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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

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.

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