The Leu33Pro polymorphism in the ITGB3 gene does not modify BRCA1/2-associated breast or ovarian cancer risks: results from a multicenter study among 15,542 BRCA1 and BRCA2 mutation carriers

Abstract

Integrins containing the β3 subunit are key players in tumor growth and metastasis. A functional Leu33Pro polymorphism (rs5918) in the β3 subunit of the integrin gene (ITGB3) has previously been suggested to act as a modifier of ovarian cancer risk in Polish BRCA1 mutation carriers. To investigate the association further, we genotyped 9,998 BRCA1 and 5,544 BRCA2 mutation carriers from 34 studies from the Consortium of Investigators of Modifiers of BRCA1/2 for the ITGB3 Leu33Pro polymorphism. Data were analysed within a Cox-proportional hazards framework using a retrospective likelihood approach. There was marginal evidence that the ITGB3 polymorphism was associated with an increased risk of ovarian cancer for BRCA1 mutation carriers (per-allele Hazard Ratio (HR) 1.11, 95% CI 1.00–1.23, p-trend 0.05). However, when the original Polish study was excluded from the analysis, the polymorphism was no longer significantly associated with ovarian cancer risk (HR 1.07, 95% CI 0.96–1.19, p-trend 0.25). There was no evidence of an association with ovarian cancer risk for BRCA2 mutation carriers (HR 1.09, 95% CI 0.89–1.32). The polymorphism was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers. The ITGB3 Leu33Pro polymorphism does not modify breast or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers.

Important role of integrins in the cancer biology

“…Although some integrin-binding proteins do not play a direct role in breast cancer, we briefly discuss them because of their importance in cell migration and cell adhesion, which are important processes in tumor growth. In breast cancer and ovarian cancer tissues, all of the integrins that heterodimerize with the β3 subunit play an important role in tumor growth and metastasis [55].…”

Genetic Variation at 9p22.2 and Ovarian Cancer Risk for BRCA1 and BRCA2 Mutation Carriers

“…To date, a number of studies (22,23) have investigated candidate variants as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. However, none of the variants have been validated in independent datasets.…”

Functional Polymorphism Rs710218 in the Gene Coding GLUT1 Protein is Associated With In-Stent Restenosis

“…The mean age in our population was, however, over 60 years and males were the prevailing group, which could potentially influence the distribution of genotypes for some polymorphisms -particularly those potentially associ- ated with cancer and thus with a greater risk of death at young age. The analyzed polymorphism of ITGB3 was associated with an increased risk of breast cancer, ovarian cancer, melanoma [23] and non-Hodgkin lymphomas [21], although not all authors confirmed that association [31].…”