Association of genetic variations in DNA-methyltransferases, histone-methyltransferases, and methylated DNA-binding proteins with recurrence and survival in early-stage non-small cell lung cancer treated with surgery alone or surgery and chemotherapy.

Abstract

7010 Background: Genetic polymorphic variants (SNPs) of DNA- and histone-modifying genes, in particular O6- methylguanine DNA-methyltransferase (MGMT), have been implicated in increased risk for development of lung cancer. Methods: 165 SNPs in these genes were genotyped in 461 stage 1 and 2 non-small cell lung cancer (NSCLC) patients treated with surgery (N=337) or surgery and chemotherapy (N=124) and analyzed for association with recurrence and survival. Median survival times and recurrence rates were 89.1 months and 27.5 % (93/337) for surgery and >133.6 months and 29% (36/124) for surgery and chemotherapy, respectively. Results: We identified three classes of SNPs that were differentially prognostic or predictive of recurrence and survival in early stage NSCLC. Class 1 contained two SNPs (in MGMT) which were prognostic biomarkers for clinical outcome independent of treatment modality. Six SNPs in class 2 (MBD2, SUV39H2, MBD4, EZH1(2x), EZH2) correlated with treatment outcome for surgery alone, but not with surgery and chemotherapy, hence their effect could be reversed by chemotherapy. The last class 3 contained SNPs, which were associated with surgery and chemotherapy, but not surgery alone. For example, we observed hazard ratios for rs4751104 for recurrence of surgery and chemotherapy of 4.94 (95% CI, 1.92-12.71) and 0.89 (95% CI, 0.47- 1.67) for surgery alone. The association of most SNPs remained significant after adjusting for multiple comparisons using a q-value at 10%. By using a combination of SNPs in class 2 or 3, we were able to build genetic predictors for outcome of surgery or surgery and chemotherapy, with p < 10-6 and < 10-4, respectively. Conclusions: These results suggest that specific genetic variations in the genes mentioned above modulate clinical outcomes in patients who undergo surgery or surgery and chemotherapy for early stage NSCLC. These results may be used to build predictive models for identifying surgical patients at increased risk of adverse outcome, who may benefit from addition of chemotherapy independent of clinical stage. No significant financial relationships to disclose.