The impact of MET, IGF-1, IGF1R expression and EGFR mutations on survival of patients with non-small-cell lung cancer

PLoS One. 2017 Jul 25;12(7):e0181527. doi: 10.1371/journal.pone.0181527. eCollection 2017.

Abstract

Introduction: To compare the efficacy of silver in situ hybridization (SISH) and immunohistochemistry (IHC) in detecting MET and IGF1R alterations and to investigate their prevalence and prognostic significance. A possible correlation between MET receptor expression, MET gene alterations and the two most frequent occurring EGFR gene mutations was also investigated.

Materials and methods: Stage I to IIIA tumors from 326 patients with NSCLC were immunohistochemically tested for protein expression of MET and IGF-1. Their cytoplasmic expression was compared with the gene copy number of the MET and IGF1Rgenes by SISH in paraffin-embedded, formalin-fixed material. Correlations were made with the immunohistochemical expression of two frequent EGFR mutations and clinicopathological variables. Univariate and multivariate survival analyses was used to evaluate the prognostic efficacy of the tested markers.

Results: In univariate analyses, high cytoplasmic MET expression showed a significant negative prognostic effect in adenocarcinoma patients (p = 0.026). MET gene to chromosome 7 ratio was a significant positive prognostic marker (p = 0.005), probably only due to the highly negative prognostic significance of chromosome 7 polysomy (p = 0.002). High IGF1R gene copy number was a negative prognostic marker for all NSCLC patients (p = 0.037). In the multivariate analysis, polysomy of chromosome 7 in tumor cells correlated significantly and independently with a poor prognosis (p = 0.011). In patients with adenocarcinoma, a high cytoplasmic MET expression was an independent negative prognostic marker (p = 0.013). In males a high IGF1R gene copy number to chromosome 15 count ratio was significantly and independently correlated to a poor prognosis (p = 0.018).

Conclusion: MET protein expression provides superior prognostic information compared with SISH. Polysomy of chromosome 7 is an independent negative prognostic factor in NSCLC patients. This finding has an important implication while examining genes located on chromosome 7 by means of SISH. High IGF1R gene copy number to chromosome 15 count ratio is an independent predictor of inferior survival in male patients with primary NSCLC.

MeSH terms

  • Aged
  • Carcinoma, Non-Small-Cell Lung / diagnosis
  • Carcinoma, Non-Small-Cell Lung / epidemiology
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Chromosomes, Human, Pair 7 / genetics
  • ErbB Receptors / genetics*
  • Female
  • Gene Dosage
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunohistochemistry
  • Insulin-Like Growth Factor I / genetics*
  • Lung / metabolism
  • Lung / pathology*
  • Lung Neoplasms / diagnosis
  • Lung Neoplasms / epidemiology
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Male
  • Middle Aged
  • Mutation
  • Prognosis
  • Proto-Oncogene Proteins c-met / genetics*
  • Receptor, IGF Type 1
  • Receptors, Somatomedin / genetics*
  • Retrospective Studies
  • Survival Analysis

Substances

  • IGF1R protein, human
  • Receptors, Somatomedin
  • Insulin-Like Growth Factor I
  • EGFR protein, human
  • ErbB Receptors
  • MET protein, human
  • Proto-Oncogene Proteins c-met
  • Receptor, IGF Type 1

Grants and funding

This research was funded by the Northern Norway Regional Health Authority (Helse Nord), Grant number SFP1032-12. The authors would like to acknowledge Roche Diagnostics Norway for providing our research laboratory with the two SISH antibodies MET gene and IGF1-R. Roche. The publication charges for this article have been funded by a grant from the publication fund of UiT The Arctic University of Norway. The Northern Norway Regional Health Authority, The Arctic University of Norway, and Roche Diagnostics Norway had no role in study design, data collection and analysis, results, decision to publish, or preparation of the manuscript.