High mesothelin expression in advanced lung adenocarcinoma is associated with KRAS mutations and a poor prognosis

Oncotarget. 2015 May 10;6(13):11694-703. doi: 10.18632/oncotarget.3429.


Mesothelin is a cell surface glycoprotein which is highly expressed in several epithelial cancers and may have a role in cell adhesion and metastases. In this study, we used prospectively obtained clinical and pathological data to characterize mesothelin expression in advanced lung adenocarcinoma. Tissue was obtained from patients who underwent molecular profiling of potentially actionable genes on a trial of molecular profiling and targeted therapies in advanced thoracic malignancies. We immunohistochemically evaluated the intensity, and the percentage of cells expressing mesothelin in 93 advanced lung adenocarcinomas. The evaluation was blinded for molecular data and outcome. Mutations of EGFR, KRAS, BRAF, AKT1, PIK3CA and HER2 were assessed by pyrosequencing; HER2 amplification and ALK translocation were assessed by fluorescence in situ hybridization. 53% of advanced lung adenocarcinomas expressed mesothelin to some degree; high mesothelin expression, defined as mesothelin positivity in more than 25% of cells, was found in 24% of patients. High mesothelin expression was associated with inferior survival (median 18.2 months vs. 32.9 months; P = 0.014). High mesothelin expression was strongly associated with mutant KRAS (P < 0.0001) and wild-type EGFR (P = 0.002). Our results provide strong rationale to explore anti-mesothelin targeted therapies in advanced lung adenocarcinoma especially in the KRAS-mutant subgroup.

Trial registration: ClinicalTrials.gov NCT01306045.

Keywords: EGFR; KRAS; mesothelin; non-small cell lung cancer.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adenocarcinoma / chemistry*
  • Adenocarcinoma / genetics*
  • Adenocarcinoma / mortality
  • Adenocarcinoma / pathology
  • Adenocarcinoma of Lung
  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / analysis*
  • Biomarkers, Tumor / genetics*
  • DNA Mutational Analysis
  • Female
  • GPI-Linked Proteins / analysis*
  • Gene Amplification
  • Genetic Predisposition to Disease
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization, Fluorescence
  • Kaplan-Meier Estimate
  • Lung Neoplasms / chemistry*
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / mortality
  • Lung Neoplasms / pathology
  • Male
  • Mesothelin
  • Middle Aged
  • Mutation*
  • Neoplasm Staging
  • Phenotype
  • Pilot Projects
  • Predictive Value of Tests
  • Prospective Studies
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Receptor, ErbB-2 / genetics
  • Risk Factors
  • United States
  • Up-Regulation
  • Young Adult


  • Biomarkers, Tumor
  • GPI-Linked Proteins
  • KRAS protein, human
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Proto-Oncogene Proteins p21(ras)
  • Mesothelin

Associated data

  • ClinicalTrials.gov/NCT01306045