Abstract
IntroductionTo 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 methodsStage 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.ResultsIn 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).ConclusionMET 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.
Highlights
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
High IGF1R gene copy number to chromosome 15 count ratio is an independent predictor of inferior survival in male patients with primary non-small cell lung cancer (NSCLC)
We retrospectively examined a non-selected group of NSCLC patients, which was examined in previous works by our research group.[17]Clinical, demographic and histopathological variables are presented in Table 1.Of the 326 NSCLC patients, the majority were male (76%) and most (96%) were previous or present smokers
Summary
Due to observations reporting MET activation and treatment resistance following anti EGFR treatment,[12, 13] we aimed to immunohistochemically study the prevalence and possible correlation between MET expression and two major forms of mutant EGFR; E746-A750deletion mutation of exon 19 (EGFRdel) and the single L858R deletion mutation of exon 21 (EGFRmut). The chief aim of our study was to investigate the prognostic role of MET expression and the MET gene copy number gain in NSCLC. We aimed to determine a possible correlation between the MET receptor expression, MET GCNC, and the IGF-1 axis
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