Using tissue microarrays it was shown that membranous C-terminal MET immunoreactivity and ectodomain (ECD) shedding are associated with poor prognosis in oral cancer. Seen the potential diagnostic value, extrapolation of these results to whole tissue sections was investigated. Since MET orchestrates epithelial to mesenchymal transition (EMT), results were benchmarked to loss of E-cadherin; a readout for EMT known to be associated with poor prognosis. C-terminal MET, N-terminal MET, and E-cadherin immunoreactivities were examined on formalin-fixed paraffin-embedded parallel sections of 203 oral cancers using antibody clones D1C2, A2H2-3 and NCH-38. Inter- and intra-antibody relations were examined using a novel scoring system, nonparametric distribution and median tests. Survival analyses were used to examine the prognostic value of the observed immunoreactivities. Assessment of the three clones revealed MET protein status (no, decoy, transmembranous C-terminal positive), ECD shedding and EMT. For C-terminal MET positive cancers, D1C2 immunoreactivity is independently associated with poor overall survival (OS; HR=2.40; 95% CI, 1.25 to 4.61 and P=0.008) and disease free survival (DFS; HR=1.83; 95% CI 1.07 – 3.14; P=0.027). For both survival measures, this is also the case for ECD shedding (43.4% with HR=2.30; 95% CI, 1.38 to 3.83 and P=0.001 versus HR=1.87; 95% CI 1.19 – 2.92; P=0.006) and loss of E-cadherin (55.3% with HR=2.21; 95% CI, 1.30 to 3.77 and P=0.004 versus HR=1.90; 95% CI 1.20 – 3.01; P=0.007). The developed scoring system accounts for MET protein status, ECD shedding, EMT, and is prognostically informative. These findings may contribute to development of companion diagnostics for MET-based targeted therapy.
Copyright © 2020. Published by Elsevier Inc.