title: ERCC2 genotypes and a corresponding haplotype are linked with breast cancer risk in a German population.
abstract: 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 (Asp(312)Asn) and ERCC2_18880_A>C (Lys(751)Gln) 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 (Asp(312)Asp) 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 (Gln(751)Gln) genotype (OR, 3.69; 95% CI, 1.76-7.74). We identified ERCC2_6540_G/ERCC2_18880_C (Asp(312)/Gln(751)) 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 Asp(312)Asp and the haplotype encoding Asp(312)/Gln(751).
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, D-70376 Stuttgart, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Justenhoven
authors.forename: Ute
authors.initials: U
authors.lastname: Hamann
authors.forename: Beate
authors.initials: B
authors.lastname: Pesch
authors.forename: Volker
authors.initials: V
authors.lastname: Harth
authors.forename: Sylvia
authors.initials: S
authors.lastname: Rabstein
authors.forename: Christian
authors.initials: C
authors.lastname: Baisch
authors.forename: Caren
authors.initials: C
authors.lastname: Vollmert
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.forename: Yon-Dschun
authors.initials: YD
authors.lastname: Ko
authors.forename: Thomas
authors.initials: T
authors.lastname: Brüning
authors.forename: Hiltrud
authors.initials: H
authors.lastname: Brauch
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D016022:Case-Control Studies; D004265:DNA Helicases / Q000235:genetics*; D004252:DNA Mutational Analysis; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005858:Germany / Q000453:epidemiology; D006239:Haplotypes; D006801:Humans; D008875:Middle Aged; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D014157:Transcription Factors / Q000235:genetics*; D051759:Xeroderma Pigmentosum Group D Protein
chemical_list: D004268:DNA-Binding Proteins; D014157:Transcription Factors; D004265:DNA Helicases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human