Polymorphisms in ERCC2 and overall survival (OS) in early stage non-small cell lung cancer (NSCLC)

Abstract

9524 Background: ERCC2 is an important enzyme in nucleotide excision repair. Polymorphisms in the ERCC2 gene may affect DNA repair capacity and prognosis. Methods: We evaluated the relationship between the ERCC2 Asp312Asn and Lys751Gln polymorphisms and OS among surgically resected Stage I and II NSCLC patients. Genotyping was done using modified PCR-RFLP methods, Kaplan-Meier methods and log-rank test were used to compare OS by polymorphism status. Cox proportional hazards models were used to adjust for possible confounding variables. Results: There were 405 patients in this study. Median age 69 yrs; 51% male; 52% Stage IA, 29% IB, 4% IIA, 15% IIB. 63% lobectomy; 23% wedge resection; 7% pneumonectomy; 3% sleeve lobectomy; 3% bilobectomy; 1% other. 49% adenocarcinoma; 29% squamous; 12% BAC; 4% large cell; 6% other NSCLC. Genotype frequencies were in Hardy-Weinberg equilibrium: Asp/Asp 40%, Asp/Asn 45%, Asn/Asn 15%; Lys/Lys 44%, Lys/Gln 41%, Gln/Gln 15%. The two polymorphisms were linked. Median follow-up time was 5.9 yrs. There were 209 deaths. Median survival time (MST) was longer among patients carrying the variant Asn or Gln allele: MST Arg/Arg 5.4 yrs; Arg/Asn or Asn/Asn 7.5 yrs (log-rank test, p = 0.06); MST Lys/Lys 5.0 yrs; Lys/Gln or Gln/Gln 7.6 yrs (log-rank test, p < 0.01). On univariate analysis, age, sex, stage, BAC histology, and the Lys751Gln polymorphism were significantly associated with OS, while the Arg312Asn polymorphism had a borderline association. After adjusting for age, sex, stage, and BAC histology, carrying the Asn or Gln variant alleles was associated with improved OS (HR 0.72, 95% CI 0.55–0.95, p = 0.02; HR 0.63, 95% CI 0.47–0.83, p < 0.01; respectively). Conclusions: Carrying the variant allele of the ERCC2 Arg312Asn or Lys751Gln polymorphism is associated with improved OS in surgically resected Stage I/II NSCLC. Supported by NIH grants CA074386, CA092824, 5T32CA071345. No significant financial relationships to disclose.