""""""""Incorporating intermediate biomarkers of folate with colorectal cancer"""""""" The goal of this proposal is to measure intermediate biomarkers and to evaluate these with statistical methods designed to elucidate the underlying etiologic mechanism of colorectal cancer. The proposal leverages existing genetic data from studies conducted within the Colon Cancer Family Registry (Colon CFR), an NCI-supported consortium initiated in 1997 and dedicated to the establishment of a comprehensive collaborative infrastructure for interdisciplinary studies in the genetics and genetic epidemiology of colorectal cancer. The subjects include 1,531 controls genotyped in a candidate gene study of FOCM pathway genes (RO1CA112237), and 999 controls genotyped in a genome wide association study of colon CFR cases (U01CA122839). In these subjects, we will evaluate plasma measures within one carbon metabolism (plasma folate, vitamins B2, B6, B12, methionine, methyl malonic acid, creatinine, plasma total Hcy (tHcy), and DNA methylation in circulating lymphocytes (PBL)). In addition, we build upon our previous work in developing statistical methods for modeling genetic associations in putative disease pathways. These models integrate various levels of data, e.g. genotypes, gene expression, biomarkers, and exogenous exposures, with prior information to build more comprehensive statistical models for better prioritization, estimation, and characterization of genetic effects.

Public Health Relevance

The overall goal of this proposal is to gain further insight into the underlying etiologic mechanism of colorectal cancer. We will accomplish this by first measuring intermediate biomarkers relevant to folate associated one- carbon metabolism in subjects with existing genotype data from a related candidate gene pathway-based and genome-wide association studies (GWAS). Then using novel statistical methods, we will investigate SNP- biomarker, SNP-disease, and pathway-disease associations to provide more insight into the complex effects of folate on the colorectal carcinogenic process.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA140561-02
Application #
8329606
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Zhu, Claire
Project Start
2011-09-07
Project End
2016-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$462,872
Indirect Cost
$180,633
Name
University of Southern California
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Newcombe, Paul J; Conti, David V; Richardson, Sylvia (2016) JAM: A Scalable Bayesian Framework for Joint Analysis of Marginal SNP Effects. Genet Epidemiol 40:188-201
Bough, K J; Lerman, C; Rose, J E et al. (2013) Biomarkers for smoking cessation. Clin Pharmacol Ther 93:526-38
Quintana, M A; Conti, D V (2013) Integrative variable selection via Bayesian model uncertainty. Stat Med 32:4938-53
Baurley, James W; Conti, David V (2013) A scalable, knowledge-based analysis framework for genetic association studies. BMC Bioinformatics 14:312
Quintana, Melanie A; Schumacher, Fredrick R; Casey, Graham et al. (2012) Incorporating prior biologic information for high-dimensional rare variant association studies. Hum Hered 74:184-95
Liang, Wei E; Thomas, Duncan C; Conti, David V (2012) Analysis and optimal design for association studies using next-generation sequencing with case-control pools. Genet Epidemiol 36:870-81
Quintana, Melanie A; Berstein, Jonine L; Thomas, Duncan C et al. (2011) Incorporating model uncertainty in detecting rare variants: the Bayesian risk index. Genet Epidemiol 35:638-49