Several genome wide association (GWA) studies of colorectal cancer (CRC) have been published and have reported a number of significantly associated hits that have been robustly replicated in populations of European ancestry. It is expected that the number of identified CRC associations will increase through International efforts such as those described in Areas 1 and 3 of this proposal. To date there has been only modest emphasis on characterizing the putative causal variant(s) associated with these findings and even less effort directed towards developing a comprehensive understanding of their biological relevance. Such functional studies will be necessary if we are to fully exploit the potential of GWA studies. Meeting this challenge will not be simple, as the majority of the associations identified to date through GWA studies do not target coding exons of genes, but instead target variants that lie in non-coding regions near genes or within gene-poor regions making it more difficult to determine their functional consequences. The goal of this proposal is therefore to establish a comprehensive strategy to study the biological implications of the diverse associations identified through GWA studies of CRC. We will pursue selected validated hits and novel hits identified through the proposed studies described in Areas 1 and 3 of this study. We will leverage information from state-of-the-art ChlP-seq and RNA-seq approaches and incorporate in silico methods to identify candidate causal variants in genie or regulatory regions. The functional effects of putative causal variants will be validated using comprehensive gene-specific molecular and biochemical analyses. Successful completion of our Aims should lead to a better understanding of biological mechanisms underiying genetic associations with colorectal cancer risk. The proposed study will functionally characterize new genes that predispose to colorectal cancer. This functional characterization of new genes will provide important insight into the biological mechanisms underiying genetic risk for colorectal cancer and should reveal important targets for cancer prevention and treatment

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19CA148107-04
Application #
8548277
Study Section
Special Emphasis Panel (ZCA1-SRLB-4)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2013
Total Cost
$548,243
Indirect Cost
Name
University of Southern California
Department
Type
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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