The HER2 I655V polymorphism and breast cancer risk in Ashkenazim

Background: Over-expression of the human epidermal growth factor receptor 2 (Her2) protooncogene is associated with poor prognosis among female patients with breast cancer. A polymorphism in the HER2 gene (I655V) has been associated with an elevated risk of breast cancer in some ethnic groups. Methods: Subjects from a community-based study of 5318 Ashkenazim from the Washington, DC area were selected for analysis of the I655V HER2 germline polymorphism. We estimated age-specific breast cancer risk from HER2 I655V based on the family history data, using the female first-degree relatives of the study participants and a novel extension of the kin cohort method. Results: The estimated cumulative risk of breast cancer to age 70 was approximately 30% higher among HER2 I655V carriers than noncarriers (RR = 1.33; 95% confidence interval [CI] = 1.03-1.83). The effect of the allele seems stronger at younger ages (among women younger than 50 years, RR = 2.11; CI = 1.39-3.28) and especially among younger women with a family history of breast cancer (RR = 8.9; CI = 1.9-19.7). Increased risk of breast cancer associated with the I655V allele was also observed among BRCA1/2 mutation carriers, although these results are based on small numbers. Conclusion: These analyses suggest that the HER2 valine allele might be associated with increased risk of breast cancer, especially in young women and in women with a family history of the disease.