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Grant Details

Grant Number: 2R01CA059045-10A1 Interpret this number
Primary Investigator: Potter, John
Organization: Fred Hutchinson Cancer Research Center
Project Title: Genome-Wide Association Study of Nonsynonymous Snps in Colon Cancer
Fiscal Year: 2007
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Abstract

DESCRIPTION (provided by applicant): At least 20%, perhaps as much as one-third of colon cancer is attributable to inherited factors. Identifying genetic variants is important to elucidate underlying mechanisms of colon cancer, the second leading cause of cancer death in the US. In the first 10 years of this grant, we have investigated several candidate-gene pathways. Our findings have contributed to the current understanding that numerous common genetic variants, with moderate associations, add substantially to the overall risk. To accelerate the discovery of colon cancer-related variants, we propose a genome-wide association study for all common amino-acid- altering (nonsynonymous) genetic variants in the human genome. Given recent advancements in genotyping technology, a genome-wide study has become feasible and presents the logical and critical next step to further explore the impact of genetic variants in this cancer. To address this research question, we have assembled an interdisciplinary team and established a new collaboration with the Women's Health Initiative (WHI) to ensure an appropriately powered study and the capacity to replicate study findings. We will focus on nonsynonymous single nucleotide polymorphisms (nsSNPs), which alter the amino-acid sequence of the protein and are more likely to be functionally relevant. We will conduct a genome-wide association study of all common nonsynonymous SNPs in the human genome (about 20,000). To balance sample size and cost efficiency, we propose a two-stage design. Stage I will be conducted within our existing multi-center, population-based colon cancer case-control study (530 cases, 530 matched controls). Stage II, an independent replication of findings from stage I, will be conducted in two study populations: (a) a different set of participants from our case-control study (800 cases and 800 matched controls) and (b) a nested case-control study within the WHI Observational Study cohort (930 cases, 930 matched controls). We will use appropriate high-throughput genotype technologies in both stages (stage I: MegaAllele(tm) System from Affymetrix and stage II: GoldenGate assay from Illumina). The study is powered to establish moderate gene-cancer associations (odds ratio of 1.4 for SNPs with minor allele frequency of 20%) while eliminating false-positive findings. We will further explore interactions between genes and environmental risk factors. The large number of well-characterized cases with DNA samples and detailed outcome and exposure assessment in both study populations provide an excellent resource. We expect that results will identify new candidate pathways and will improve our understanding of the molecular mechanisms of colon carcinogenesis; ultimately, the findings should provide directions for screening and prevention strategies.

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Publications

Use of pathway information in molecular epidemiology.
Authors: Thomas DC, Conti DV, Baurley J, Nijhout F, Reed M, Ulrich CM
Source: Hum Genomics, 2009 Oct;4(1), p. 21-42.
PMID: 21072972
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C-reactive protein genotypes and haplotypes, polymorphisms in NSAID-metabolizing enzymes, and risk of colorectal polyps.
Authors: Poole EM, Bigler J, Whitton J, Sibert JG, Potter JD, Ulrich CM
Source: Pharmacogenet Genomics, 2009 Feb;19(2), p. 113-20.
PMID: 19077918
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Mismatch repair polymorphisms and risk of colon cancer, tumour microsatellite instability and interactions with lifestyle factors.
Authors: Campbell PT, Curtin K, Ulrich CM, Samowitz WS, Bigler J, Velicer CM, Caan B, Potter JD, Slattery ML
Source: Gut, 2009 May;58(5), p. 661-7.
EPub date: 2008 Jun 3.
PMID: 18523027
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Folate and cancer prevention: a closer look at a complex picture.
Authors: Ulrich CM
Source: Am J Clin Nutr, 2007 Aug;86(2), p. 271-3.
PMID: 17684194
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Genetic polymorphisms in one-carbon metabolism: associations with CpG island methylator phenotype (CIMP) in colon cancer and the modifying effects of diet.
Authors: Curtin K, Slattery ML, Ulrich CM, Bigler J, Levin TR, Wolff RK, Albertsen H, Potter JD, Samowitz WS
Source: Carcinogenesis, 2007 Aug;28(8), p. 1672-9.
EPub date: 2007 Apr 21.
PMID: 17449906
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DNA alkylation and DNA methylation: cooperating mechanisms driving the formation of colorectal adenomas and adenocarcinomas?
Authors: Grady WM, Ulrich CM
Source: Gut, 2007 Mar;56(3), p. 318-20.
PMID: 17339242
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Folate supplementation: too much of a good thing?
Authors: Ulrich CM, Potter JD
Source: Cancer Epidemiol Biomarkers Prev, 2006 Feb;15(2), p. 189-93.
PMID: 16492904
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Nutrigenetics in cancer research--folate metabolism and colorectal cancer.
Authors: Ulrich CM
Source: J Nutr, 2005 Nov;135(11), p. 2698-702.
PMID: 16251633
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Microsomal epoxide hydrolase polymorphisms are not associated with colon cancer risk.
Authors: Robien K, Curtin K, Ulrich CM, Bigler J, Samowitz W, Caan B, Potter JD, Slattery ML
Source: Cancer Epidemiol Biomarkers Prev, 2005 May;14(5), p. 1350-2.
PMID: 15894702
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MTHFR C677T and A1298C polymorphisms: diet, estrogen, and risk of colon cancer.
Authors: Curtin K, Bigler J, Slattery ML, Caan B, Potter JD, Ulrich CM
Source: Cancer Epidemiol Biomarkers Prev, 2004 Feb;13(2), p. 285-92.
PMID: 14973104
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Methionine synthase D919G polymorphism, folate metabolism, and colorectal adenoma risk.
Authors: Goode EL, Potter JD, Bigler J, Ulrich CM
Source: Cancer Epidemiol Biomarkers Prev, 2004 Jan;13(1), p. 157-62.
PMID: 14744749
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Polymorphisms in DNA repair genes and associations with cancer risk.
Authors: Goode EL, Ulrich CM, Potter JD
Source: Cancer Epidemiol Biomarkers Prev, 2002 Dec;11(12), p. 1513-30.
PMID: 12496039
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CYP2C9 and UGT1A6 genotypes modulate the protective effect of aspirin on colon adenoma risk.
Authors: Bigler J, Whitton J, Lampe JW, Fosdick L, Bostick RM, Potter JD
Source: Cancer Res, 2001 May 1;61(9), p. 3566-9.
PMID: 11325819
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A molecular variant of the APC gene at codon 1822: its association with diet, lifestyle, and risk of colon cancer.
Authors: Slattery ML, Samowitz W, Ballard L, Schaffer D, Leppert M, Potter JD
Source: Cancer Res, 2001 Feb 1;61(3), p. 1000-4.
PMID: 11221825
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Associations between family history of cancer and genes coding for metabolizing enzymes (United States).
Authors: Slattery ML, Edwards SL, Samowitz W, Potter J
Source: Cancer Causes Control, 2000 Oct;11(9), p. 799-803.
PMID: 11075868
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Western diet, family history of colorectal cancer, NAT2, GSTM-1 and risk of colon cancer.
Authors: Slattery ML, Potter JD, Ma KN, Caan BJ, Leppert M, Samowitz W
Source: Cancer Causes Control, 2000 Jan;11(1), p. 1-8.
PMID: 10680724
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Methylenetetrahydrofolate reductase, diet, and risk of colon cancer.
Authors: Slattery ML, Potter JD, Samowitz W, Schaffer D, Leppert M
Source: Cancer Epidemiol Biomarkers Prev, 1999 Jun;8(6), p. 513-8.
PMID: 10385141
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NAT2, GSTM-1, cigarette smoking, and risk of colon cancer.
Authors: Slattery ML, Potter JD, Samowitz W, Bigler J, Caan B, Leppert M
Source: Cancer Epidemiol Biomarkers Prev, 1998 Dec;7(12), p. 1079-84.
PMID: 9865425
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