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Cancer Epidemiology Biomarkers & Prevention Vol. 12, 1109-1111, October 2003
© 2003 American Association for Cancer Research

Short Communications

The HER2 I655V Polymorphism and Risk of Breast Cancer in Women < Age 40 Years1

Karen G. Montgomery, Dorota M. Gertig, Simon W. Baxter, Roger L. Milne, Gillian S. Dite, Margaret R. E. McCredie, Graham G. Giles, Melissa C. Southey, John L. Hopper2 and Ian G. Campbell

Cancer Genetics Laboratory, Victorian Breast Cancer Research Consortium, Peter MacCallum Cancer Institute, St. Andrews Place, East Melbourne, Victoria 3002 [K. G. M., S. W. B., I. G. C.]; Centre for Genetic Epidemiology, The University of Melbourne, Carlton, Victoria [D. M. G., R. L. M., G. S. D., J. L. H.] and Cancer Epidemiology Centre, The Cancer Council Victoria [G. G. G.], Carlton, Victoria; Department of Preventive and Social Medicine, University of Otago, Dunedin, New Zealand and (previously) Cancer Epidemiology Research Unit, The Cancer Council of New South Wales, Sydney, New South Wales [M. R. E. M.]; and Department of Pathology, The University of Melbourne, Parkville, Victoria 3053 [M. C. S.], Australia


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The HER2 gene controls cellular function and has prognostic significance in breast cancer. The I655V polymorphism was associated with increased risk of breast cancer in Chinese women under the age of 45 years and in women with a first-degree family history of the disease. These associations, however, have not been confirmed in several studies of older women. We conducted a population-based case-control-family study of the I655V polymorphism using 409 Australian women with breast cancer diagnosed before the age of 40 years and 299 controls frequency matched for age. The I655V polymorphism was more common in cases (P = 0.01). A recessive model, in which homozygotes were associated with an adjusted odds ratio of 2.8 (95% confidence interval 1.3–6.2; P = 0.005), gave the best fit under parsimony. Although the biological role of the I655V polymorphism is not known, large independent studies of early onset breast cancer are warranted to attempt to replicate this finding.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
HER23 is a transmembrane glycoprotein with tyrosine kinase activity that has several functions, including the control of cellular proliferation. Amplification and/or overexpression of HER2, present in 30% of breast cancers, is associated with poor prognosis (1 , 2) . The use of a recombinant humanized monoclonal antibody that specifically targets HER2 may increase the clinical benefit of first-line chemotherapy in women with breast cancers that overexpress HER2 (3) .

An isoleucine to valine polymorphism at codon 655 (I655V) was reported to be associated with an increased risk of breast cancer in a Chinese population (4) . Of the six subsequent studies that investigated the risk of breast cancer associated with this HER2 I655V polymorphism, two reported a positive association (5 , 6) , whereas four found no association (7, 8, 9, 10) . It is difficult to interpret these studies given that the characteristics of the samples were different, and some lacked statistical power. Interestingly, in the two that reported a positive association, the only effect evident was in women diagnosed before age 45 years (4) or in women with a first-degree family history of breast cancer (5) , groups in which inherited genetic effects on susceptibility are expected to be more pronounced. In the present study, we evaluated the association between the HER2 I655V polymorphism and breast cancer risk before the age of 40 years using Australian women.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects.
Subjects were drawn from the Australian Breast Cancer Family Study, a population-based, case-control-family study of early onset breast cancer carried out in Melbourne and Sydney during the period 1992 through 1995 that has been described in detail previously (11 , 12) . Briefly, women under the age of 40 at diagnosis of a first primary invasive breast cancer were identified through the Victorian and New South Wales cancer registries. Controls were selected from the electoral roll (registration for voting is compulsory in Australia) by use of stratified random sampling and were frequency matched for age. Response rates were 73% in both cases and controls (11) . Case subjects, control subjects, and their relatives were administered the same questionnaire on risk factors (see Ref. 11 for characteristics of study participants). For each case and control, a detailed family history was recorded for all first- and second-degree relatives, and verification of all family cancers was sought through cancer registries, pathology reports, clinical records, and death certificates. Blood samples were collected from subjects at the time of interview. Written informed consent was obtained from all subjects, and approval of the study protocol was obtained from the relevant ethics committees.

Molecular Analysis.
A total of 409 cases and 299 controls were genotyped for the HER2 I655V polymorphism using a dual color allele-specific PCR assay described previously (7) . Briefly, PCR amplifications were performed using HEX- and FAM-labeled forward primers (5-CAGCCCTCTGACGTCCATCA-3 and 5-CAGCCCTCTGACGTCCATCG-3) and a common reverse primer (5'-TCCTCAGCTCCGTCTCTTTC-3'). Ten percent of the genotyping was confirmed with a PCR and restriction fragment length polymorphism assay described previously (13) .

Statistical Methods.
The Hardy-Weinberg equilibrium assumption was assessed by the standard method of comparing the observed numbers of individuals in the different genotype categories with those expected under Hardy-Weinberg equilibrium for the estimated allele frequency and assessing the Pearson goodness-of-fit statistic against the {chi}2 distribution with one degree of freedom. Genotype distributions were compared with the use of contingency table analysis.

We conducted a case-control analysis using unconditional multiple logistic regression to fit models assuming: (a) dominant inheritance (i.e., women with one or two valine alleles had the same increased risk); (b) codominant inheritance (i.e., risk could differ across all three genotypes); or (c) recessive inheritance (i.e., only women with two valine alleles were at the increased risk). For all analyses, adjustment was made for demographic variables (study site, country of birth, education, and marital status) and putative breast cancer risk factors (age, parity, oral contraceptive use, height, and family history; Ref. 11 ).

All analyses were performed by the use of Stata 7.0 statistical software (StataCorp., College Station, Texas). All statistical tests and Ps were two tailed, and, after convention, statistical significance was taken as a nominal P of <0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
There was no evidence of a deviation from Hardy-Weinberg equilibrium among the cases (P = 0.5) or controls (P = 0.9). The frequency of the valine allele in controls (0.187; SE 0.016) was similar to that found in other studies of Caucasian populations (10 , 11) and less than in cases (0.245; SE 0.015, P = 0.01).

Table 1Citation shows odds ratios and 95% CIs for the effects on breast cancer risk of HER2 I655V genotypes according to different models of inheritance. Odds ratios adjusted for demographic, reproductive, and lifestyle variables did not differ greatly from the crude estimates. There was evidence of an increased risk under dominant inheritance (P = 0.04), codominant inheritance (P = 0.01), and recessive inheritance (P = 0.005). The recessive model gave an increased risk of 2.8-fold (95% CI 1.3–6.2; P = 0.005) and provided the best fit under parsimony; the codominant model did not give an improved fit (P = 0.2), and the dominant model gave a worse fit for the same number of parameters (difference in log likelihood = 1.5). Stratification by body mass index, family history of cancer, alcohol consumption, or oral contraceptive use revealed no evidence for a modification of the recessive effect on breast cancer risk by these factors, albeit with limited power (data not shown).


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  		Table 1 Odds ratios and 95% CIs for breast cancer risk by HER2 genotype

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our study, of women diagnosed before the age of 40 years, has demonstrated that homozygosity for the valine allele was associated with an increased risk of early onset breast cancer. This finding is consistent with the increased breast cancer risk observed by Xie et al. (4) among Chinese women diagnosed before age 45 years. Overexpression of HER2 is detected in a large proportion of breast cancers, indicating that activation of this gene is an important step in breast carcinogenesis. Consequently, it is plausible that functional polymorphisms in this gene that enhance HER2 activity may represent breast cancer predisposing alleles.

There is currently no direct information regarding any biological role of the I655V polymorphism, located in the transmembrane region of HER2. However, oncogeneic mutations have been reported in the transmembrane region of the related mouse gene neu (14) and an amino substitution at position 659 in HER2 has also been shown to increase transforming ability in NIH3T3 cells (15) . It is possible, therefore, that the I655V polymorphism in HER2 may also have functional consequences. In light of our finding of a recessively inherited risk of early onset breast cancer associated with this polymorphism, investigations into the functional implications of the isoleucine to valine substitution, and attempts to replicate this association in independent and sufficiently large studies, are warranted.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported by the Victorian Breast Cancer Research Consortium, the National Health and Medical Research Council, the Victorian Health Promotion Foundation, the National Breast Cancer Foundation, and the Cancer Councils of New South Wales and Victoria. Back

2 To whom requests for reprints should be addressed, at Centre for Genetic Epidemiology, The University of Melbourne, Level 2, 723 Swanston Street, Carlton, Victoria 3053, Australia. Phone: (61)-3-8344-0697; Fax: (61)-3-9349-5815; E-mail: j.hopper{at}unimelb.edu.au Back

3 The abbreviations used are: HER2, human epidermal growth factor receptor 2; CI, confidence interval. Back

Received 2/28/03; revised 7/ 6/03; accepted 7/23/03.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Slamon D. J., Clark G. M., Wong S. G., Levin W. J., Ullrich A., McGuire W. L. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science (Wash. DC), 235: 177-182, 1987.[Abstract/Free Full Text]
  2. Pegram M. D., Finn R. S., Arzoo K., Beryt M., Pietras R. J., Slamon D. J. The effect of HER-2/neu overexpression on chemotherapeutic drug sensitivity in human breast and ovarian cancer cells. Oncogene, 15: 537-547, 1997.[Medline]
  3. Osoba D., Slamon D. J., Burchmore M., Murphy M. Effects on quality of life of combined trastuzumab and chemotherapy in women with metastatic breast cancer. J. Clin. Oncol., 20: 3106-3113, 2002.[Abstract/Free Full Text]
  4. Xie D., Shu X. O., Deng Z., Wen W. Q., Creek K. E., Dai Q., Gao Y. T., Jin F., Zheng W. Population-based, case-control study of HER2 genetic polymorphism and breast cancer risk. J. Natl. Cancer Inst. (Bethesda), 92: 412-417, 2000.[Abstract/Free Full Text]
  5. Wang-Gohrke S., Chang-Claude J. Re: Population-based, case-control study of HER2 genetic polymorphism and breast cancer risk. J. Natl. Cancer Inst. (Bethesda), 93: 1657-1659, 2001.[Free Full Text]
  6. McKean-Cowdin R., Kolonel L. N., Press M. F., Pike M. C., Henderson B. E. Germ-line HER-2 variant and breast cancer risk by stage of disease. Cancer Res., 61: 8393-8394, 2001.[Abstract/Free Full Text]
  7. Baxter S. W., Campbell I. G. Re: Population-based, case-control study of HER2 genetic polymorphism and breast cancer risk. J. Natl. Cancer Inst. (Bethesda), 93: 557-559, 2001.[Free Full Text]
  8. Ameyaw M., Thornton N., McLeod H. L. Re: Population-based, case-control study of HER2 genetic polymorphism and breast cancer risk. J. Natl. Cancer Inst. (Bethesda), 92: 1947 2000.[Free Full Text]
  9. Keshava C., McCanlies E. C., Keshava N., Wolff M. S., Weston A. Distribution of HER2V655) genotypes in breast cancer cases and controls in the United States. Cancer Lett., 173: 37-41, 2001.[Medline]
  10. Hishida A., Hamajima N., Iwata H., Matsuo K., Hirose K., Emi N., Tajima K. Re: Population-based, case-control study of HER2 genetic polymorphism and breast cancer risk. J. Natl. Cancer Inst. (Bethesda), 94: 1807-1808, 2002.[Free Full Text]
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  12. Hopper J. L., Chenevix-Trench G., Jolley D. J., Dite G. S., Jenkins M. A., Venter D. J., McMredie M. R. E., Giles G. G. Design and analysis issues in a population-based, case-control-family study of the genetic epidemiology of breast cancer and the Co-operative Family Registry for Breast Cancer Studies CFRBCS). J. Natl. Cancer Inst. Monogr., 26: 95-100, 1999.
  13. Papewalis J., Yu. N., Rajewsky M. F. G to A polymorphism at amino acid codon 655 of the human erbB-2/HER2 gene. Nucleic Acids Res., 19: 5452 1991.[Free Full Text]
  14. Bargmann C. I., Weinberg R. A. Oncogenic activation of the neu-encoded receptor protein by point mutation and deletion. EMBO J., 7: 2043-2052, 1988.[Medline]
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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
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