Affiliation of authors: M. Hauptmann, A. J. Sigurdson, N. Chatterjee, D. A. Hill, M. M. Doody (Division of Cancer Epidemiology and Genetics), J. L. Rutter, J. P. Struewing (Center for Cancer Research), National Cancer Institute, Department of Health and Human Services, Bethesda, MD.
Correspondence to: Michael Hauptmann, PhD, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd., Bethesda, MD 20892 (e-mail: hauptmann{at}nih.gov).
Overexpression of the HER2 (also known as NEU and ERBB2) proto-oncogene is associated with poor prognosis among female patients with breast cancer. A single-nucleotide polymorphism in the transmembrane domain-coding region at codon 655 of the HER2 gene that exchanges an isoleucine (Ile) for a valine (Val) was associated with breast cancer in a Chinese study (1), particularly among subjects younger than 45 years of age, but subsequent evidence did not confirm this finding. In a recent study among Ashkenazim, Rutter et al. (2) also found an association, particularly in women with early-onset breast cancer and in women with a family history of breast cancer. We used the kincohort design (3) to evaluate the HER2 single-nucleotide polymorphism in a cohort of female relatives of case patients with breast cancer within a large cohort study.
In a cohort of 146 022 U.S. radiologic technologists, 83 748 women responded to at least one of two surveys (between 1984 and 1989 and between 1993 and 1998) (4). Of 1345 women, most of whom were white, who reported a medically confirmed primary breast cancer and were alive on December 31, 1999, 746 probands were located who returned a blood sample by mail and provided, by telephone interview, a family census of female first-degree relatives including their birth and death dates and their cancer history. Demographic, reproductive, and family cancer histories were similar among participants and nonparticipants, i.e., women who did not provide a blood sample. The participants provided data on 189 first-degree relatives with breast cancer and 2231 without breast cancer (Table 1). The probands were genotyped with a TaqMan 5'-nuclease assay (Integrated DNA Technologies, Coralville, IA) described elsewhere (2).
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The frequency of the Val allele in case probands was 24%, in agreement with earlier reports in Caucasians (57). If we assume a dominant mode of inheritance, the cumulative RRs for Ile/Val and Val/Val genotypes versus Ile/Ile genotypes were 0.70 (95% confidence interval [CI] = 0.30 to 1.85) up to age 50 years and 1.51 (95% CI = 0.83 to 2.49) up to age 70 years. If we assume a recessive mode of inheritance, the RRs for the Val/Val genotype versus the Ile/Ile and Ile/Val genotypes were 1.37 (95% CI = 0.00 to 3.98) up to age 50 years and 2.54 (95% CI = 0.40 to 3.63) up to age 70 years (Table 1). The estimated absolute risk at age 70 years among women with the Val/Val genotype was 0.25 (95% CI = 0.04 to 0.34).
This kincohort study is a useful supplement to the casecontrol design because case probands are prevalent and, therefore, survival might affect the casecontrol analysis but not the kincohort analysis. In addition, relatives of radiologic technologists do not have an elevated background risk of breast cancer from occupational radiation exposure. Our kincohort analysis used relatives of case patients with breast cancer, so that absolute risk estimates would be too high if there are other sources of familial aggregation. Furthermore, RR estimates reflecting the effect of the HER2 genotype in subjects with a family history of breast cancer may not be equal to RRs in the general population if HER2 interacts with other familial risk factors.
Although we did not find a statistically significant association in our relatively small study, given the prior associations between the HER2 Val allele and the risk of breast cancer (1,2,7), our observation of an RR of 2.5 by age 70 years suggests that the association might be real. We did not, however, confirm that the effect is especially pronounced at younger ages (1,2). Additional information on the functional relevance of the HER2 Val allele would substantially improve the final interpretation of whether it is a risk allele for breast cancer.
References
1 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;92:4127.
2 Rutter JL, Chatterjee N, Wacholder S, Struewing JP. The HER2 I655V polymorphism and breast cancer risk in Ashkenazim. Epidemiology. In press 2003.
3 Chatterjee N, Wacholder S. A marginal likelihood approach for estimating penetrance from kin-cohort designs. Biometrics 2001;57:24552.[CrossRef][ISI][Medline]
4 Mohan AK, Hauptmann M, Freedman DM, Ron E, Matanoski GM, Lubin JH, et al. Cancer and other causes of mortality among radiologic technologists in the United States. Int J Cancer 2003;103:25967.[CrossRef][ISI][Medline]
5 Baxter SW, Campbell IG. Re: Population-based, case-control study of HER2 genetic polymorphism and breast cancer risk. J Natl Cancer Inst
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6 Ameyaw MM, Thornton N, McLeod HL. Re: Population-based, case-control study of HER2 genetic polymorphism and breast cancer risk. J Natl Cancer Inst
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7 Wang-Gohrke S, Chang-Claude J. Re: Population-based, case-control study of HER2 genetic polymorphism and breast cancer risk. J Natl Cancer Inst
2001;93:16579.
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