Integrating Tumor and Organoid DNA Methylation Profiles Reveals Robust Predictors of Chemotherapy Response in Rectal Cancer DOI Creative Commons
David Lukacsovich,

Wini Zambare,

Chao Wu

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 4, 2025

Abstract Rectal cancer patients display heterogeneous responses to neoadjuvant treatment—including the intensive total therapy (TNT)—and reliable biomarkers are lacking guide which tumors will benefit most from these regimens. Here, we profiled DNA methylation in tumor tissue and matched patient-derived organoids (PDOs) 18 rectal cases (50 samples), leveraging Illumina MethylationEPIC array quality control filters that retained 771,964 CpG sites. Analyses used linear models (for tissue-only or PDO-only) a joint mixed-effects approach (accounting for patient-level random effects) identify significant CpGs associated with log-transformed FOLFOX IC50. We found PDOs faithfully recapitulate patient-tumor patterns (Spearman’s correlation >0.95 among replicate organoids), model uncovered 745 tied sensitivity, many of were missed analyses. Differentially methylated regions reinforced broader epigenetic blocks near TSS enhancer may modulate chemo-resistance, while pathway enrichment pinpointed focal adhesion, ECM–receptor interaction, calcium signaling, folate metabolism as key processes. A risk score derived significantly predicted progression-free survival an independent colorectal cohort (p=0.019), outperforming single-sample–based signatures. These findings suggest combining profiles both can expose robust drivers response, aiding development clinically actionable TNT.

Language: Английский

Integrating Tumor and Organoid DNA Methylation Profiles Reveals Robust Predictors of Chemotherapy Response in Rectal Cancer DOI Creative Commons
David Lukacsovich,

Wini Zambare,

Chao Wu

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 4, 2025

Abstract Rectal cancer patients display heterogeneous responses to neoadjuvant treatment—including the intensive total therapy (TNT)—and reliable biomarkers are lacking guide which tumors will benefit most from these regimens. Here, we profiled DNA methylation in tumor tissue and matched patient-derived organoids (PDOs) 18 rectal cases (50 samples), leveraging Illumina MethylationEPIC array quality control filters that retained 771,964 CpG sites. Analyses used linear models (for tissue-only or PDO-only) a joint mixed-effects approach (accounting for patient-level random effects) identify significant CpGs associated with log-transformed FOLFOX IC50. We found PDOs faithfully recapitulate patient-tumor patterns (Spearman’s correlation >0.95 among replicate organoids), model uncovered 745 tied sensitivity, many of were missed analyses. Differentially methylated regions reinforced broader epigenetic blocks near TSS enhancer may modulate chemo-resistance, while pathway enrichment pinpointed focal adhesion, ECM–receptor interaction, calcium signaling, folate metabolism as key processes. A risk score derived significantly predicted progression-free survival an independent colorectal cohort (p=0.019), outperforming single-sample–based signatures. These findings suggest combining profiles both can expose robust drivers response, aiding development clinically actionable TNT.

Language: Английский

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