Affiliations of authors: S. Wang-Gohrke, Molecular Biology Laboratory, Department of Obstetrics and Gynecology, University of Ulm, Germany; J. Chang-Claude, Division of Clinical Epidemiology, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
Correspondence regarding molecular biology: Shan Wang-Gohrke, M.D., Molecular Biology Laboratory, Department of Obstetrics and Gynecology, University of Ulm, Prittwitzstrasse 43, D-89075 Ulm, Germany (e-mail: shan.wang{at}medizin.uni-ulm.de).Correspondence regarding epidemiology: Jenny Chang-Claude, Ph.D., Division of Clinical Epidemiology, Deutsches Krebsforschungszentrum, Postfach 101949, 69009 Heidelberg, Germany (e-mail: J.Chang-Claude{at}dkfz.de).
A valine-to-isoleucine polymorphism at codon 655 (Val655Ile) was first reported in the Journal (1) to be associated with an increased risk of breast cancer in a population-based, casecontrol study among a Han Chinese population. The distribution of the polymorphism, however, was found to vary considerably between ethnic groups (2). Baxter and Campbell (3) then reported that genotype frequencies of HER2 Val655Ile were similar between case patients and control subjects in a hospital-based, case control study among British women younger than 40 years. This observation raises the question of 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.
We used a large population-based 1 : 2 age-matched casecontrol study among German Caucasian women to determine whether the polymorphism of the HER2 Val655Ile polymorphism alters the risk for breast cancer by the age of 50 years. We also investigated whether this polymorphism interacts with other risk factors previously shown to be related to breast cancer in the study. As described previously (4), patients were diagnosed with incident in situ or invasive breast cancer before 51 years of age, and two control subjects per case patient matched by exact age and study region were selected from random lists of residents supplied by the population registries. The study was reviewed by the ethics committee of the University of Heidelberg. Overall, 706 (70% of eligible) case patients and 1381 (61% of eligible) population control subjects participated. This analysis is restricted to 615 case patients and 1078 control subjects who also provided a blood sample and have at least one parent of German nationality. The mean ages of case patients and control subjects were 42.5 and 42.6 years, respectively. With the size of this study, we have 84% statistical power to detect an odds ratio of 1.4 at a 5% statistical significance level (two-sided test) for a dominant allele with a prevalence of 20%.
The Val655Ile polymorphism was analyzed by using the previously described polymerase chain reactionrestriction fragment length polymorphism assay (1). The frequency of the valine allele (0.24 in case patients and 0.23 in control subjects) was similar to that reported previously for Caucasians and higher than among Chinese subjects. We observed neither a deviation from the expected HardyWeinberg distribution nor a statistically significant difference in the genotype distribution of the cancer group compared with the control group among this German Caucasian population (P = .83). This lack of association remained when the data were stratified into two groups by age, i.e., 45 years or younger and older than 45 years (Table 1). We also did not find any difference when the cancer case patients were stratified according to histologic subtype, stage, grade, and hormone receptor status. However, when we examined the interaction between the HER2 polymorphism and other risk factors for breast cancer, we found statistically significant evidence for a differential effect by family history of breast cancer in a first-degree relative (P = .04 for interaction). Compared with wild-type Ile/Ile homozygotes, being a carrier of the valine allele was associated with a twofold increased risk for breast cancer only among women with a positive family history of breast cancer (Table 1
). This statistical interaction was not reported in the Shanghai breast cancer study; however, that study would not have had adequate power due to the low rate of women with a family history of breast cancer (3.3%3.7%) (1).
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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 cancer risk [letter]. J Natl Cancer Inst 2000;92:1947.
3
Baxter SW, Campbell IG. Re: Population-based, casecontrol study of HER2 genetic polymorphism and breast cancer risk [letter]. J Natl Cancer Inst 2001;93:5579.
4 Chang-Claude J, Eby N, Kiechle M, Bastert G, Becher H. Breastfeeding and breast cancer risk by age 50 among women in Germany. Cancer Causes Control 2000;11:68795.[Medline]
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