AS224 - GWAS for nonsynonymous SNPs in colon cancer (GECCO)

Investigator Names and Contact Information

Ulrike Peters (upeters@fredhutch.org)

Introduction/Intent

Introduction/Intent

Perhaps one-third of colon cancer is attributable to inherited factors. Identifying genetic variants is important to elucidate underlying mechanisms of this, the third leading cause of cancer in US women. We propose a genome-wide association study of nonsynonymous variants, which alter the amino-acid sequence of the protein and are more likely to be functionally relevant. As a secondary aim, we will investigate interactions between genes and environment, including postmenopausal hormone use. We will explore 20,000 single nucleotide polymorphisms (SNPs) including most common nonsynonymous variants in the study population. To balance sample size and cost efficiency, we propose a two-stage design. Stage I will be conducted within an existing colon cancer case-control study (776 cases, 776 matched controls) and stage II, an independent replication of significant findings, will be a nested case-control study within the Women's Health Initiative Observational Study (930 cases, 3720 matched controls). The study is powered to investigate moderate gene-cancer associations (odds ratio of 1.4 for common variants) while eliminating most false positives. Together, the two study populations provide an almost unique resource because of the number of well-characterized cases with DNA samples and detailed exposure assessment. We will use only 1 μg DNA per subject.

We propose the following primary specific aim:

1. To conduct a genome-wide association study on 20,000 amino-acid-altering SNPs to identify genes that are unequivocally associated with risk of colon cancer, a prominent disease among women

As secondary aims we propose:

1. To investigate interactions between amino-acid-altering SNPs that are identified as part of our primary aim (gene-gene interactions)
2. To examine interactions between amino-acid-altering SNPs identified in specific aim 1 and established risk factors for colon cancer: use of hormone replacement therapy and non-steroidal anti-inflammatory drugs, body mass index, physical activity, smoking, folate, and calcium (gene-environment interactions)

Updated Specific Aims as of 10/1/09:

1. Competitive supplement to CA059045 (one year):

• 1. Primary genome-wide scan on 2,640 colorectal cancer cases and 2,640 controls and use of additional 3,000 historical controls. All studies are well characterized, population-based, prospective cohorts: WHI (1126 cases, 1126 controls – Caucasians), NHS, HPFS, and PHS.

2. U01 CA137088 (four years): GECCO

• 1. Conduct a meta-analysis of existing GWAS data +2,640 cases and 5,640 controls from the competitive supplement.
• 2. Replicate the top 7,600 hits from the GWAS meta-analysis in nine study populations (PLCO, MEC, CARET, WHI (258 cases, 1042 controls – Minorities), VITAL and four population based case-controls study). Total sample size 6,548 cases and 8,430 controls.
• 3. Sequence up to ten newly identified colorectal cancer susceptibility loci in 48 whites and 48 African American cases.
     -4. Genotype new genetic variants identified via sequencing in the entire replication study

Results/Findings

Some of the publications related to this ancillary study are: 962, 1060, 1557, 1566, 1567, 1582, 1689, 1691, 1695, 1726, 1806, 1931, 2057.

For a complete, up-to-date list of WHI papers related to this ancillary study, please use the searchable Bibliography section of this website. To search for papers by study number, access the Simple Search, and enter the study number in the “Related Studies” field.