Abstract
3040 Background: ERCC1 and ERCC2,two major components of the NER pathway, are critical to platinum chemotherapy function. We demonstrated previously that DNA repair gene single nucleotide polymorphisms (SNPs) are associated with overall survival (OS) in platinum-treated NSCLC patients. We hypothesized that NER gene haplotypes (i.e., combinations of polymorphic markers on a single chromosome segment) are associated with NSCLC OS. Methods: Four SNPs (ERCC1 C8092Aand C19007T; ERCC2 Asp312Asn and Lys751Gln) were genotyped in 124 stage III (61%) and IV (39%) NSCLC patients treated with platinum chemotherapy. Haplotypes were generated using Partition Ligation-Expectation Maximization algorithms. Results: Median age was 59 (32–77); 48% were female; median follow-up was 64.6 months. Median survival time (MST) was 15.7 months; by stage, MST was 29.6 (IIIA), 17.9 (IIIB), and 10.1 (IV) months. Stage was not associated with any haplotypes. Strong linkage disequilibrium was observed for the two ERCC1polymorphisms, and separately for the ERCC2polymorphisms. ERCC1 haplotype frequencies were: 25% (8092A-19007C), 15% (8092C-19007C), 59% (8092C-19007T), and 1% (8092A-19007T); ERCC2frequencies were: 7% (312Asp-751Gln), 27% (312Asn-751Gln), 62% (312Asp-751Lys), and 4% (312Asn-751Lys). The ERCC1 8092A-19007Cand ERCC2 312Asn-751Glnhaplotypes were associated with significantly decreased OS (p=0.014 and p=0.0004, respectively, logrank test, see table). The combination of high-risk haplotypes from both NER genes was also highly prognostic (p=0.002, logrank test). Conclusions: Specific ERCC1and ERCC2haplotypes confer significantly decreased OS in platinum-treated advanced NSCLC patients. NER gene haplotypes provide prognostic information in NSCLC OS in addition to that previously reported with SNPs. Supported by NIH grants CA092824 and CA074386. No significant financial relationships to disclose.
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