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A Novel Polymorphism in the Promoter Region of ERBB4 Is Associated with Breast and Colorectal Cancer Risk

Matja Rokavec^1,2,3, Christina Justenhoven^1,2, Werner Schroth^1,2, Monica Adina Istrate^1,2, Susanne Haas⁴, Hans-Peter Fischer⁴, Caren Vollmert⁵, Thomas Illig⁵, Ute Hamann⁶, Yon-Dschun Ko⁷, Damjan Glava³ and Hiltrud Brauch^1,2

Authors' Affiliations: ¹ Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany; ² Department of Clinical Pharmacology University Tübingen, Tübingen, Germany; ³ Department of Molecular Genetics, Institute of Pathology, Medical Faculty, University of Ljubljana, Slovenia; ⁴ Institute of Pathology, Medical Faculty of the University of Bonn, Germany; ⁵ GSF-National Research Center for Environment and Health, Institute of Epidemiology, Neuherberg, Germany; ⁶ Deutsches Krebsforschungszentrum, Heidelberg, Germany; and ⁷ Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus Bonn, Germany

Requests for reprints: Hiltrud Brauch, Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstrasse 112, 70376 Stuttgart, Germany. Phone: 49-711-8101-3705; Fax: 49-711-85-9295; E-mail: hiltrud.brauch{at}ikp-stuttgart.de.

Purpose: The receptor tyrosine kinase ERBB4/HER4 plays a role in cell division, migration, differentiation, as well as apoptosis, and is frequently overexpressed in breast and colorectal tumors. To understand the role of genetic variations in the regulation of ERBB4 expression, we identified new polymorphisms and investigated their functional implication and risk association with breast and colorectal cancer.

Experimental Design: We screened colorectal tumors from 92 patients for genetic variants at the ERBB4 ATG –1000 bp 5'-regulatory region by denaturing high-performance liquid chromatography and sequencing. Variants were subjected to DNA-protein interaction analyses (electrophoretic mobility shift assay), reporter gene assays in breast cancer cell lines MDA134 and MDA157, and immunohistochemical analyses of breast tumors. We established genotype frequencies within a breast cancer case-control collection (1,021 cases, 1,015 population-based controls) and a colorectal cancer case-control collection (459 cases, 569 blood donors) using matrix-assisted laser desorption ionization/time of flight mass spectrometry. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were assessed by multivariate logistic regression.

Results: We identified five new germ line variants –815 A>T, –782 G>T, –638 insTC, –267 C>G, and –219 del10bp. Two variants showed in vitro functional effects. The –782T allele showed lower protein binding affinity and lower promoter activity compared with the –782G allele, however, the –815T allele showed higher protein binding affinity and higher promoter activity. The –782T variant was identified as a risk allele for breast and colorectal cancer (OR, 1.59; 95% CI, 1.06-2.34 and OR, 2.21; 95% CI, 1.22-3.99, respectively).

Conclusion: The ERBB4 –782 G>T polymorphism, by virtue of its in vitro functional implication and incidence, is a risk factor for breast and colorectal cancer.

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