Method Profile
Organoid morphology and exon-level MDM2 analysis are linked with expression signatures and a separate public nutlin-response dataset.
Explore whether a promoter-associated expression axis adds drug-response information beyond TP53 status.
63 organoid specimens from 22 colorectal cancer patients for discovery; independent public nutlin data from 65 colorectal cancer organoid lines, including 17 TP53 wild-type and 48 mutant lines.
Image classification, exon-level/isoform analysis and signature scoring; reanalysis of measured organoid response, cell-line measurements and predicted tumor sensitivity as separate evidence layers.
Discovery data
HCT-series primary/metastatic colorectal tumor organoids, 792 images and 63 transcriptome-array specimens.
Expression quantities
Exon-based Splicing Index, downstream P1/P2 signatures and directly quantified transcript-level P2_index, kept as distinct measures.
Drug data
Public nutlin-3 organoid IC50 data and GDSC2, a measured cell-line drug-sensitivity dataset; bulk-tumor drug-response estimates generated with oncoPredict, an R package that predicts tumor drug response from cell-line screening data.
Account for repeated specimens within patients and retain correction for multiple testing. Interpret measured IC50 separately from model-derived tumor sensitivity and expression-group associations.
Reanalyze independent organoid nutlin response and ask whether P2 signature association persists after TP53 adjustment.
65 independent colorectal cancer organoid lines: 17 TP53 wild-type and 48 mutant. The discovery collection has 63 specimens from 22 patients.
TP53 wild type versus mutant; unadjusted versus TP53-adjusted P2 signature associations.
Wild-type lines were more nutlin-sensitive (P = 7.4×10⁻8). The TP53-adjusted P2 association had partial rho −0.331, raw P = 0.0071 and FDR = 0.056, so independence was not established after correction.
A version 2 preprint relates MDM2 promoter-associated programs to organoid morphology and reanalyzes nutlin response. Patient-adjusted morphology and TP53-adjusted organoid drug associations retain important statistical limits.
