MDM2 promoter P1/P2 switching and colorectal cancer lineage plasticity: deep-learning morphology classification at 98.5% accuracy, with higher P2 index in TP53 wild-type tumors and greater Nutlin-3a sensitivity
Using 63 organoid samples from 22 colorectal cancer patients, external validation in TCGA-COAD/READ (n=624) and GSE39582 (n=536) totaling 1,160 cases, public cell line panels (GDSC2, DepMap), and 65 lines from an independent patient-derived CRC organoid biobank, the study tested whether usage of the dual MDM2 promoters (P1/P2) acts as a molecular switch separating a chromosomal-instability type from an environment-adaptive type (microsatellite instability/serrated pathway with gastric metaplasia), finding deep-learning morphological classification at 98.5% test accuracy (64/65), morphology corresponding to P1/P2 isoform usage (median Type1 fraction 0.826 versus 0.444 in P1-dominant samples; non-Type1 cystic mucinous morphology in P2-dominant samples, AUC 0.