title: Genetic variants in the HER2 gene: Influence on HER2 overexpression and loss of heterozygosity in breast cancer.
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 the HER2 gene, genomic DNA was obtained from 361 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 5' 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 HER2 expression. However, the proline allele of the Ala1170Pro SNP was associated with a higher frequency of HER2 overexpression (56% versus 43%, p = 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 = 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.
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Paul O'Gorman Building, Medical School, Newcastle upon Tyne, NE2 4HH, UK; Northern Centre for Cancer Care, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, High Heaton, Newcastle upon Tyne, NE7 7DN, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Cresti
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Paul O'Gorman Building, Medical School, Newcastle upon Tyne, NE2 4HH, UK; Northern Centre for Cancer Care, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, High Heaton, Newcastle upon Tyne, NE7 7DN, UK.
authors.forename: Joanne
authors.initials: J
authors.lastname: Lee
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Paul O'Gorman Building, Medical School, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Rourke
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Paul O'Gorman Building, Medical School, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Despina
authors.initials: D
authors.lastname: Televantou
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Paul O'Gorman Building, Medical School, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: David
authors.initials: D
authors.lastname: Jamieson
authors.affiliation: Northern Centre for Cancer Care, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, High Heaton, Newcastle upon Tyne, NE7 7DN, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Verrill
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Paul O'Gorman Building, Medical School, Newcastle upon Tyne, NE2 4HH, UK. Electronic address: alan.boddy@sydney.edu.au.
authors.forename: Alan V
authors.initials: AV
authors.lastname: Boddy
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D019656:Loss of Heterozygosity; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis / Q000235:genetics*; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human
keywords: Breast cancer; HER2; Pharmacogenomics; Tumour heterogeneity