Purpose: Non-small cell lung cancers (NSCLC) comprise multiple distinct biological groups with different prognoses. For example, patients with epithelial-like (EL) tumors have a better prognosis and exhibit greater sensitivity to inhibitors of the epidermal growth factor receptor (EGFR) pathway than patients with mesenchymal-like (ML) tumors. Here we test the hypothesis that EL NSCLCs can be distinguished from ML NSCLCs on the basis of global DNA methylation patterns. Experimental Design: To determine whether phenotypic subsets of NSCLC can be defined based on their DNA methylation patterns, we combined microfluidics-based gene expression analysis and genome-wide methylation profiling. We derived robust classifiers for both gene expression and methylation in cell lines and tested these classifiers in surgically resected NSCLC tumors. We validate our approach using quantitative RT-PCR and methylation specific PCR in formalin-fixed biopsies from NSCLC patients who went on to fail front-line chemotherapy. Results: We show that patterns of methylation divide NSCLCs into EL and ML subsets as defined by gene expression and that these signatures are similarly correlated in NSCLC cell lines and tumors. We show that DNA methylation differences predict EL or ML phenotypes NSCLC cell lines, surgically resected tumors, and formalin-fixed biopsies from NSCLC patients who went on to fail front-line chemotherapy. Conclusions: Our data demonstrate that patterns of DNA methylation can divide non-small lung cancers into two phenotypically distinct subtypes of tumors and provide proof of principle that differences in DNA methylation can be used as a platform for predictive biomarker discovery and development.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1732. doi:1538-7445.AM2012-1732