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ERCC2 Genotypes and a Corresponding Haplotype Are Linked with Breast Cancer Risk in a German Population

¹ Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany; ² Deutsches Krebsforschungszentrum, Heidelberg, Germany; ³ Berufsgenossenschaftliches Forschungsinstitut für Arbeitsmedizin, Ruhr University Bochum, Bochum, Germany; ⁴ GSF-National Research Center for Environment and Health, Institute of Epidemiology, Neuherberg, Germany; and ⁵ Department of Internal Medicine, Johanniter Krankenhaus and University of Bonn, Bonn, Germany

Requests for reprints: Hiltrud Brauch, Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, D-70376 Stuttgart, Germany. Phone: 49-711-8101-3705; Fax: 49-711-859-295. E-mail: hiltrud.brauch{at}ikp-stuttgart.de

The polygenic concept of breast cancer susceptibility calls for the identification of genetic variants that contribute to breast cancer risk. Reduced DNA repair proficiencies in women with breast cancer pointed to a possible role of DNA repair enzymes in the risk to develop the disease. The nucleotide excision repair enzyme encoded by the excision repair cross-complementing group 2 gene ERCC2 (formerly XPD) known to cause skin cancer by germ line mutations has multiple regulatory cellular functions, including nucleotide excision repair, basal transcription, cell cycle control, and apoptosis. ERCC2 polymorphisms ERCC2_6540_G>A (Asp³¹²Asn) and ERCC2_18880_A>C (Lys⁷⁵¹Gln) within the coding region of this evolutionarily highly conserved gene have been of functional relevance and therefore are potential candidates to confer breast cancer susceptibility. Using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, we analyzed genotype frequencies in constitutional DNA of study participants of a German case-control study that included 688 cases of incident breast cancer and 724 population-based, age-matched controls. We identified ERCC2_6540_GG (Asp³¹²Asp) as an at-risk genotype [odds ratio (OR), 2.06; 95% confidence interval (95% CI), 1.39-3.07]. The ERCC2_6540_GG-associated breast cancer risk was even higher in women who were also carriers of the ERCC2_18880_CC (Gln⁷⁵¹Gln) genotype (OR, 3.69; 95% CI, 1.76-7.74). We identified ERCC2_6540_G/ERCC2_18880_C (Asp³¹²/Gln⁷⁵¹) as the most potent risk-conferring haplotype (OR, 3.49; 95% CI, 2.30-5.28). To our knowledge, this is the first study assigning breast cancer risk to both the ERCC2 genotype encoding Asp³¹²Asp and the haplotype encoding Asp³¹²/Gln⁷⁵¹.

Key Words: Breast cancer • DNA repair polymorphisms and risk • Polymorphisms related to cell growth, differentiation, metastatic, potential, apoptosis • Descriptive, risk factor, and methodologic studies • Methodology for SNP detection

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