Breast cancer risk is linked with ERCC2 genotypes and a corresponding haplotype in a German population
2005; American Association for Cancer Research; Volume: 65; Linguagem: Inglês
ISSN
1538-7445
AutoresChristina Justenhoven, Ute Hamann, Beate Pesch, Volker Harth, Sylvia Rabstein, Christian Baisch, Yon‐Dschun Ko, Thomas Brüning, Caren Vollmert, Thomas Illig, Hiltrud Brauch,
Tópico(s)BRCA gene mutations in cancer
Resumo4070 The polygenic concept of breast cancer susceptibility calls for the identification of genetic variants contributing to breast cancer risk. Suspect molecular risks may include enzymes involved in hormone metabolism/catabolism and DNA repair. 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 (NER) enzyme encoded by the excision repair cross-complementing group 2 gene ERCC2 (formerly XPD) known to cause skin cancer by germline mutations has multiple regulatory cellular functions including NER, 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 shown to be of functional relevance, and therefore be potential candidates to confer breast cancer susceptibility. Using MALDI-TOF MS methodology we analyzed genotype frequencies in constitutional DNA of study participants of a German case-control study including 688 incident breast cancer cases and 724 population-based, age-matched controls. We identified ERCC2_6540_GG (Asp312Asp) as an at-risk genotype (OR 2.06; 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) (OR 3.69, 95% CI: 1.76-7.74) or ERCC2_18880_AC (Lys751Gln) genotype (OR 2.61, 95% CI: 1.77-3.85). We identified ERCC2_6540_G/ERCC2_18880_C (312Asp751Gln) 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 312Asp/751Gln. We are currently exploring the role of other polymorphisms of DNA repair and hormone metabolism and will present how these integrate with the ERCC2 associated breast cancer risk in our population.
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