncology, and Consortium for Biomedical Research on Epidemiology and Public Health (CIBERESP), Barcelona E08907, Spain, Colorectal Cancer Group, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona E08907, Spain.
Marta
M
Crous-Bou
Cancer Prevention and Control Program, Catalan Institute of Oncology, and Consortium for Biomedical Research on Epidemiology and Public Health (CIBERESP), Barcelona E08907, Spain, Colorectal Cancer Group, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona E08907, Spain.
Laia
L
Paré-Brunet
Cancer Prevention and Control Program, Catalan Institute of Oncology, and Consortium for Biomedical Research on Epidemiology and Public Health (CIBERESP), Barcelona E08907, Spain, Colorectal Cancer Group, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona E08907, Spain.
Antoni
A
Berenguer
Cancer Prevention and Control Program, Catalan Institute of Oncology, and Consortium for Biomedical Research on Epidemiology and Public Health (CIBERESP), Barcelona E08907, Spain, Colorectal Cancer Group, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona E08907, Spain.
Elisabet
E
Guino
Cancer Prevention and Control Program, Catalan Institute of Oncology, and Consortium for Biomedical Research on Epidemiology and Public Health (CIBERESP), Barcelona E08907, Spain, Colorectal Cancer Group, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona E08907, Spain.
Adriana
A
Lopez-Doriga
Gastroenterology Service, Bellvitge University Hospital, Barcelona E08907, Spain and.
Jordi
J
Guardiola
Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona E08907, Spain, General and Digestive Surgery Service, Bellvitge University Hospital, Barcelona E08907, Spain.
Sebastiano
S
Biondo
Medical Oncology Service, Catalan Institute of Oncology, Barcelona E08907, Spain.
Ramon
R
Salazar
Cancer Prevention and Control Program, Catalan Institute of Oncology, and Consortium for Biomedical Research on Epidemiology and Public Health (CIBERESP), Barcelona E08907, Spain, Colorectal Cancer Group, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona E08907, Spain, Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona E08907, Spain, v.moreno@iconcologia.net.
Victor
V
Moreno
D016022:Case-Control Studies; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D041321:Chromosomes, Human, X; D015179:Colorectal Neoplasms / Q000235:genetics*; D005136:Eye Proteins / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D008562:Membrane Glycoproteins / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012313:RNA
D005136:Eye Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D012313:RNA; C588266:COLCA1 protein, human; C588267:POU2AF3 protein, human; C517831:DIP2B protein, human; C095276:GPR143 protein, human; C101060:SHROOM2 protein, human