111 MET ECD shedding and poor DFS 1.39–3.41 and P = 0.001 for uniform negativity and HR = 2.23; 95% CI, 1.16–4.27 and P = 0.016 for uniform positivity). Although counterintuitive, the finding that both low and high expression of a receptor tyrosine kinase is associated with poor prognosis is for example also reported for ERBB2 in primary breast cancers (33). The association of the uniform positive staining pattern with poor prognosis concurs with the knowledge that increased MET immunoreactivity has been described to be associated with poor prognosis of head and neck squamous cell carcinoma (10, 34). Subsequent multivariable survival analyses—combining the uniform negative and positive staining patterns—revealed that the uniform staining pattern showed an interaction with vasoinvasive growth (18). Assuming that the effect of the MET staining pattern was subservient to that of vasoinvasive growth, final multivariable survival analyses for disease-free survival (HR = 2.92; 95% CI, 1.80–4.76 and P < 0.001) and overall survival (HR = 3.48; 95% CI, 2.08–5.80 and P = 0.001) was restricted to patients showing no histopathological signs of vasoinvasive growth (n = 136). Given the low number of HPV negative oropharyngeal SCC, it was decided to exclude these cancers from the survival analyses performed in this paper. The disease-free survival (HR = 1.72; 95% CI, 1.07–2.77 and P = 0.025) and overall survival (HR = 1.74; 95% CI, 1.06–2.87 and P = 0.030) of the 156 oral squamous cell carcinoma patients included for MET protein status analysis are significantly lower than those of the excluded oral squamous cell carcinoma patients (n = 54). A possible explanation might be the high number of stage I cancers in the excluded sample population (Supplementary Table 12). When investigating the association of MET protein status with disease-free survival and overall survival using univariable survival analysis, the results showed that patients with MET negative cancers perform significantly worse for both survival measures than those with cancers showing the MET decoy receptor or transmembranous MET with or without the ectodomain. This finding is in line with the result described above and in (18) that C-terminal MET negativity is associated with poor disease-free survival and overall survival. This is as expected, since the boundaries used here for MET negativity were the same as those used in (18) and all cancers negative for C-terminal MET were also negative for N-terminal MET. Univariable survival analysis was also performed for MET ectodomain shedding and for clinico-histopathological characteristics of patients diagnosed with cancers positive for transmembranous C-terminal MET. Within this category, 14 (93.3%) cancers show the uniform positive staining pattern for C-terminal MET (18, Supplementary 4
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