title: Elevated phospho-S6 expression is associated with metastasis in adenocarcinoma of the lung.
abstract: OBJECTIVE
  The primary objective of this study was to determine whether markers of differentiation and activation of the Akt pathway are associated with metastasis in adenocarcinoma of the lung.
  
  
  METHODS
  Paired primary and metastatic tumor samples were obtained from 41 patients who had undergone resection of both primary lung adenocarcinoma and brain metastatic lesions. Paired samples were compared for relative expression of thyroid transcription factor 1 (TTF-1) and E-cadherin as potential markers of differentiation. Activation of the Akt pathway was assessed by expression of p-Akt and p-S6. Biomarkers that showed relative discordance in expression between the matched pairs were then assessed in a cohort of 77 primary lung adenocarcinomas. Validation was done in an independent cohort of 82 primary lung adenocarcinomas.
  
  
  RESULTS
  Among the 41 matched pairs, E-cadherin (23 discordant pairs) and TTF-1 (18 discordant pairs) were overexpressed in primary tumors (20 of 23 and 15 of 18, respectively). In contrast, p-S6 overexpression was significantly associated with metastatic tumors (20 of 21 discordant pairs). The expression of E-cadherin, p-S6, and TTF-1 was evaluated in 77 primary lung adenocarcinomas, in which high p-S6 expression was associated with shorter time to metastasis. The association of p-S6 with metastasis was then validated in an independent set of 82 tumors. In multivariable analysis, p-S6 expression was a negative independent predictor of metastasis-free survival after adjustment for tumor stage.
  
  
  CONCLUSIONS
  The biomarker p-S6 is overexpressed in metastatic tumors. In primary tumors, higher p-S6 expression is associated with shorter metastatic-free survival. This biomarker has the potential for risk stratification in future clinical trials.
authors.affiliation: Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: J Matthew
authors.initials: JM
authors.lastname: McDonald
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Pelloski
authors.forename: Alicia
authors.initials: A
authors.lastname: Ledoux
authors.forename: Menghong
authors.initials: M
authors.lastname: Sun
authors.forename: Gabriela
authors.initials: G
authors.lastname: Raso
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Komaki
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.forename: B Nebiyou
authors.initials: BN
authors.lastname: Bekele
authors.forename: Ken
authors.initials: K
authors.lastname: Aldape
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D001932:Brain Neoplasms / Q000378:metabolism / Q000556:secondary*; D015820:Cadherins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012269:Ribosomal Proteins / Q000378:metabolism*; D014157:Transcription Factors
chemical_list: D014408:Biomarkers, Tumor; D015820:Cadherins; D004268:DNA-Binding Proteins; D012269:Ribosomal Proteins; C504003:TTF1 protein, human; D014157:Transcription Factors; D051057:Proto-Oncogene Proteins c-akt