Abstract Human epidermal growth factor receptor 2 (HER2) overexpression in breast cancer is
an indicator of poor prognosis and is the pre-requisite for treatment with the agents targeting this
member of the epidermal growth factor receptor family. In order to determine the influence of
these common single-nucleotide polymorphisms (SNPs) in theHER2 gene, genomicDNAwas obtained
from361 patients with breast cancer, aged between 29 and 82 years. Samples of tumour tissue
were obtained from 241 (66%) patients and material for extraction of DNA is isolated from
surrounding normal tissue by laser capture microdissection. Genotyping was performed using
the Taqman fluorogenic 50 nuclease assay. Of the 360 patients with definitive determination of
HER2 status, 49% were positive. The Ile655Val SNP had no influence on the frequency of
HER2expression.However, the proline allele of the Ala1170ProSNPwas associated with a higher
frequency of HER2 overexpression (56% versus 43%, p Z 0.015). Where the germline genotype
was homozygous, the tumour genotype was identical in every case and for both SNPs. In
HER2-positive tumours, heterozygosity was maintained in only 15% and 18% of the Ile655Val
and Ala1170Pro SNPs, respectively. This was lower than in the HER2-negative tumours (46%
and 43%, respectively). Normal breast tissue (n Z 23) retained the germline genotype in all but
one case. The underlying link between the Ala1170Pro SNP and HER2 positivity is not known,
nor is the significance of HER2 overexpression and loss of heterozygosity in breast cancer. However,
these results illustrate the complexity of HER2 genotype and overexpression in this disease.
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