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Association between Phosphatidylinositol 3-Kinase Regulatory Subunit p85 Met326Ile Genetic Polymorphism and Colon Cancer Risk

Authors' Affiliations: ¹ Departments of Family Medicine-Research Division, Epidemiology, and Biostatistics, Case Western Reserve University/University Hospitals of Cleveland; ² Case Center for Transdisciplinary Research on Energetics and Cancer, Case Comprehensive Cancer Center; ³ Department of Cancer Biology, Lerner Research Institute, The Cleveland Clinic, Cleveland, Ohio; and ⁴ Cancer Control Program, University of Kentucky, Lexington, Kentucky

Requests for reprints: Li Li, Department of Family Medicine-Research Division, Case Western Reserve University, 11001 Cedar Avenue, Suite 306, Cleveland, OH 44106-7136. Phone: 216-368-5437; E-mail: lxl62{at}cwru.edu.

Purpose: The phosphatidylinositol 3-kinase signaling pathway is frequently activated in cancer. Emerging evidence supports the p85 regulatory subunit gene, PIK3R1, as a novel oncogene.

Experimental Design: We examined the association of a functional missense polymorphism (Met326Ile) of PIK3R1 with colon cancer risk in a population-based case-control study of 421 incident cases and 483 controls.

Results: In our base unconditional logistic regression model controlling for age, gender, and race, we observed a 47% increase in risk among those carrying one or two copies of the 326Ile variant (P = 0.01). Further adjustment for family history of colorectal cancer, body mass index, nonsteroidal anti-inflammatory drugs, smoking, alcohol consumption, and physical activity strengthened the association [odds ratio (OR), 1.73; 95% confidence interval (CI), 1.24-2.42, P = 0.001]. The association was more pronounced among those older than 64 years (OR, 2.10; 95% CI, 1.19-3.70, P = 0.01). Evaluation of the genotypes assuming an additive mode of inheritance showed a significant trend for gene-dose response, where compared with Met/Met, the OR estimates for Ile/Met and Ile/Ile were 1.68 (95% CI, 1.19-2.37) and 2.27 (95% CI, 0.98-5.29), respectively (P for trend = 0.001).

Conclusions: This study is the first to describe a significant association between a germ line functional variant in PIK3R1 and cancer, providing new evidence supporting a role for PIK3R1 in the development of colon cancer.