DNA repair, multidrug resistance and metabolic enzyme genes polymorphisms as predictors of clinical outcome in resected non-small cell lung cancer (NSCLC)

Abstract

22121 Background: Early stage NSCLC is considered a potentially curable disease following complete resection. Gene expression profiles can identify patients (pts) with a higher risk of recurrence. We hypothesized those differents polymorphisms profiles could help to predict disease outcome. Methods: NSCLC paraffin-embebed samples were obtained from 58 pts who underwent curative pulmonary resection. We analyze 17 polymorphisms: 8 DNA repair polymorphisms: XRCC5(T/C), XRCC5(A/G), XPA(T/C), XPC(Gln939Lys), ERCC1(Lys259Thr), ERCC2(Lys751Gln), ERCC5(Asp1104His) and ERCC5(His49His); 7 metabolic enzyme polymorphisms: EPOXH1(His139Arg), EPOXH1(Tyr113His), CYP2C8(Arg139Lys), CYP2C8(Lys399Arg), GSTP1(G/A), GSTT1(C/T), NAT2–1(Arg197Gln); and 2 multidrug resistance polymorphisms: MDR1(Ile1145Met), MDR1(G412G). The analysis were performed using real-time polymerase chain reaction allelic discrimination TaqMan assay. Results: 58 primary lung cancer cases were included between January 1997 to December 2001. 56 males, 2 females. Median age was 65. Histology: 44.8% adenocarcinoma and 50% squamous cell carcinoma. Stage: I 36.9%, II 25.9% and III 15.5%. 56% relapsed. The presence of ERCC1 (34.5 vs 71 m wild type (WT); p=0.022), XPC (39.6 vs 73.9 m WT; p=0.035), XRCC5(A/G)(12.5 vs 66.9 m WT; p=0.006) or CYP2C8 (Arg139Lys) (26.8 vs 70.8 WT m; p=0.009) polymorphism were associated with worse time to progression (TTP). A metabolic enzyme polymorphisms (NAT 2–1) better outcome (87.6 vs 43 m WT, p=0.008). For survival (OS) pts with XRCC5(A/G) (31.5 vs 65.9 m WT, p=0.054), ERCC1 (38.5 vs 71.5 m WT; p=0.017) and MDR-1(Ile1145Met) (34.7 vs 69.7 m WT; p=0.021) showed worse results. In multivariate analysis stage (p=0.001), sex (p=0.003), XRCC5 (A/G) (p=0.006), ERCC1 (p=0.004), NAT 2–1 (p=0.006) for TTP and stage (p=0.008) and sex (p=0.054) for survival were identified as an independent prognostic factors. Conclusions: we report associations between some DNA repair, metabolic enzyme and multidrug resistance polymorphisms and clinical outcome in resected NSCLC pts. No significant financial relationships to disclose.