A multilayered in silico analysis links UHRF1, DNA methylation and developmental chromatin memory to lineage-dependent prognosis in gastric, renal and adrenal cancers

Biotti, J.; Muccillo, L.; Macchi, F.; Spadarotto, M.; Gino, C.; Finocchiaro, M.; Magnani, E.; Corso, S.; Migliore, C.; Conticelli, D.; Serio, S.; Papait, R.; Donnarumma, F.; Mazzone, P.; Albano, F.; Colantuoni, V.; Tamburello, M.; Mazzoccoli, G.; Colangelo, T.; Alberio, T.; Falco, G.; Sigala, S.; Giordano, S.; Fasano, M.; Furlan, D.; Bonapace, I. M.

doi:10.64898/2026.08.14.742686

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bioRxiv · 10.64898/2026.08.14.742686

A multilayered in silico analysis links UHRF1, DNA methylation and developmental chromatin memory to lineage-dependent prognosis in gastric, renal and adrenal cancers

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Abstract

Aberrant DNA methylation is a hallmark of cancer, but its clinical interpretation remains debated. UHRF1, a key epigenetic adaptor for DNA methylation maintenance and chromatin bivalency regulation in embryonic stem cells, is frequently overexpressed yet shows context-dependent prognostic behaviour. By integrating bulk and single-cell transcriptomics, CpG-resolution methylation, developmental chromatin states, immune profiling and clinical outcomes across gastric (STAD), clear-cell renal (KIRC) and adrenal (ACC) carcinomas, we identified a four-class UHRF1-embryonic morphogenesis (UHRF1-EM) framework resolving this paradox. This axis revealed an inverse prognostic pattern: whilst across all three tumours EM-low and EM-high states mark better or worse prognosis, respectively, UHRF1-high levels associate with favourable outcome in STAD (UH-EML), and unfavourable in KIRC and ACC (UH-EMH). The classification proved reproducible and independently prognostic after adjustment for stage and molecular subtypes, outperforming existing classifiers and exceeding pathological stage in KIRC and ACC. Multivariable models incorporating UHRF1-EM yielded uniformly positive {Delta}C-indices. Hypermethylation associated with the UHRF1-EM axis was enriched at ESC bivalent developmental loci (EM and oncofoetal genes), but not at housekeeping cell-cycle sites. In STAD, this pattern was related to oncofoetal gene downregulation and best prognosis, whereas in KIRC and ACC it matched with gene-body/enhancer methylation, higher EM expression, immunosuppressive microenvironments and worst prognosis. Together, these findings establish the UHRF1-EM axis as a clinically robust molecular classifier and support a mechanistic model in which tumour-specific epigenetic engagement of developmental loci may contribute to the prognostic inversion, providing a foundation for further mechanistic experimental validation.

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Biotti, J., Muccillo, L., Macchi, F., Spadarotto, M., Gino, C., Finocchiaro, M., Magnani, E., Corso, S., Migliore, C., Conticelli, D., Serio, S., Papait, R., Donnarumma, F., Mazzone, P., Albano, F., Colantuoni, V., Tamburello, M., Mazzoccoli, G., Colangelo, T., Alberio, T., Falco, G., Sigala, S., Giordano, S., Fasano, M., Furlan, D., Bonapace, I. M.. 2026-08-19. A multilayered in silico analysis links UHRF1, DNA methylation and developmental chromatin memory to lineage-dependent prognosis in gastric, renal and adrenal cancers. https://doi.org/10.64898/2026.08.14.742686

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