Genome-Wide Association Study of Metachronous Colorectal Adenoma Risk among Participants in the Selenium Trial

Abstract

Genetic variants related to colorectal adenoma may help identify those who are at highest risk of colorectal cancer development or illuminate potential chemopreventive strategies. The purpose of this genome-wide association study was to identify genetic variants that are associated with risk of developing a metachronous colorectal adenoma among 1,215 study participants of European descent from the Selenium Trial. Associations of variants were assessed with logistic regression analyses and validated in an independent case-control study population of 1,491 participants from the Colorectal Cancer Study of Austria (CORSA). No statistically significant genome-wide associations between any variant and metachronous adenoma were identified after correction for multiple comparisons. However, an intron variant of FAT3 gene, rs61901554, showed a suggestive association (P = 1.10 × 10⁻⁶) and was associated with advanced adenomas in CORSA (P = 0.04). Two intronic variants, rs12728998 and rs6699944 in NLRP3 were also observed to have suggestive associations with metachronous lesions (P = 2.00 × 10⁻⁶) in the Selenium Trial and were associated with advanced adenoma in CORSA (P = 0.03). Our results provide new areas of investigation for the genetic basis of the development of metachronous colorectal adenoma and support a role for FAT3 involvement in the Wnt/β-catenin pathway leading to colorectal neoplasia.

Trial Registration number: NCT00078897 (ClinicalTrials.gov).

Author Contributions

Mario Trejo: Conceptualization, Methodology, Software, Validation, Formal Analysis, Investigation, Writing original draft. Ken Batai: Conceptualization, Methodology, Software, Validation, Formal Analysis, Investigation, Writing original draft, and Writing revision. Yuliang Chen: Formal Analysis. Stefanie Brezina: Validation, Formal Analysis, Data Curation, Writing, review and editing. H-H Sherry Chow: Conceptualization, Investigation, and Writing review and editing. Nathan Ellis: Conceptualization, Investigation, Writing original draft, supervision. Peter Lance: Conceptualization, Investigation, Writing, review and editing, Funding acquisition. Chiu-Hsieh Hsu: Conceptualization. Kristen Pogreba-Brown: Writing, review and editing. Maria Bishop: Writing, review and editing. Andrea Gsur: Validation, Formal Analysis, Data Curation, Writing, review and editing. Elizabeth Jacobs: Conceptualization, Methodology, Software, Validation, Formal Analysis, Investigation, Writing original draft, Supervision, Funding acquisition.

Disclosure Statement

The authors report there are no competing interests to declare.

Funding Information

This work was supported by the National Institutes of Health under the following grants: National Cancer Institute under P30 CA023074, R01CA151708, P01 CA041108, and R01CA151708.

Data Availability Statement

Data for the Selenium Trial are available through dbGaP.