Abstract 2249: Use of telomere length and genetic variations in maintenance genes to predict risk of recurrence and survival in patients with early-stage non-small cell lung cancer

Abstract

Abstract Purpose: Telomeres play a key role in maintaining chromosome stability. Telomere length and genetic variations in maintenance genes may be associated with risk of lung cancer. A significant number of patients with non-small cell lung cancer (NSCLC) will develop recurrence after resection. To potentially identify this subgroup of patients, we hypothesized that telomere length in peripheral blood as well as genetic variations in maintenance genes would have significant predictive value for recurrence and survival after curative resection in NSCLC. Methods: This is a prospective study involving patients with early stage NSCLC who underwent resection at MD Anderson Cancer Center between 1991 and 2007. Relative telomere length (RTL) of peripheral leukocytes was measured by real-time PCR in 473 patients. 159 single nucleotide polymorphisms (SNPs) within 12 maintenance genes were genotyped in 467 patients who were treated with surgery only (N=340) or surgery and chemotherapy (N=127). The risk of recurrence was estimated as hazard ratios (HRs) and 95% confidence intervals (CIs) using a multivariable Cox proportional hazard regression model. Results: Long telomere length was associated with increased risk of recurrence (1.13 vs. 1.07, P=0.047). This increased risk was more pronounced in female (HR=2.25; 95% CI, 1.02-4.96, P=0.044) and adenocarcinoma subgroups (HR=2.19; 95% CI, 1.05-4.55, P=0.036). SNPs that were predictive of recurrence (P<0.05) were distributed into 3 different risk groups according to varying HRs when treated with surgery only or surgery plus chemo; A=should receive surgery only (HR<1 in surgery only and HR>1 in surgery+chemo); B=should receive surgery and chemo (HR>1 in surgery only and HR<1 in surgery+chemo); C=no benefit from either treatment (HR>1 in both groups). For example, patients with the 2 variant alleles of rs733396 had significantly increased risk of developing recurrence if treated with surgery alone (HR=1.85, 95% CI,1.04-3.29, P=0.036), but adding chemotherapy to patients with the same variant had a protective effect (HR=0.31, 95% CI, 0.09-1.04, P=0.057) thereby placing this variant into group B. In terms of survival, we categorized patients into favorable, intermediate and unfavorable groups based on the number of unfavorable genotypes they have. Unfavorable group (>9 unfavorable SNPs) had 3.23 fold increase in risk of overall death with median survival time (MST) of 55 months compared to favorable group (0-6 unfavorable SNPs) with MST of 136 months. Conclusions: Long telomere length is associated with increased risk of recurrence in early stage NSCLC after curative resection. Our proposed risk-prediction model using prognostic SNPs within telomere maintenance genes may be used to guide therapy and determine prognosis of patients following resection. [Supported by NCI CA 111646, CA 55769 and CA 70907] Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2249. doi:10.1158/1538-7445.AM2011-2249