Genetic variations in epigenetic genes are predictors of recurrence in stage I or II non-small cell lung cancer patients

Abstract

Purpose: Early-stage non-small cell lung cancer (NSCLC) is potentially curable, however, many patients develop recurrent disease. Therefore, identification of biomarkers that can be used to predict patient's risk of recurrence and survival is critical. Genetic polymorphisms or single-nucleotide polymorphisms (SNP) of DNA- and histone-modifying genes, particularly those of O(6)-methylguanine DNA-methyltransferase (MGMT), have been linked to an increased risk of lung cancer as well as treatment outcomes in other tumors.

Experimental design: We assessed the association of 165 SNPs in selected epigenetic enzyme genes, DNA methyltransferases, and methyl-CpG-binding proteins with cancer recurrence in 467 patients with stage I or II NSCLC treated with either surgery alone (N = 340) or surgery plus (neo)-adjuvant chemotherapy (N = 127).

Results: We found several SNPs to be strongly correlated with tumor recurrence. We identified 10 SNPs that correlated with the outcome in patients treated with surgery alone but not in patients treated with surgery and adjuvant chemotherapy, which suggested that the addition of platinum-based chemotherapy could reverse the high genetic risk of recurrence. We also identified 10 SNPs that predicted the risk of recurrence in patients treated with surgery plus adjuvant chemotherapy but not in patients treated with surgery alone. The cumulative effect of these SNPs significantly predicted outcomes with P-values of 10(-9) and 10(-6), respectively.

Conclusions: The first set of genotypes may be used as novel predictive biomarkers to identify patients with stage I NSCLC, who could benefit from adjuvant chemotherapy, and the second set of SNPs might predict response to adjuvant chemotherapy.

Figure 1

Kaplan–Meier estimates for recurrence based on the cumulative effect of favorable genotypes predictive for surgery only stratified by genetic risk groups (solid line, high-risk patients; dotted line, intermediate (IM)-risk patients; and dashed line, low-risk patients). Left, patients treated with surgery alone. Right, patients treated with surgery and adjuvant platinum-based chemotherapy.

Figure 2

Kaplan–Meier estimates for recurrence based on the cumulative effect of favorable genotypes predictive for surgery in combination with adjuvant chemotherapy stratified by genetic risk groups (solid line, high-risk patients; dotted line, intermediate (IM)-risk patients; and dashed line, low-risk patients). Left, patients treated with surgery alone. Right, patients treated with surgery and adjuvant platinum-based chemotherapy.