153 MET, ECD shedding, and loss of E-cadherin multivariable analyses were performed correcting for age at diagnosis, pT, pN, extranodal extension, and degree of differentiation. The results show that MET ECD shedding remains significantly associated with survival (HR = 2.39; 95% CI = 1.29 to 4.43; P = 0.006 for OS and HR = 1.94; 95% CI = 1.14 to 3.30; P = 0.015 for DFS; Table 4). Table 4: Multivariable analysis—in view of ectodomain shedding within the D1C2 uniform positive staining pattern—of overall survival and disease-free survival for patients having cancers positive for transmembranous C-terminal MET in the gradient toward the periphery and/or uniform positive staining pattern (n = 152). Variable Overall survival Disease-free survival HR 95% CI P-value HR 95% CI P-value Age at diagnosis* 1.32 1.05 – 1.66 0.017 1.24 1.02 – 1.51 0.032 pT ≥ 1 1.78 0.91 – 3.49 0.092 1.32 0.76 – 2.29 0.325 pN ≥ 2 2.39 1.17 – 4.91 0.017 1.84 0.95 – 3.57 0.071 Extranodal extension present 1.20 0.53 – 2.72 0.661 1.02 0.47 – 2.20 0.967 Poor – undifferentiated opposed to well – moderate 0.95 0.44 – 2.05 0.894 0.79 0.39 – 1.61 0.513 ≥ 10% of cancer cells undergo ectodomain shedding in the D1C2 uniform positive staining pattern 2.39 1.29 – 4.43 0.006 1.94 1.14 – 3.30 0.015 * The HR was based on 10 year intervals. Discussion Although MET is an interesting target for therapy (5-7), its status as a biomarker is unclear, and there is a lack of appropriate CDx (9, 12, 13, 15). Using TMAs, it was shown that C-terminal MET immunoreactivity and shedding are prognostically informative for OSCC (17, 18). The present study shows that these results can be extrapolated to WTSs using a novel two-dimensional scoring system. The scoring system divides the variable staining pattern into two categories – gradient toward the periphery and gradient toward the center – which are mutually exclusive for both MET antibodies (D1C2 and A2H2-3) and the E-cadherin antibody (NCH38). This is expected as transcription of MET is induced by hepatocyte growth factor (HGF) (21), which is produced by fibroblasts residing in the stromal compartment of cancers (22, 23). MET itself facilitates transcriptional downregulation of E-cadherin through transcription factors such as Snail/SNAI1 (24). Such transcriptional downregulation of E-cadherin also provides an explanation for the associations observed 5
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