Ten genetic loci for colorectal cancer have been identified from published genome wide association (GWA) studies of colorectal cancer (CRC) and have been robustly replicated in populations of European ancestry. We hypothesize that additional novel risk loci will be identified by joint analyses in which data of approximately 7,000 cases and 7,000 controls from the five existing GWA studies are combined and validated in additional independent samples of cases and controls. In addition, combining genotypic data will allow analyses to be stratified according to demographic and clinico-pathological parameters, and permit studies to identify gene-gene interaction effects that specifically increase CRC risk. Genetic loci identified by pooled analyses will be examined in more detail here in Area 1 "Discovery Expansion and Replication" as well as Area 3 "Epidemiologic Studies" in additional case-control studies and nested case-control studies derived from two prospective cohort studies (Melbourne and ACS Cancer Prevention Study II Nutrition Cohort) to determine the extent that these and previously identified common variants are associated with risk. Finally, follow-up fine mapping studies, together with functional analyses in Area 2 - "Biological Studies", will help to identify the specific causal factors that influence risk of CRC. The goal of this proposal is therefore to establish find new genetic associations through pooled analyses, independently replicate these findings to confirm genotype-phenotype associations, fine-map association signals, and pursue gene-gene interactions with high-density data. The proposed study will comprehensively and efficiently identify new genes that predispose to colorectal cancer. This work has considerable potential to reveal new important targets for cancer prevention and treatment.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program--Cooperative Agreements (U19)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-SRLB-4)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Southern California
Los Angeles
United States
Zip Code
Closa, Adria; Cordero, David; Sanz-Pamplona, Rebeca et al. (2014) Identification of candidate susceptibility genes for colorectal cancer through eQTL analysis. Carcinogenesis 35:2039-46
Cheng, Iona; Kocarnik, Jonathan M; Dumitrescu, Logan et al. (2014) Pleiotropic effects of genetic risk variants for other cancers on colorectal cancer risk: PAGE, GECCO and CCFR consortia. Gut 63:800-7
Wang, Hansong; Burnett, Terrilea; Kono, Suminori et al. (2014) Trans-ethnic genome-wide association study of colorectal cancer identifies a new susceptibility locus in VTI1A. Nat Commun 5:4613
Hazelett, Dennis J; Rhie, Suhn Kyong; Gaddis, Malaina et al. (2014) Comprehensive functional annotation of 77 prostate cancer risk loci. PLoS Genet 10:e1004102
Biancolella, Michela; Fortini, Barbara K; Tring, Stephanie et al. (2014) Identification and characterization of functional risk variants for colorectal cancer mapping to chromosome 11q23.1. Hum Mol Genet 23:2198-209
Du, Mengmeng; Zhang, Xuehong; Hoffmeister, Michael et al. (2014) No evidence of gene-calcium interactions from genome-wide analysis of colorectal cancer risk. Cancer Epidemiol Biomarkers Prev 23:2971-6
Fortini, Barbara K; Tring, Stephanie; Plummer, Sarah J et al. (2014) Multiple functional risk variants in a SMAD7 enhancer implicate a colorectal cancer risk haplotype. PLoS One 9:e111914
Freedman, Matthew L; Monteiro, Alvaro N A; Gayther, Simon A et al. (2011) Principles for the post-GWAS functional characterization of cancer risk loci. Nat Genet 43:513-8