title: Mesothelin overexpression is a marker of tumor aggressiveness and is associated with reduced recurrence-free and overall survival in early-stage lung adenocarcinoma.
abstract: OBJECTIVE
  In an effort to identify molecular markers of tumor aggressiveness and therapeutic targets in lung adenocarcinoma (ADC), we investigated the expression of mesothelin (MSLN) in lung ADC, as well as its biologic and clinical relevance.
  
  
  METHODS
  In a training and validation set of patients with early-stage (I-III) lung ADC (n = 1,209), a tissue microarray consisting of tumors and normal lung tissue was used to examine the association between MSLN expression and recurrence-free survival (RFS) and overall survival (OS). The influence of MSLN overexpression on lung ADC was investigated in vitro and in vivo by use of clinically relevant orthotopic and metastatic xenogeneic and syngeneic mouse models.
  
  
  RESULTS
  MSLN was expressed in 69% of lung ADC tumors, with one in five patients strongly expressing MSLN and no expression in normal lung tissue. Increased MSLN expression was associated with reduced OS [HR = 1.78; 95% confidence interval (CI), 1.26-2.50; P < 0.01] and RFS (HR = 1.67; 95% CI, 1.21-2.27; P < 0.01) in multivariate analyses, even after adjustment for currently known markers of tumor aggressiveness in lung ADC: male sex, smoking history, increasing stage, morphologic pattern, visceral pleural invasion, lymphatic or vascular invasion, and mutation status. In vitro, lung ADC cells overexpressing MSLN demonstrated increased cell proliferation, migration, and invasion; in vivo, mice with MSLN(+) tumors demonstrated decreased survival (P = 0.001).
  
  
  CONCLUSIONS
  MSLN expression in patients with early-stage lung ADC is associated with increased risk of recurrence and reduced OS, indicating that MSLN expression is a molecular marker of tumor aggressiveness and a potential target for therapy.
authors: Authors' Affiliations: Division of Thoracic Surgery; Center for Cell Engineering; Departments of Pathology, Epidemiology and Biostatistics, and Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors: Stefan S
authors: SS
authors: Kachala
authors: Adam J
authors: AJ
authors: Bograd
authors: Jonathan
authors: J
authors: Villena-Vargas
authors: Kei
authors: K
authors: Suzuki
authors: Elliot L
authors: EL
authors: Servais
authors: Kyuichi
authors: K
authors: Kadota
authors: Joanne
authors: J
authors: Chou
authors: Camelia S
authors: CS
authors: Sima
authors: Eva
authors: E
authors: Vertes
authors: Valerie W
authors: VW
authors: Rusch
authors: William D
authors: WD
authors: Travis
authors: Michel
authors: M
authors: Sadelain
authors: Prasad S
authors: PS
authors: Adusumilli
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000368:Aged; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018572:Disease-Free Survival; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008297:Male; D000090204:Mesothelin; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000378:metabolism*; D009368:Neoplasm Transplantation
chemical_list: D014408:Biomarkers, Tumor; D058851:GPI-Linked Proteins; C000715527:MSLN protein, human; C000715528:Msln protein, mouse; D000090204:Mesothelin