Colorectal cancer (CRC) is a common malignancy in Western countries. However, its frequency varies four-fold among US ethnic/racial minorities, with Japanese Americans (JAs) and African Americans (AAs) having a marked excess risk for the disease. Moreover, in contrast to JA patients who experience a better survival than whites, AAs with CRC present at a later stage and have a shorter, stage-adjusted survival than whites. The poor outcome of AA patients is not completely explained by their reduced access to medical care. These ethnic/racial disparities constitute an important public health challenge and also offer unique opportunities for etiologic research. This collaborative application will build upon the existing colorectal cancer Cooperative Family Registry (CFR) resource by recruiting additional families of AA (N=979) and Japanese (N=448) descent in Northern California, Southern California, North Carolina and Hawaii, using the CFR core protocol. We will then use the data and samples collected from a total of 1,514 AA, 745 JA and 750 white population-based families in the CFR to test the following hypotheses: 1) DNA mismatch repair deficiency is a more common pathogenic pathway to CRC in AAs, compared to whites, as reflected by a greater prevalence of tumor microsatellite instability (MSI); 2) Functional gene variants and environmental exposures related to chemical carcinogenesis and methyl group metabolism are associated with an increased risk of MSI-high CRC, particularly in AAs and JAs; 3) Functional variants in cell proliferation- and angiogenesis-related genes are associated with risk of advanced-stage CRC and poor overall survival, particularly in AAs; 4) Functional variants in genes related to response to 5-fluorouracil/oxaliplatin chemotherapy are associated with shorter disease-free and overall survival, especially in AA s; 5) Other gene variants that are rare in whites but relatively common in AAs and JAs are associated with CRC and may significantly contribute to the etiology of the disease in these groups. The power to test these hypotheses will not be adequate without the proposed expanded recruitment. The insight into biological pathways gained by this project may lead to new means of prevention and treatment that may help not only to alleviate health disparities in the US but also better control CRC among all ethnic/racial groups.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA104132-05
Application #
7488826
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Seminara, Daniela
Project Start
2004-09-28
Project End
2011-06-30
Budget Start
2008-07-01
Budget End
2011-06-30
Support Year
5
Fiscal Year
2008
Total Cost
$1,811,155
Indirect Cost
Name
University of Hawaii
Department
Type
Organized Research Units
DUNS #
965088057
City
Honolulu
State
HI
Country
United States
Zip Code
96822
Jenkins, Mark A; Win, Aung Ko; Templeton, Allyson S et al. (2018) Cohort Profile: The Colon Cancer Family Registry Cohort (CCFRC). Int J Epidemiol 47:387-388i
DeRycke, Melissa S; Gunawardena, Shanaka; Balcom, Jessica R et al. (2017) Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes. Mol Genet Genomic Med 5:553-569
Raskin, Leon; Guo, Yan; Du, Liping et al. (2017) Targeted sequencing of established and candidate colorectal cancer genes in the Colon Cancer Family Registry Cohort. Oncotarget 8:93450-93463
Wang, Hansong; Schmit, Stephanie L; Haiman, Christopher A et al. (2017) Novel colon cancer susceptibility variants identified from a genome-wide association study in African Americans. Int J Cancer 140:2728-2733
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
Wang, Hansong; Haiman, Christopher A; Burnett, Terrilea et al. (2013) Fine-mapping of genome-wide association study-identified risk loci for colorectal cancer in African Americans. Hum Mol Genet 22:5048-55
Dalal, P; Leslie, N D; Lindor, N M et al. (2010) Motor tics, stereotypies, and self-flagellation in primrose syndrome. Neurology 75:284-6
Luchtenborg, Margreet; White, Kami K L; Wilkens, Lynne et al. (2007) Smoking and colorectal cancer: different effects by type of cigarettes? Cancer Epidemiol Biomarkers Prev 16:1341-7