|Grant Number:||5R01CA129063-04 Interpret this number|
|Primary Investigator:||Le Marchand, Loic|
|Organization:||University Of Hawaii At Manoa|
|Project Title:||Inflammation and Innate Immunity Genes and Colorectal Cancer Risk|
DESCRIPTION: Because of the many similarities between chronic inflammation and the malignant process, and because of the elimination of early neoplastic cells by immune surveillance, there has been a long standing interest in the role of inflammation and innate immunity in cancer. Theses relationships are thought to be particularly relevant to colorectal cancer (CRC) because of its well-established strong associations with history of inflammatory bowel disease and use of non-steroidal anti-inflammatory drug, and the presence in the gut of a remarkably abundant immune system that is constantly stimulated by commensal bacteria. The proposed study will use existing data and specimens from the Colon Cancer Family Registry (CCFR) and the Multiethnic Cohort (MEC) to test the hypothesis that inherited variants in key genes in the inflammation and innate immunity pathways result in a pro-inflammatory predisposition and weak cytotoxic defense that confer an increased risk of CRC. We propose in Aim 1 to conduct a case-control study using the White discordant sibpairs participating in the Colon CFR (2,488 CRC cases, 4,280 controls) to test the association of CRC with ~700 tagSNPs in genes in these pathways. The 38 genes selected were prioritized based on biological relevance and functional evidence. For each locus, tagSNPs will be selected using linkage disequilibrium (R2>0.9, MAF>0.05) from a dense SNP map constructed primarily from HapMap. In Aim 2, we will test approximately 10% of the most strongly associated SNPs in Aim 1, as well as additional tagSNPs at these loci and AIMs, in a second case-control study (2,768 CRC cases and 2,768 controls) nested in the MEC, in order to validate the findings and investigate heterogeneity of effects across ethnic/racial groups. The family-based design will fully protect Aim 1 against population stratification. Aim 2 will take advantage of the genetic and lifestyle heterogeneity of MEC participants and of the prospective nature of their exposure data to control Type I error, assess effect heterogeneity across ethnic/racial populations, and investigate GxG and GxE interactions. The association of inherited variants in inflammation or innate immunity-related genes with CRC would corroborate the etiologic role of persistent, sub-clinical inflammation in this cancer. It may also provide a means to identify susceptible sub-groups which may particularly benefit from NSAIDs chemoprevention and screening. PUBLIC HEALTH RELEVANCE: The proposed study will test the association of inherited variants in inflammation and innate immunity-related genes with colorectal cancer in order to confirm the causative role of persistent, sub-clinical inflammation for this cancer. It may also provide a means to identify susceptible sub-groups which may particularly benefit from intensive screening and/or primary prevention with non-steroidal inflammatory drugs.
A review of the application of inflammatory biomarkers in epidemiologic cancer research.
Authors: Brenner DR, Scherer D, Muir K, Schildkraut J, Boffetta P, Spitz MR, Le Marchand L, Chan AT, Goode EL, Ulrich CM, Hung RJ
Source: Cancer Epidemiol Biomarkers Prev, 2014 Sep;23(9), p. 1729-51.
EPub date: 2014 Jun 24.
Genetic variation in prostaglandin synthesis and related pathways, NSAID use and colorectal cancer risk in the Colon Cancer Family Registry.
Authors: Resler AJ, Makar KW, Heath L, Whitton J, Potter JD, Poole EM, Habermann N, Scherer D, Duggan D, Wang H, Lindor NM, Passarelli MN, Baron JA, Newcomb PA, Le Marchand L, Ulrich CM
Source: Carcinogenesis, 2014 Sep;35(9), p. 2121-6.
EPub date: 2014 Jun 7.
Genetic variation in UGT genes modify the associations of NSAIDs with risk of colorectal cancer: colon cancer family registry.
Authors: Scherer D, Koepl LM, Poole EM, Balavarca Y, Xiao L, Baron JA, Hsu L, Coghill AE, Campbell PT, Kleinstein SE, Figueiredo JC, Lampe JW, Buck K, Potter JD, Kulmacz RJ, Jenkins MA, Hopper JL, Win AK, Newcomb PA, Ulrich CM, Makar KW
Source: Genes Chromosomes Cancer, 2014 Jul;53(7), p. 568-78.
EPub date: 2014 Mar 28.
Genetic variation in the inflammation and innate immunity pathways and colorectal cancer risk.
Authors: Wang H, Taverna D, Stram DO, Fortini BK, Cheng I, Wilkens LR, Burnett T, Makar KW, Lindor NM, Hopper JL, Gallinger S, Baron JA, Haile R, Kolonel LN, Henderson BE, Newcomb PA, Casey G, Duggan D, Ulrich CM, Le Marchand L
Source: Cancer Epidemiol Biomarkers Prev, 2013 Nov;22(11), p. 2094-101.
EPub date: 2013 Sep 17.
C-reactive protein, lipid-soluble micronutrients, and survival in colorectal cancer patients.
Authors: Cooney RV, Chai W, Franke AA, Wilkens LR, Kolonel LN, Le Marchand L
Source: Cancer Epidemiol Biomarkers Prev, 2013 Jul;22(7), p. 1278-88.
EPub date: 2013 May 15.
Serum CRP and IL-6, genetic variants and risk of colorectal adenoma in a multiethnic population.
Authors: Ognjanovic S, Yamamoto J, Saltzman B, Franke A, Ognjanovic M, Yokochi L, Vogt T, Decker R, Le Marchand L
Source: Cancer Causes Control, 2010 Jul;21(7), p. 1131-8.
EPub date: 2010 Mar 24.