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
Su, Yu-Ru; Di, Chongzhi; Bien, Stephanie et al. (2018) A Mixed-Effects Model for Powerful Association Tests in Integrative Functional Genomics. Am J Hum Genet 102:904-919
Neumeyer, Sonja; Banbury, Barbara L; Arndt, Volker et al. (2018) Mendelian randomisation study of age at menarche and age at menopause and the risk of colorectal cancer. Br J Cancer 118:1639-1647
Weigl, Korbinian; Chang-Claude, Jenny; Knebel, Phillip et al. (2018) Strongly enhanced colorectal cancer risk stratification by combining family history and genetic risk score. Clin Epidemiol 10:143-152
Carr, Prudence R; Weigl, Korbinian; Jansen, Lina et al. (2018) Healthy Lifestyle Factors Associated With Lower Risk of Colorectal Cancer Irrespective of Genetic Risk. Gastroenterology 155:1805-1815.e5
Jeon, Jihyoun; Du, Mengmeng; Schoen, Robert E et al. (2018) Determining Risk of Colorectal Cancer and Starting Age of Screening Based on Lifestyle, Environmental, and Genetic Factors. Gastroenterology 154:2152-2164.e19
Wang, Xiaoliang; Chan, Andrew T; Slattery, Martha L et al. (2018) Influence of Smoking, Body Mass Index, and Other Factors on the Preventive Effect of Nonsteroidal Anti-Inflammatory Drugs on Colorectal Cancer Risk. Cancer Res 78:4790-4799
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
Gu, Fangyi; Zhang, Han; Hyland, Paula L et al. (2017) Inherited variation in circadian rhythm genes and risks of prostate cancer and three other cancer sites in combined cancer consortia. Int J Cancer 141:1794-1802
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

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