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 (Val655Ile) (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 Val655Ile 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 Val655Ile 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′-CAGCCCTCTGACGTCCATCA-3′) 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.

Table 1.

Summary of genotyping for the valine-655 to isoleucine (Val655Ile) polymorphism in U.K. subjects

  No. with specified genotype (%)   
Group No. of subjects Ile/Ile Val/Ile Val/Val Valine allele frequency P
*P values were calculated by combining valine homozygotes and valine/isoleucine heterozygotes and using Fisher's exact test (two-sided). 
Control 256 138 (53.9) 101 (39.4) 17 (6.6) 0.264  
Breast cancer 315 190 (60.3) 109 (34.6) 16 (5.1) 0.224 .13 
Ovarian cancer 314 183 (58.3) 107 (34.1) 24 (7.6) 0.247 .31 
  No. with specified genotype (%)   
Group No. of subjects Ile/Ile Val/Ile Val/Val Valine allele frequency P
*P values were calculated by combining valine homozygotes and valine/isoleucine heterozygotes and using Fisher's exact test (two-sided). 
Control 256 138 (53.9) 101 (39.4) 17 (6.6) 0.264  
Breast cancer 315 190 (60.3) 109 (34.6) 16 (5.1) 0.224 .13 
Ovarian cancer 314 183 (58.3) 107 (34.1) 24 (7.6) 0.247 .31 

References

References
1
Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene.
Science
 
1987
;
235
:
177
–82.
2
Aunoble B, Sanches R, Didier E, Bignon YJ. Major oncogenes and tumor suppressor genes involved in epithelial ovarian cancer.
Int J Oncol
 
2000
;
16
:
567
–76.
3
Gregory RK, Powles TJ, Salter J, Chang JC, Ashley S, Dowsett M. Prognostic relevance of cerbB2 expression following neoadjuvant chemotherapy in patients in a randomised trial of neoadjuvant versus adjuvant chemoendocrine therapy.
Breast Cancer Res Treat
 
2000
;
59
:
171
–5.
4
Pegram MD, Finn RS, Arzoo K, Beryt M, Pietras RJ, Slamon DJ. The effect of HER-2/neu overexpression on chemotherapeutic drug sensitivity in human breast and ovarian cancer cells.
Oncogene
 
1997
;
15
:
537
–47.
5
Papewalis J, Nikitin AYu, Rajewsky MF. G to A polymorphism at amino acid codon 655 of the human erbB-2/HER2 gene.
Nucleic Acids Res
 
1991
;
19
:
5452
.
6
Xie D, Shu XO, Deng Z, Wen WQ, Creek KE, Dai Q, et al. Population-based, case–control study of HER2 genetic polymorphism and breast cancer risk.
J Natl Cancer Inst
 
2000
;
92
:
412
–7.
7
Ameyaw M, Thornton N, McLeod HL. Re: Population-based, case–control study of HER2 genetic polymorphism and breast cancer risk [letter].
J Natl Cancer Inst
 
2000
;
92
:
1947
.