title: Characterizing the clinical relevance of an embryonic stem cell phenotype in lung adenocarcinoma.
abstract: OBJECTIVE
  Cancer cells possess traits reminiscent of those ascribed to normal stem cells. It is unclear whether these phenotypic similarities are the result of a common biological phenotype, such as regulatory pathways.
  
  
  METHODS
  Lung cancer cell lines with corresponding gene expression data and genes associated with an embryonic stem cell identity were used to develop a signature of embryonic stemness (ES) activity specific to lung adenocarcinoma. Biological characteristics were elucidated as a function of cancer biology/oncogenic pathway dysregulation. The ES signature was applied to three independent early-stage (I-IIIa) lung adenocarcinoma data sets with clinically annotated gene expression data. The relationship between the ES phenotype and cisplatin (current standard of care) sensitivity was evaluated.
  
  
  RESULTS
  Pathway analysis identified specific regulatory networks [Ras (P = 0.0005), Myc (P = 0.0224), wound healing (P < 0.0001), chromosomal instability (P < 0.0001), and invasiveness (P < 0.0001)] associated with the ES phenotype. The prognostic relevance of the ES signature, as related to patient survival, was characterized in three cohorts [CALGB 9761 (n = 82; P = 0.0001), National Cancer Institute Director's Challenge Consortium (n = 442; P = 0.0002), and Duke (n = 45; P = 0.06)]. The ES signature was not prognostic in prostate, breast, or ovarian adenocarcinomas. Lung tumors (n = 569) and adenocarcinoma cell lines (n = 31) expressing the ES phenotype were more likely to be resistant to cisplatin (P < 0.0001 and P = 0.006, respectively).
  
  
  CONCLUSIONS
  Lung adenocarcinomas that share a common gene expression pattern with normal human embryonic stem cells were associated with decreased survival, increased biological complexity, and increased likelihood of resistance to cisplatin. This indicates the aggressiveness of these tumors.
authors.affiliation: Division of Oncology, Department of Medicine, Duke University, Durham, North Carolina. USA.
authors.forename: Marvaretta
authors.initials: M
authors.lastname: Stevenson
authors.forename: William
authors.initials: W
authors.lastname: Mostertz
authors.forename: Chaitanya
authors.initials: C
authors.lastname: Acharya
authors.forename: William
authors.initials: W
authors.lastname: Kim
authors.forename: Kelli
authors.initials: K
authors.lastname: Walters
authors.forename: William
authors.initials: W
authors.lastname: Barry
authors.forename: Kristin
authors.initials: K
authors.lastname: Higgins
authors.forename: Sascha A
authors.initials: SA
authors.lastname: Tuchman
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Crawford
authors.forename: Gordana
authors.initials: G
authors.lastname: Vlahovic
authors.forename: Neal
authors.initials: N
authors.lastname: Ready
authors.forename: Mark
authors.initials: M
authors.lastname: Onaitis
authors.forename: Anil
authors.initials: A
authors.lastname: Potti