The rare ERBB2 variant Ile654Val is associated with an increased familial breast cancer risk

Background

Overexpression of the proto-oncogene ERBB2 (HER2/NEU) has been observed in 20–30% of breast cancers involving ligand-independent activation and more aggressive growth behaviour, reduced response to chemotherapy and hormonal therapy, as well as poor prognosis. Genetic alterations within ERBB2 have been shown to induce carcinogenesis and metastasis.

Methods

The ERBB2 variants Ile654Val, Ile655Val and Ala1170Pro were investigated for their influence on familial breast cancer risk by sequencing and TaqMan allelic discrimination.

Results

The case–control study analysing 348 German familial breast cancer cases and 960 controls showed no significant association of Ile655Val and Ala1170Pro with familial breast cancer risk. Differences in haplotype frequencies between cases and controls could not be detected either. The ERBB2 variant Ile654Val, however, revealed an increased risk for carriers of the heterozygous Val654 allele (odds ratio = 2.56, 95% confidence interval = 1.08-6.08, P = 0.028).

Conclusion

The rare Val654 is linked to the more frequent Val655, resulting in two consecutive valine residues instead of two isoleucine residues within the transmembrane domain. Computational analyses suggest that the Val654–Val655 allele provokes receptor dimerisation and activation, thus stimulating kinase activity and cell transformation. We hypothesise that ERBB2 Val654 represents an oncogenic variant that might, in addition, influence clinical outcome and predict worse prognosis. The occurrence of the Val654–Val655 haplotype in human breast cancer cells (MCF-7) supports the significance of our results.