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Overexpression of the proto-oncogene ERBB2 (HER2/NEU) has been observed in 20-30% of breast cancers involving poor prognosis. Genetic alterations within ERBB2 have been shown to induce carcinogenesis and metastasis. We investigated eight annotated single nucleotide polymorphisms for occurrence in familial breast cancer samples. The confirmed variants Ile654Val, Ile655Val and Ala1170Pro were analysed in subsequent epidemiological studies on familial breast cancer risk. While Ala1170Pro resides within a C-terminally located regulatory domain, the two adjacent polymorphisms Ile654Val and Ile655Val are part of the transmembrane domain. A case-control study analysing a cohort of 348 German familial breast cancer cases and 960 corresponding controls showed no significant association of either Ile655Val (OR = 1.05, 95% CI = 0.82-1.34, P = 0.728) or Ala1170Pro (OR = 0.94, 95% CI = 0.74-1.20, P = 0.632) with familial breast cancer risk. Differences in haplotype frequencies between cases and controls could also not be detected. The ERBB2 variant Ile654Val, however, revealed an increased risk for carriers of the heterozygous Val654 allele (OR = 2.56, 95% CI = 1.08-6.08, P = 0.028). The rare Val654 variant is linked with the more frequent Val655, resulting in two consecutive valine instead of two isoleucine residues within the transmembrane domain. Computational analyses suggest that the Val654-Val655 allele provokes receptor dimerization and activation, thus stimulating kinase activity and cell transformation. We hypothesize that ERBB2 Val654 represents an oncogenic variant which might, in addition, influence clinical outcome and predict a worse prognosis.

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