Correlation between MET Gene Copy Number by Silver In Situ Hybridization and Protein Expression by Immunohistochemistry in Non-small Cell Lung Cancer

Abstract

Purpose The MET receptor is involved in the pathogenesis and progression of non-small-cell lung cancer (NSCLC). Clinical trials with MET inhibitors in NSCLC are planned with patient selection based on immunohistochemistry (IHC) and/or gene copy number assessment. Therefore, a detailed understanding of relationship between these markers and prognosis is essential. Methods This study included tumors from 189 NSCLC patients who underwent pulmonary resection (median follow-up 5.3 years). MET expression was evaluated by IHC on tissue microarrays and scored according to hybrid (H) score (range: 0–400) and by scoring system used in the MetMAb trial (≥50% of cells with moderate or strong staining). MET gene copy number was assessed by silver in-situ hybridization (SISH, N=140 patients). Results Median MET IHC H-score was 60 (range: 0–400; N=174). There were no associations between clinical and pathological characteristics, disease-free or overall survival according to median value (P=0.36 and P=0.38, respectively) or other cut-points. According to MetMAb scoring criteria, IHC positivity rate was 25%, again with no associations to clinico-pathological features nor survival. In 140 tumors evaluable for MET copy number, three (2.1%) showed gene amplification and 14 (10%) had tumors with average of 5 or more copies/nucleus. There were no associations of MET copy number with clinical characteristics, disease-free or overall survival with any analyzed cut-points. Correlation between MET copy number and protein expression was significant (Pearson’s r=0.42, P<0.0001). Conclusions There is a significant correlation between MET protein expression and MET gene copy number in operable NSCLC, but neither is associated with prognosis.

MET Is a Potential Target across All Papillary Renal Cell Carcinomas: Result from a Large Molecular Study of pRCC with CGH Array and Matching Gene Expression Array

“…Interestingly, the first report from Glokhova and colleagues (33) demonstrated that gene copy number increase was associated with upregulation of MET expression. This observation is not limited to kidney cancer: similar correlations between MET gene copy number and protein expression level measured by immunohistochemistry have also been reported in nonsmall cell lung cancer (34). Previous cytologic reports identified chromosome 7 trisomy as a common feature of pRCC (11).…”

Analytical Validation of BRAF Mutation Testing from Circulating Free DNA Using the Amplification Refractory Mutation Testing System

“…MET amplification has been classified by using MET:CEP7 ratio as low (!1.8 to 2.2), intermediate (>2.2 to <5), and high (!5). 131 Other…”

Biomarkers in Lung Adenocarcinoma: A Decade of Progress

“…[53][54][55] Phase 2 studies of combined erlotinib and Met inhibition using a monovalent anti-Met receptor antibody (MetMAb) have shown some benefit in patients with Met protein overexpression by immunohistochemistry 56 ; phase 3 trials of combined Met and EGFR inhibition are now underway. 57 MET gene copy number and protein expression are significantly correlated 58,59 ; however, in exceptional cases, strong Met protein expression may be seen in the absence of MET copy number gain. 60 To date, the best biomarker for assessing Met activation status has not been established; indeed the definition of positivity based on expression level or copy number is still a matter of debate and will likely not be resolved until larger studies of outcomes following treatment with Met-targeted agents come to fruition.…”