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
Boonstra, Philip S; Mukherjee, Bhramar; Gruber, Stephen B et al. (2016) Tests for Gene-Environment Interactions and Joint Effects With Exposure Misclassification. Am J Epidemiol 183:237-47
Fehringer, Gordon; Kraft, Peter; Pharoah, Paul D et al. (2016) Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations. Cancer Res 76:5103-14
Su, Yu-Chen; Gauderman, William James; Berhane, Kiros et al. (2016) Adaptive Set-Based Methods for Association Testing. Genet Epidemiol 40:113-22
Scarbrough, Peter M; Weber, Rachel Palmieri; Iversen, Edwin S et al. (2016) A Cross-Cancer Genetic Association Analysis of the DNA Repair and DNA Damage Signaling Pathways for Lung, Ovary, Prostate, Breast, and Colorectal Cancer. Cancer Epidemiol Biomarkers Prev 25:193-200
Markowitz, Sanford D; Nock, Nora L; Schmit, Stephanie L et al. (2016) A Germline Variant on Chromosome 4q31.1 Associates with Susceptibility to Developing Colon Cancer Metastasis. PLoS One 11:e0146435
Sanz-Pamplona, Rebeca; Gil-Hoyos, Raúl; López-Doriga, Adriana et al. (2016) Mutanome and expression of immune response genes in microsatellite stable colon cancer. Oncotarget 7:17711-25
Zeng, Chenjie; Matsuda, Koichi; Jia, Wei-Hua et al. (2016) Identification of Susceptibility Loci and Genes for Colorectal Cancer Risk. Gastroenterology 150:1633-45
Schmit, Stephanie L; Rennert, Hedy S; Rennert, Gad et al. (2016) Coffee Consumption and the Risk of Colorectal Cancer. Cancer Epidemiol Biomarkers Prev 25:634-9
Phipps, Amanda I; Passarelli, Michael N; Chan, Andrew T et al. (2016) Common genetic variation and survival after colorectal cancer diagnosis: a genome-wide analysis. Carcinogenesis 37:87-95
Karami, Sara; Han, Younghun; Pande, Mala et al. (2016) Telomere structure and maintenance gene variants and risk of five cancer types. Int J Cancer 139:2655-2670

Showing the most recent 10 out of 50 publications