Prognostic significance of nuclear excision (NER) and base excision (BER) DNA repair gene polymorphisms in esophageal cancer

Abstract

2511 Background: DNA repair pathways are involved in cisplatin-induced damage (NER pathway) & radiation damage (BER pathway). Some single nucleotide polymorphisms (SNPs) of DNA repair genes are associated with DNA repair capacity, cancer risk & outcomes. We investigated the prognostic significance of 7 NER/BER SNPs on disease free (DFS) & overall survival (OS) in esophageal cancer. Methods: 150 patients with esophageal cancer treated with cisplatin-based chemoradiation & surgery were genotyped for BER (XRCC1 Arg399Gln; APE1 Asp148Glu; hOGG1 Ser326Cys) & NER (ERCC1 8092C/A; ERCC1 codon 118 C/T; XPD Asp312Asn; XPD Lys751Gln) SNPs. Analysis involved Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models. Results: Median age: 63 years (range 28–80); 91% male; 100% ECOG performance status (PS) 0–1; adenocarcinoma 79%; stages IIA 22%, IIB 30%, III 33%, and IVA 15%. No SNPs were associated with stage or PS. Multiple NER SNP was independently prognostic for OS and DFS (see Table ). When compared to individuals who were wildtype in all four studied NER SNPs, individuals with variants in all four NER SNPs were associated with substantial improvement in OS (Adjusted Hazard Ratio (AHR) = 0.40, 95% confidence interval (CI) = 0.2–0.7) and DFS (AHR = 0.44, 95%CI = 0.2–0.8). Furthermore, increasing numbers of variant genotypes were associated with a progressive increase in OS & DFS when all seven NER/BER pathway SNPs were analysed together ( Table ). There was a 3.8- fold increase in OS (75 vs. 20 months) and five-fold increase in DFS (51 vs. 10 months) when comparing individuals with 6–7 SNPs with variant alleles to individuals with 0–1 SNPs with variant alleles. Conclusions: The ERCC1 8092 C/A, XPD Asp312Asn & XPD Lys751Gln SNPs in the NER pathway are associated individually with prognosis in esophageal cancer patients treated with cisplatin-based trimodality regimens. In addition, as the number of NER and BER SNPs carrying variant alleles increased, OS and DFS improved dramatically. [Table: see text] No significant financial relationships to disclose.