Integrin β3 Leu33Pro homozygosity and risk of cancer

Background: Increased tumor cell expression of integrins containing the beta(3) subunit is associated with increased progression to invasive tumors, whereas inhibition of beta(3) integrin expression and/or function may reduce tumor growth and metastasis. The Leu33Pro polymorphism of the beta(3) subunit modulates the function of alpha(IIb)beta(3) integrin. We examined whether this polymorphism influences cancer risk. Methods: Using participants (n = 9242) from the Copenhagen City Heart Study with 24 years of follow-up and endpoints from the Danish Cancer Registry, we assessed the risk of all cancers and of 27 cancer types in individuals who carry the Leu33Pro polymorphism (heterozygotes and homozygotes) relative to those without the polymorphism (non-carriers). Relative risks (RRs) of cancer and 95% confidence intervals (CIs) were calculated by Cox proportional hazards regression analysis. Differences in cumulative cancer incidence (per 10000 person-years) were tested using log-rank statistics. Statistical tests were two-sided. Results: Among the participants, 70.0% were non-carriers, 27.3% were heterozygotes, and 2.7% were homozygotes. We detected 1296 participants with a first cancer. Cumulative incidences in non-carriers, heterozygotes, and homozygotes were 81, 83, and 112, respectively (homozygotes versus non-carriers, P = .02). The age-adjusted RR of all cancers in homozygotes relative to non-carriers was 1.4 (95% CI = 1.1 to 1.9). Incidences in non-carriers, heterozygotes, and homozygotes were 3, 4, and 16 for ovarian cancer; 19, 24, and 36 for breast cancer; and 2, 3, and 7 for melanoma (homozygotes versus non-carriers; P = .002, P = .06, and P = .03, respectively). The age-adjusted RR in homozygotes relative to non-carriers was 4.7 (95% CI = 1.6 to 14) for ovarian cancer, 1.9 (95% CI = 1.0 to 3.7) for breast cancer, and 3.5 (95% Cl = 1.1 to 12) for melanoma. Adjustment for other cancer risk factors did not alter these results. Heterozygotes did not differ from non-carriers with respect to cancer risk. Conclusion: Individuals homozygous for the Leu33Pro polymorphism of the beta(3) integrin subunit have an increased cancer risk.