Abstract 847: LINE-1 hypomethylation is a marker of poor prognosis in stage IA non-small cell lung cancer

Abstract

Abstract Introduction: Non-small cell lung cancer (NSCLC) has a relatively poor prognosis and is a leading cause of cancer death worldwide. A substantial proportion of NSCLC patients suffer a recurrence following curative tumor resection, even when they have early stage disease. Molecular markers that are able to predict patient prognosis after surgery are therefore of clinical relevance, especially for early stage NSCLC. Global hypomethylation and the hypermethylation of gene promoter regions are common events in tumor DNA and are possible markers to predict clinical course of NSCLC patients. The aim of this study was to evaluate the prognostic significance of both global hypomethylation and gene promoter hypermethylation in DNA from NSCLC. Methods: Genomic DNA was obtained from tumor tissue of 379 NSCLC patients who underwent surgery. Methylation levels were measured by real-time PCR following bisulfite modification of DNA and were correlated with clinicopathological parameters and patient prognosis. Methylation of long interspersed nuclear element 1 (LINE-1) was used as a surrogate marker for global methylation. Hypermethylation of the APC, CDH13 and RASSF1 promoter regions was also evaluated. Results: Tumor tissue showed significantly higher CDH13 and RASSF1 methylation levels compared to normal lung tissue, but lower LINE-1 methylation levels. APC, RASSF1 and LINE-1 methylation levels were significant prognostic factors in univariate analysis of an initial cohort of 234 cases. APC and LINE-1 methylation remained significant prognostic factors in multivariate analysis that included age, gender, smoking history, histological type and pathological stage. LINE-1 methylation showed marginally significant prognostic value in stage IA and IB disease. To examine whether LINE-1 methylation was an independent prognostic factor, the study cohort was expanded to 364 cases. In sub-group analysis of stage IA cases with expanded cohort, survival was significantly worse for patients with LINE-1 hypomethylation. Multivariate analysis also revealed that LINE-1 methylation had significant prognostic value for stage IA NSCLC patients. Sub-group analysis failed to show prognostic value for LINE-1 methylation in all other NSCLC disease stages. Conclusion: LINE-1 hypomethylation was an independent marker of poor prognosis in stage IA NSCLC. Validation of this finding in additional tumor cohorts could have clinical relevance for the management of early stage NSCLC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 847.