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Modification of Breast Cancer Risk in Young Women by a Polymorphic Sequence in the egfr Gene

¹Institute for Clinical Chemistry and Laboratory Medicine, University of Muenster, Muenster, Germany; ²German Cancer Research Center, Heidelberg, Germany; ³Carcinogen Identification and Evaluation, IARC, WHO, Lyon, France; and ⁴Institute of Pathology, University of Muenster, Muenster, Germany

	ABSTRACT

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The regulation of the epidermal growth factor receptor (egfr) gene in human cancer is not yet fully understood. Recent data on a polymorphic CA repeat located at the 5'-regulatory sequence in intron 1 of the egfr gene [egfr CA simple sequence repeat (SSR) I] point to a possible inheritance of cancer risk associated with the egfr gene. Furthermore, we have detected frequent allelic imbalances restricted to the egfr CA SSR I in breast cancer tissue and nontumorous breast tissue adjacent to invasive and in situ breast cancer representing amplifications. Therefore, we conducted a population-based case-control study to assess the relationship between the egfr polymorphism and breast cancer risk. Cases with a first primary breast cancer by age 50 years and age-matched population controls provided information on known and suspected risk factors. The allelic length of the egfr CA SSR was determined in 616 cases and 1072 population-sampled controls. Genotypes were categorized for analysis by allele length. Multivariate logistic regression was used to compare genotype distributions, accounting for other risk factors, and to investigate gene-environment interactions. We found a modifying effect, albeit no main effect, of the allelic length of the egfr polymorphism on breast cancer risk. The presence of two long alleles (19 CA) was associated with a significantly elevated odds ratio (OR) of 10.4 [95% confidence interval (CI), 1.85–58.70] among women with a first-degree family history of breast cancer (P = 0.015 for interaction). The risk increase associated with high red meat consumption (OR, 10.68; 95% CI, 1.57–72.58) and the protective effect of high vegetable intake (OR, 0.07; 95% CI, 0.004–1.07) was also most pronounced among carriers of two long alleles (19 CA). The length of the egfr CA SSR may increase the risk for familial breast cancers, and its effect could be modulated by dietary factors.

	Introduction

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Breast cancer is the most common incident cancer and the second most common fatal cancer among women in Western countries. Some 15–20% of cases are associated with family history of breast cancer, but only 15% of familial risk can be explained by an inherited mutation in highly penetrant genes, such as BRCA1 and BRCA2 (1, 2, 3) . It is now widely accepted that cancer susceptibility can also be due to low-penetrance genetic variants and gene-environment interactions (4) . The search for those genes has been directed mainly to functionally significant variants in genes that are known or assumed to be biologically related to breast cancer (5) .

Animal models have shown that an increased expression of oncogenes coding for tyrosine kinase receptors is involved in early breast carcinogenesis (6) . In particular, an increased rate of breast cancer due to overexpression of the epidermal growth factor receptor (EGFR) was observed in transgenic mice (7) . However, the regulation of the egfr gene in human cancers is not yet fully understood. Data from studies on a polymorphic CA repeat located at the 5'-regulatory sequence in the intron 1 of the egfr gene [egfr CA simple sequence repeat (SSR) I] suggest that this polymorphic site may play a role in cancer susceptibility. Recently, we reported that the basal transcription activity of the gene was inversely related to the number of CA repeats in that CA SSR I (8) . Moreover, we detected frequent allelic imbalances (AIs) restricted to the egfr CA SSR I in breast cancer tissue indicative of amplifications (9 , 10) . These amplifications almost always involved the regulatory sequence centered by the CA SSR I of intron 1 and led to EGFR overexpression (10) . As also described recently by our research group, the close proximity of an inducible fragile site next to the egfr gene suggests that exogenous factors such as nutritional habits may play an important role in the induction of egfr amplifications (10) . Therefore, we investigated whether the length of the inherited alleles of the CA SSR I in the egfr gene is associated with disease risk, particularly with regard to family history of cancer and dietary pattern, in a large case-control study of breast cancer.

	Materials and Methods

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Study Population.
The population-based case-control study consisted of German-speaking women resident in two study regions (Freiburg and Rhein-Neckar-Odenwald) in southern Germany. Breast cancer patients under the age of 51 years at the time of diagnosis of incident in situ or invasive breast cancer were eligible for the study. They were either approached in the hospital or contacted by a letter from the attending physician after discharge. Two controls matched by exact age and study region were selected for each case from a random list of residents provided by the population registries. These control persons were invited to participate by letter. Overall, 706 of 1005 eligible cases (70.2%), and 1381 of 2257 eligible controls (61.2%) participated (11) .

The study participants completed a self-administered risk factor questionnaire including information on demographic factors, anthropometric measures, and menstrual, reproductive, and breast-feeding history and family history of cancer. For analysis of dietary factors, the 1451 participants of the study region Rhein-Neckar-Odenwald were asked to complete a 176-item food frequency questionnaire after they had filled out a risk factor questionnaire. The participants were asked to document their nutritional habits in the year before the diagnosis of breast cancer or questionnaire completion. The food frequency questionnaire was developed at the German Cancer Research Center (Deutsches Krebsforschungszentrum) in Heidelberg, Germany and validated for food group, energy, and nutrient intake (11 , 12) . The food item list was defined on the basis of the dietary intake results in the German National Food Consumption Survey. The food frequency questionnaire was returned by 1288 of the 1451 participants (88.8%). Of these, 258 participants were excluded due to various reasons such as a high number of missing items or extreme over- and underreporting (13) .

This analysis includes only German cases and controls, from whom questionnaire data and DNA from a blood sample were available. A total of 616 cases and 1072 controls were included in molecular analysis; genotyping was successful for 604 cases and 1063 controls. Nutritional and genotyping data were available from 1000 participants (311 cases and 689 controls).

Genotype Analysis.
Genomic DNA isolation from peripheral blood was performed using the QIAamp Blood Kit (Qiagen), and tumor tissue DNA was extracted using the QIAamp DNA Mini Kit (Qiagen) according to the manufacturer’s instructions. As a control for PCR fragment length, DNA from the tumor cell line MDA-MB-468 was analyzed.

PCR amplification was performed using AmpliTaq DNA polymerase (Applera) in a 25-µl reaction volume containing 200 nM of each primer, 1x GeneAmp buffer II, 2 mM MgCl₂, 100 µM of each GeneAmp deoxynucleoside triphosphate (Applera), and 20 ng of sample DNA. The primer sequences are specific for microsatellite marker egfr in intron 1 of egfr gene:forward primer, 5'-GTT-TGA-AGA-ATT-TGA-GCC-AAC-C; and reverse primer, 5'-TTC-TTC-TGC-ACA-CTT-GGC-AC. Downstream primers were labeled with a fluorescent dye ([F]-amidite-6-carboxy fluorescein). Separation was done with a four-color laser-induced fluorescence capillary electrophoresis system (ABI PRISM 310 DNA Analyzer and ABI PRISM 3700 DNA Analyzer). One to two µl of the amplified PCR products were diluted in 20 µl of water (high-performance liquid chromatography grade) containing 0.5 µl of GENESCAN 500 (Tamra) or 400 HD (Rox) fluorescent size standard (Applera). Denatured PCR fragments were separated on the ABI PRISM 310 and ABI PRISM 3700 DNA Analyzer (Applera). Evaluation of the collected data was accomplished with GeneScan Analysis Software (Applera). All analyses were performed at least in duplicates of independent PCRs.

Genotypes were categorized for analysis by allele size and frequency. The length of the CA repeat is inversely associated with transcriptional activity of the gene and directly associated with the likelihood of an AI. Therefore, we first modeled the egfr polymorphism in three ways to reflect the activity of specific alleles: (a) having at least one short allele, considering the shorter of the two alleles for each subject; (b) having at least one long allele; and (c) the combined effect of the two alleles, by assessing the mean allele length for each subject. In addition, the egfr polymorphism was assessed by dichotomization of the sample into two groups based on the observed distribution of the repeats as well as previous analysis of transcriptional activity and likelihood for AI by allele size. We defined the cutoffs for a shorter allele with 16, 17, and 18 CA repeats and a longer allele with 17, 18, and 19 CA repeats, respectively.

Statistical Methods.
The allele frequencies in cases and controls were compared, and the difference was assessed by the ² test. The risk of breast cancer associated with egfr genotype and other risk factors was assessed using logistic regression modeling with stratification according to age (in years). Odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated using the proportional hazards regression procedure of the statistical software package SAS Release 8.12 (SAS Institute, Cary, NC). Analyses were adjusted for lifetime duration of breastfeeding in months (as a continuous variable), first-degree family history of breast cancer (mother, sister, or daughter), number of full-term pregnancies (classified in three categories of 0, 1–2, and 3 full-term pregnancies), age at menarche (classified in three categories of <13 years, 13–14 years, and 15 years of age), and alcohol consumption (0 g/day, 18 g/day, and 19 g/day). The procedure of nutritional analyses has been described in detail elsewhere (13) . In short, for evaluations considering nutritional factors, the calculated consumption of various food groups was analyzed as a categorical variable (in quartiles) based on item consumption among controls only. The relative risk of breast cancer was estimated for higher quartiles of food consumption in comparison with the lowest quartile of consumption. To test categorized variables for trend, the categories were scored and entered into the regression analysis as ordinal variables.

We also investigated whether the different genotypes interact with other risk factors previously shown to be related to breast cancer. Effect modification of dietary risk factors and risk associated with family history by genotype was evaluated for three models by defining the long allele to be 17, 18, and 19 CA repeats. Interactions between genetic and other variables were measured by using multiplicative terms and evaluated by the likelihood ratio tests.

	Results

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Mean ages of the 604 cases and 1063 controls were 42.4 and 42.6 years, respectively. Table 1 shows the distribution of different risk factors for cases and controls and the corresponding ORs. As reported previously, a larger number of full-term births and a longer duration of breastfeeding were associated with a significantly reduced breast cancer risk. Cases reported the occurrence of first-degree family history of breast cancer significantly more often than controls.

Association of the Allelic Length of the egfr CA SSR with Breast Cancer Risk.
The exploratory analysis did not yield significantly increased ORs associated with carrying a shorter or longer of the two alleles at a specific cutpoint (Figs. 1 and 2) .

View larger version (4K): [in this window] [in a new window] [Download PPT slide]   Fig. 1. Odds ratios of breast cancer associated with the longer allele. Odds ratios and the 95% confidence intervals are presented for those having at least one long allele (designated by the CA repeat lengths on the X axis), considering the longer of the two alleles for each subject.

View larger version (5K): [in this window] [in a new window] [Download PPT slide]   Fig. 2. Odds ratios of breast cancer associated with the shorter allele. Odds ratios and the 95% confidence intervals are presented for those having at least one short allele (designated by the CA repeat lengths on the X axis), considering the shorter of the two alleles for each subject.

Effect Modification of Long egfr CA SSR Alleles.
We analyzed the data for a modification of the effect of the length of the egfr CA SSR alleles on breast cancer risk by family history. Breast cancer patients with family history of breast cancer in a first-degree relative were more frequently carriers of two alleles of 19 CA repeats than patients without family history (17.1% and 8.7%, respectively). Merely 3.4% of the controls with a positive family history carried two long alleles (Table 3) . The presence of two long alleles egfr CA SSR was associated with an elevated OR of 10.4 (95% CI, 1.8–58.7) among women with a first degree family history of breast cancer, but not among women without such a family history (OR, 1.8; 95% CI, 0.7–4.6), providing strong evidence for differential effects of the egfr CA SSR polymorphism on disease risk by a first-degree family history (P = 0.015 for interaction). Case-only analysis confirmed these results, albeit with borderline statistical significance. A much weaker differential effect of allele length on risk of breast cancer by family history was observed at a cutoff of 18 CA repeats for the longer allele (P = 0.0047), but not at a cutoff of 17 CA repeats for the longer allele (data not shown).

For red meat intake, the analysis of dietary factors stratified by the egfr genotype yielded a significant trend in breast cancer risk with increasing consumption for both carriers of two longer alleles and carriers of two shorter alleles. Again, the most pronounced effect was observed at a cutoff of 19 CA repeats for the longer allele and 18 CA for the shorter allele; therefore, these results will be presented (Table 4 ; P for trend, 0.03 and 0.02, respectively). The significant trend for homozygous carriers of either allele (P = 0.03 and 0.02, respectively) was predominantly due to the high ORs associated with the highest consumption quartile, although stronger for carriers of two 19 CA repeat alleles (OR, 10.68; 95% CI, 1.57–72.58) than carriers of two 18 CA repeat alleles (OR, 1.86; 95% CI, 1.06–3.27; Table 4 ). An association was not found for the heterozygous carriers of one long and one short allele (P for trend, 0.85). Interaction between the egfr polymorphism and red meat consumption was tested by scoring the red meat consumption categories but was not found to be significant.

	Discussion

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In a population-based case-control study in Germany, we tested the hypothesis that the CA SSR polymorphism in intron 1 of egfr affects breast cancer risk. Overall, we did not find an association of allelic length of the egfr CA SSR polymorphism with breast cancer risk. However, we observed that the presence of two long alleles, particularly when defined as 19 CA repeats, of the egfr CA SSR was associated with a significantly elevated OR among women with a first-degree family history of breast cancer, but not among women without such a family history. The differential effects of allelic length of the egfr CA SSR on disease risk by a first-degree family history were statistically significant, even after a Bonferroni adjustment for multiple comparisons using three different definitions for the longer allele (P = 0.015 for interaction). This was confirmed in a case-only analysis of the patients. To our knowledge, this is the first report of a possible relevance of this common intronic polymorphism for familial breast cancer.

Furthermore, our data suggested that the risk increase associated with high red meat consumption and the protective effect of high vegetable intake may be additionally enhanced among carriers of two longer alleles, particularly for alleles of 19 CA repeats, in comparison with the total population (13) .

We cannot exclude that selection bias may have contributed to the study results because not all women had provided blood samples. However, the distribution of all relevant epidemiological variables did not differ between those with DNA samples and those without DNA samples. Dietary information was not available from all study subjects of the one study region involved. Here again, we found little difference between the original study population and the subgroup providing dietary information with respect to relevant epidemiological variables, so that the effect of selection bias may be negligible.

Recall bias of family history of breast cancer would have to be differential for noncarriers and carriers of the long allele to result in the observed differential effect by family history, and this seems rather unlikely. Recall bias may be a source of measurement error of dietary habits. Our previously reported results of an inverse association with vegetable intake and a positive association with high red meat consumption are compatible with findings of other studies. The dietary intake levels observed in our study population are comparable with the intake data described in other large German studies (German European Prospective Investigation into Nutrition and Cancer centers) by means of the same validated assessment tool (14 , 15) . Therefore, we have some assurance that the collected data are valid.

As mentioned above, the presence of two long alleles of the egfr CA SSR (most pronounced for 19 CA repeats) was strongly associated with an increased risk among women with a first-degree family history of breast cancer in this study. In experimental studies, we found that the length of the inherited polymorphic CA SSR in the 5'-regulatory sequence of intron 1 of the egfr gene, on one hand, was inversely associated with its transcriptional activity and, on the other hand, directly associated with the likelihood of AI (9 , 10) . The second observation was further supported by interethnic studies (16) . Japanese women presented very homogenously with predominantly longer alleles containing 19 CA dinucleotides, as compared with Caucasians. Moreover, Japanese breast cancers had a significantly higher prevalence of AI, indicating gene amplifications, as compared with their German counterparts. Furthermore, it has already been shown that the number of repeats itself affects the mutation rate of nucleotide repeats (17) .

We can also postulate that other genetic factors and/or lifestyle factors in women with a family history of breast cancer may render a higher probability of mutation in the longer allele. This is further supported by our most recent data that a putative fragile site is located close to the egfr gene and that these AIs were already present in the surrounding normal, nontumorous breast tissue (10) . Besides, EGFR expression underlies further complex regulation mechanisms influenced by extrinsic factors. These factors appear to predominantly concern lifestyle, especially dietary factors, which are likely to be shared in a family. This is known, for instance, for genistein derived from soy, which reduced EGFR expression in rats (6) . We did not have adequate statistical power to show how dietary factors may have contributed to the increased risk associated with the presence of two long alleles of the egfr CA SSR in women with a positive family history. In the whole study group, however, the risk increase associated with high red meat consumption and the protective effect of high vegetable intake were most pronounced among carriers of two 19 CA alleles. Heterocyclic aromatic amines are found in meat cooked at high temperatures for long duration. They could induce mutations because, after metabolic activation, heterocyclic aromatic amines can react directly with DNA and efficiently induce mitotic recombination (18) . On the other hand, protection from DNA damage can be mediated by antioxidants in vegetables (19) . Therefore, longer alleles of the egfr CA SSR may contribute to a higher risk of breast cancer caused by environmental factors. We speculate that in the case of two longer alleles of the CA SSR I, a mutant clone would become dominant after an undetermined number of cell divisions due to natural selection acting to increase the frequency of advantageous alleles in breast glandular cells. However, the impact of both the increase in transcription activity with a low number of CA repeats and the increase of likelihood for an AI at the egfr locus leading to EGFR overexpression with a high number of CA repeats should reach an equilibrium for the genotypes with a long allele and a short allele. In fact, no significant association between food pattern and cancer risk could be determined for this subgroup in our study. In the case of the two shorter alleles, extrinsic factors may play only a secondary role because of the inherent higher transcriptional activity and lower likelihood for AI.

In conclusion, our data support the assumption that the egfr CA SSR polymorphism is a causal factor for some cases of familial breast cancer and that its effect may be modulated by dietary factors. Additional epidemiological studies are needed to support this association, and further experimental work is needed to define the molecular mechanisms leading to AIs at the egfr CA SSR I locus and to explain the intriguing network of exogenous and endogenous factors causing breast cancer.

	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.

Note: B. Brandt and J. Chang-Claude contributed equally to this work.

Requests for reprints: Burkhard Brandt, Institute of Clinical Chemistry and Laboratory Medicine, University of Muenster, Albert-Schweitzer-Strasse 33, 48149 Muenster, Germany. Phone: 49-251-83-47226; Fax: 49-251-83-47226; E-mail: brandt{at}uni-muenster.de

Received 8/21/03. Revised 10/17/03. Accepted 11/ 6/03.

	REFERENCES

Top ABSTRACT Introduction Materials and Methods Results Discussion REFERENCES

 

1. Wooster R., Weber B. L. Breast and ovarian cancer. N. Engl. J. Med., 348: 2339-2347, 2003.[Free Full Text]
2. Narod S. A. Modifiers of risk of hereditary breast and ovarian cancer. Nat. Rev. Cancer, 2: 113-123, 2002.[CrossRef][Medline]
3. Chang-Claude J. Inherited genetic susceptibility to breast cancer Miller A. B. Bartsch H. Boffeta P. Dragsted L. Vainio H. eds. . Biomarkers in Cancer Prevention. IARC Scientific Publication No. 154, 177-190, IARC Lyon, France 2001.
4. Houlston R. S., Tomlinson I. P. Detecting low penetrance genes in cancer: the way ahead. J. Med. Genet., 37: 161-167, 2000.[Abstract/Free Full Text]
5. Dunning A. M., Healey C. S., Pharoah P. D., Teare M. D., Ponder B. A., Easton D. F. A systematic review of genetic polymorphisms and breast cancer risk. Cancer Epidemiol. Biomark. Prev., 8: 843-854, 1999.[Abstract/Free Full Text]
6. Brown N. M., Wang J., Cotreno M. S., Zhao Y. X., Lamartiniere C. A. Prepubertal genistein treatment modulates TGF-, EGF and EGF-receptor mRNAs and proteins in the rat mammary gland. Mol. Cell. Endocrinol., 144: 149-165, 1998.[CrossRef][Medline]
7. Brandt R., Eisenbrandt R., Leenders F., Zschiesche W., Binas B., Juergensen C., Theuring F. Mammary gland specific hEGF receptor transgene expression induces neoplasia and inhibits differentiation. Oncogene, 20: 2129-2137, 2000.
8. Gebhardt F., Zänker K. S., Brandt B. Modulation of epidermal growth factor receptor gene transcription by a polymorphic dinucleotide repeat in intron 1. J. Biol. Chem., 274: 13176-13180, 1999.[Abstract/Free Full Text]
9. Buerger H., Gebhardt F., Beckmann A., Hutmacher K., Simon R., Lelle R. J., Boecker W., Brandt B. Length and loss of heterozygosity of an intron 1 polymorphic sequence of egfr is related to cytogenetic alterations and EGFR-expression. Cancer Res., 60: 854-857, 2000.[Abstract/Free Full Text]
10. Tidow N., Boecker A., Schmidt H., Agelopoulos K., Boecker W., Buerger H., Brandt B. Distinct amplification of an untranslated regulatory sequence in the egfr gene contributes to early steps in breast cancer development. Cancer Res., 63: 1172-1178, 2003.[Abstract/Free Full Text]
11. Chang-Claude J., Eby N., Kiechke M., Bastert G., Becher H. Breastfeeding and breast cancer risk by age 50 among women in Germany. Cancer Causes Control, 11: 687-695, 2000.[CrossRef][Medline]
12. Liu W., Innocenti F., Chen P., Das S., Cook E. H., Jr., Ratain M. J. Interethnic difference in the allelic distribution of human epidermal growth factor receptor intron 1 polymorphism. Clin. Cancer Res., 9: 1009-1012, 2003.[Abstract/Free Full Text]
13. Hermann S., Linseisen J., Chang-Claude J. Nutrition and breast cancer risk by age 50: a population-based case-control study in Germany. Nutr. Cancer, 44: 23-34, 2002.[CrossRef][Medline]
14. Bohlscheid-Thomas S., Hoting I., Boeing H. Wahrendorf: reproducibility and relative validity of food group intake in a food frequency questionnaire developed for the German part of EPIC Project. Int. J. Epidemiol., 26: S59-S71, 1997.[Abstract/Free Full Text]
15. Bohlscheid-Thomas S., Hoting I., Boeing H. Wahrendorf: reproducibility and relative validity of energy and macronutrient intake of a food frequency questionnaire developed for the German part of EPIC Project. Int. J. Epidemiol., 26: S71-S81, 1997.[Abstract/Free Full Text]
16. Bürger, H., Packeisen, J., Kersting, C., Isola, J., Böcker, W., Böcker, A., Tidow, N., Nakachi, K., Bielwaski, K., Yatabi, Y., and Brandt, B. Allelic length of a CA dinucleotide repeat in the egfr gene correlates with the frequency of amplifications of this sequence. First results of an interethnic breast cancer study. J. Pathol., in press, 2003.
17. Eckart K. A., Yan G., Hile S. E. Mutation rate and specificity analysis of tetranucleotide microsatellite DNA alleles in somatic cells. Mol. Carcinog., 34: 140-150, 2002.[CrossRef][Medline]
18. Paladino G., Weibel B., Sengstag C. Heterocyclic aromatic amines efficiently induce mitotic recombination in metabolically competent Saccharomyces cerevisiae strains. Carcinogenesis (Lond.), 20: 2143-2152, 1999.[Abstract/Free Full Text]
19. Wu A. H., Wan P., Hankin J., Tseng C. C., Yu M. C., Pike M. C. Adolescent and adult soy intake and risk of breast cancer in Asian-Americans. Carcinogenesis (Lond.), 23: 1491-1496, 2002.[Abstract/Free Full Text]

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