151 MET, ECD shedding, and loss of E-cadherin (n=152), stratified by NCH-38 uniform negativity. D. DFS for patients positive for TM C-terminal MET in the gradient toward the periphery and/or uniform positive staining pattern (n=152), stratified by NCH-38 uniform negativity. E. OS for patients positive for TM C-terminal MET in the gradient toward the periphery and/or uniform positive staining pattern (n=152), stratified by MET ECD shedding within the D1C2 uniform positive staining pattern. F. DFS for patients positive for TM C-terminal MET in the gradient toward the periphery and/or uniform positive staining pattern (n=152), stratified by MET ECD shedding within the D1C2 uniform positive staining pattern. Prognostic value of D1C2 uniform positivity Univariable survival analyses performed for D1C2 uniform positivity and the histopathological characteristics listed in Supplementary table 21 show that patients showing uniform positivity for D1C2 (n = 105, 69.1%) perform significantly worse in terms of OS (hazard ratio [HR] = 2.40; 95% confidence interval [CI] = 1.25 to 4.61; P = 0.008; Figure 3A) and DFS (HR = 1.83; 95% CI = 1.07 to 3.14; P = 0.027; Figure 3B). To test the independent value of D1C2 uniform positivity for OS and DFS, multivariable analyses were performed correcting for age at diagnosis, pT, pN, extranodal extension, and degree of differentiation. The results show that uniform positivity of D1C2 remains significantly associated with survival (HR=2.61; 95% CI = 1.20 to 5.69; P = 0.016 for OS and HR = 1.99; 95% CI = 1.05 to 3.74; P = 0.034 for DFS; Table 2). Table 2: Multivariable analysis—in view of the D1C2 uniform positive staining pattern—of overall survival and disease-free survival for patients having cancers that are 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* 1.39 1.10 – 1.74 0.005 1.27 1.05 – 1.55 0.015 pT ≥ 1 1.53 0.79 – 2.97 0.206 1.18 0.68 – 2.03 0.560 pN ≥ 2 2.65 1.34 – 5.23 0.005 1.95 1.03 – 3.68 0.040 Extranodal extension present 1.19 0.54 – 2.62 0.671 1.00 0.47 – 2.14 0.994 Poor – undifferentiated opposed to well – moderate 0.95 0.45 – 2.00 0.887 0.80 0.40 – 1.61 0.530 ≥ 10% of cancer cells show the D1C2 uniform positive staining pattern 2.61 1.20 – 5.69 0.016 1.99 1.05 – 3.74 0.034 * The HR was based on 10 year intervals. 5
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