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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA059045-14
Application #
8081831
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Seminara, Daniela
Project Start
1994-09-30
Project End
2013-05-31
Budget Start
2011-06-01
Budget End
2013-05-31
Support Year
14
Fiscal Year
2011
Total Cost
$703,218
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Zhao, Wei; Chen, Ying Qing; Hsu, Li (2017) On estimation of time-dependent attributable fraction from population-based case-control studies. Biometrics 73:866-875
Bien, Stephanie A; Auer, Paul L; Harrison, Tabitha A et al. (2017) Enrichment of colorectal cancer associations in functional regions: Insight for using epigenomics data in the analysis of whole genome sequence-imputed GWAS data. PLoS One 12:e0186518
Kerr, Kathleen F; Avery, Christy L; Lin, Henry J et al. (2017) Genome-wide association study of heart rate and its variability in Hispanic/Latino cohorts. Heart Rhythm 14:1675-1684
Pirastu, Nicola; Joshi, Peter K; de Vries, Paul S et al. (2017) GWAS for male-pattern baldness identifies 71 susceptibility loci explaining 38% of the risk. Nat Commun 8:1584
McCarthy, Shane; Das, Sayantan; Kretzschmar, Warren et al. (2016) A reference panel of 64,976 haplotypes for genotype imputation. Nat Genet 48:1279-83
Kocarnik, Jonathan M; Chan, Andrew T; Slattery, Martha L et al. (2016) Relationship of prediagnostic body mass index with survival after colorectal cancer: Stage-specific associations. Int J Cancer 139:1065-72
Zeng, Chenjie; Matsuda, Koichi; Jia, Wei-Hua et al. (2016) Identification of Susceptibility Loci and Genes for Colorectal Cancer Risk. Gastroenterology 150:1633-1645
Garcia-Albeniz, Xabier; Rudolph, Anja; Hutter, Carolyn et al. (2016) CYP24A1 variant modifies the association between use of oestrogen plus progestogen therapy and colorectal cancer risk. Br J Cancer 114:221-9
Cornelis, Marilyn C; Flint, Alan; Field, Alison E et al. (2016) A genome-wide investigation of food addiction. Obesity (Silver Spring) 24:1336-41
Kap, Elisabeth J; Seibold, Petra; Scherer, Dominique et al. (2016) SNPs in transporter and metabolizing genes as predictive markers for oxaliplatin treatment in colorectal cancer patients. Int J Cancer 138:2993-3001

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