Re: Population-based, case-control study of HER2 genetic polymorphism and breast cancer risk.

The proto-oncogene human epidermal growth factor receptor 2 (HER2) is a transmembrane glycoprotein with tyrosine kinase activity and, among other functions, controls cellular proliferation. Overexpression of HER2 has been observed in many solid tumors, including 20%–30% of breast cancers (1) and 19%–59.4% of epithelial ovarian cancers (2), and is a predictive marker for response in breast cancer (3,4). A valine-to-isoleucine polymorphism at codon 655 (ValIle) (5) was reported in the Journal (6) to be associated with an increased risk of breast cancer among a Chinese population. Subsequently, Ameyaw et al. (7) reported in the Journal that the distribution of the polymorphism varied considerably between ethnic groups, with the valine allele being detected in 20% of Caucasians but absent from an African population. They raised the possibility that any influence of the valine allele on cancer susceptibility may vary considerably between different ethnic populations. We investigated the frequency of the HER2 ValIle polymorphism in a British-based case–control study. Patients with breast cancer (n 315) were selected who had an age at disease onset of under 40 years, a family history of breast cancer irrespective of age at onset, or bilateral breast cancer irrespective of family history of breast cancer or age at onset. Women with incident cases of ovarian carcinoma (n 314) were ascertained from those undergoing primary surgery for the disease in hospitals in southeast England from 1993 through 1998. Control subjects (n 256) were all white female volunteers who either were staff members at the Princess Anne Hospital (n 125) or were patients at the Princess Anne Hospital being treated for non-neoplastic disease conditions (n 131). The mean age of the women in the breast cancer, ovarian cancer, and control groups were 38, 62, and 39 years, respectively. The ValIle polymorphism was analyzed by use of an allele-specific polymerase chain reaction (PCR). The PCR used red and green fluorescently labeled forward primers (5 -CAGCCCTCTGACGTCCATCG-3 and 5 -CAGCCCTCTGACGTCCATCA3 ) and a common reverse primer (5 TGCGGAGACTGCTGCAGGAAACGGA-3 ). The alleles were separated by electrophoresis through 6% denaturing polyacrylamide gels and analyzed with a scanning laser fluorescence imager. Genotyping was confirmed for 100 patients with a PCR and restriction fragment length polymorphism assay described previously (5). The frequency of the valine allele was similar to that reported by Ameyaw et al. (7), and the genotype frequencies among the cancer and control groups were not statistically significantly different from those expected from Hardy–Weinberg equilibrium. We did not observe any statistically significant differences in the valine allele frequency or in the genotype distribution in the cancer groups compared with the control group (Table 1). When the ovarian cancers were stratified according to histologic subtype, stage, and grade, no statistically significant differences were observed (data not shown). We conclude that the HER2 valine allele does not represent a breast or ovarian cancer risk allele, at least in a British population. The association of the valine allele with breast cancer risk reported by Xie et al. (6) was strongest among women diagnosed with breast cancer under 45 years of age. We studied predominantly patients with early-onset breast cancer (mean age 38 years), so that a difference in the age distribution is unlikely to offer an explanation for the discrepancy. Whether the association reported by Xie et al. reflects a true ethnic variation in the penetrance of the valine allele or a type I statistical error warrants further investigation.