Affiliations of authors: W. Zheng, Division of General Internal Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN; N. Kataoka, D. Xie, S. R. Young, School of Medicine, University of South Carolina, Columbia.
Correspondence to: Wei Zheng, M.D., Ph.D., Vanderbilt University Medical Center, Center for Health Services Research, Medical Center East, 6th floor, Nashville, TN 372328300 (e-mail: Zhang{at}mcmail.vanderbilt.edu).
We read with interest the letter by Drs. Baxter and Campbell regarding the association between HER2 genetic polymorphism and breast cancer risk. Drs. Baxter and Campbell found in a hospital-based, casecontrol study conducted among British women that genotype frequencies of the HER2 gene at codon 655 (Ile to Val) were similar between case patients with breast or ovarian cancer and control subjects. This finding was inconsistent with our finding in a population-based, casecontrol study conducted among Chinese women (1). In that study, we found that the Val/Val genotype was associated with an elevated risk of breast cancer, particularly among younger women (1).
We concur with Drs. Baxter and Campbell that the reported association between the valine allele and breast cancer risk warrants further investigation. As with any association studies of gene polymorphisms and cancer risk, we cannot rule out the possibility of type I error and population stratification effect on our study results. Ameyaw et al. (2) reported recently a large interracial variation in the allele frequency of the HER2 gene. Such a variation is unlikely to exist in our study population, because more than 95% of Shanghai residents belong to a single ethnic group (Han Chinese). As demonstrated by Wacholder et al. (3), population stratification is unlikely to bias substantially the results from a well-designed casecontrol study of genetic factors, particularly the one conducted in a relatively homozygous population with a similar ethnic background and cancer risk.
Although our reported study of HER2 polymorphism and breast cancer risk was conducted with a prior hypothesis, we do have some concern about the possibility of type I error. To evaluate this possibility, we recently completed a small casecase study to examine the association between HER2 polymorphism and the amplification of this gene in breast cancer tissue samples with the technique of fluorescence in situ hybridization. Paraffin-embedded tissue sections were obtained from 134 breast cancer patients, including 65 with the Ile/Ile genotype, 56 with the Ile/Val genotype, and 13 with the Val/Val genotype. Tissue-section slides were hybridized with DNA probes for the HER2 gene and the centromere of chromosome 17, and 100 cells in each sample were scored for the signals of these two markers. Any tumor tissue sample with an average oncogene amplification ratio of 2.0 or higher for the signal counts of the HER2 gene over the centromere of chromosome 17 was considered to be HER2 amplified. The amplification of the HER2 gene was found in seven (53.8%) of the 13 case patients with the Val/Val genotype, 24 (42.9%) of the 56 case patients with the Ile/Val genotype, and 21 (32.3%) of the 65 case patients with the Ile/Ile genotype (two-sided trend test, P = .095). Although this study did not directly evaluate the functional importance of the polymorphism and the association was only of borderline statistical significance, the direction of the association was consistent with the finding reported from our early study for the association between HER2 polymorphism and breast cancer risk.
Recently, we also evaluated the association between HER2 polymorphism and breast cancer risk in a small casecontrol study conducted within a cohort of postmenopausal women from the state of Iowa (4). Included in the study were 154 case patients with breast cancer diagnosed among cohort members from 1992 through 1994 and 325 cohort members who were free of cancer during the study period. Blood samples from these subjects were obtained and assayed for the Val655Ile polymorphism of the HER2 gene by use of the polymerase chain reaction and restriction fragment length polymorphism described previously (1). The frequencies of the Ile/Ile, Ile/Val, and Val/Val genotypes were 58.4%, 38.3%, and 3.3%, respectively, in case patients and 56.9%, 38.8%, and 4.3%, respectively, in control subjects (test for difference, P = .84). These genotype frequencies were close to those reported by Drs. Baxter and Campbell, suggesting no association between HER2 polymorphism and breast cancer risk among postmenopausal Iowa women.
The reasons for the inconsistent results from studies conducted among Chinese and Caucasian women are not clear, and well-designed larger studies will be needed. It is possible that the Val655Ile polymorphism per se may not be functionally significant. As we indicated in our original article (1), this polymorphism might be in linkage disequilibrium with the functional allele(s) at other site(s) in the Chinese population and a closely linked nonfunctional allele may also be useful in identifying high-risk women for breast cancer prevention. We agree that it is premature to conclude on the association between HER2 genetic polymorphism and breast cancer risk based on the limited number of studies conducted thus far. Currently, we are in the process of genotyping more case patients and control subjects for the polymorphism of the HER2 gene and will evaluate the association of this polymorphism with breast cancer in a larger study.
REFERENCES
1
Xie D, Shu XO, Deng Z, Wen WQ, Creek KE, Dai Q, et al. Population-based, casecontrol study of HER2 genetic polymorphism and breast cancer risk. J Natl Cancer Inst. 2000;92: 4127.
2
Ameyaw M, Thornton N, McLeod HL. Re: population-based, casecontrol study of HER2 genetic polymorphism and breast risk [letter]. J Natl Cancer Inst 2000;92:1947.
3
Wacholder S, Rothman N, Caporaso N. Population stratification in epidemiologic studies of common genetic variants and cancer: quantification of bias. J Natl Cancer Inst 2000;92:11518.
4
Zheng W, Gustafson DR, Sinha R, Cerhan JR, Moore D, Hong CP, et al. Well-done meat intake and the risk of breast cancer. J Natl Cancer Inst 1998;90:17249.
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