11001 Background: Cancer cells possess traits reminiscent of those ascribed to normal stem cells. It is unclear whether these phenotypic similarities between normal/embryonic stem cells and mature tumor cells, specific to lung cancer, are a result of underlying biologic processes, such as specific molecular pathways and regulatory networks. Methods: Using a large cohort of lung cancer cell lines with associated gene expression data, genes associated with an embryonic stem cell identity were used to develop a ‘signature’ representative of embryonic stemness (ES) activity specific to lung adenocarcinoma. Differential biology was evaluated using Gene Set Enrichment Analysis (GSEA) and signatures of oncogenic pathway deregulation. The ES signature was applied to three independent early (stage I - IIIa) lung adenocarcinoma data sets (N = 634) with clinically annotated gene expression data. The relationship between the ES phenotype and cisplatin sensitivity was also evaluated. Results: Using Bayesian regression analysis, a 100 gene signature representative of ES activity in lung adenocarcinoma was developed and validated in a leave-one-out-analysis. GSEA identified gene sets significantly represented in the ES signature: signature of neoplastic transformation, signature of undifferentiated cancer, BRCA pathway, and fibroblast serum response pathway, all associated with cancer invasiveness. Adenocarcinomas with ES demonstrated increased activation of RAS (p = 0.0002), MYC (p = 0.0057), wound healing (angiogenesis) (p < 0.0001), chromosomal instability (p < 0.0001), and invasiveness (p < 0.0001) gene signatures. Adenocarcinomas (N= 634) with ES had a decreased survival (p<0.04). The ES signature was not prognostic in prostate, ovarian, or breast adenocarcinomas. Lung tumors (N=634) and adenocarcinoma cell lines (N=31) with ES were more resistant to cisplatin (p<0.0001 and p=0.0063, respectively). Conclusions: Lung adenocarcinomas that share a common gene expression pattern with normal stem cells were associated with decreased survival and increased likelihood of resistance to cisplatin, indicating the aggressiveness of lung tumors with a stem cell phenotype. No significant financial relationships to disclose.