Loss of the Y chromosome drives basal identity and metastatic potential via epigenetic reprogramming in pancreatic cancer
Year: 2026
Type: preprint
Abstract: ABSTRACT Loss of the Y chromosome (LOY) has been largely unexplored in pancreatic ductal adenocarcinoma (PDAC), and no mechanistic framework previously explained its role in tumor biology. We identify LOY as a recurrent, functionally consequential alteration affecting ∼50% of male PDAC patients across two independent cohorts, with strong enrichment in advanced disease and, critically, in the basal subtype, establishing LOY as a clinically actionable biomarker. Comprehensive genomic profiling positions LOY as a distinct genetic event associated with TP53 mutations, implicating it in aggressive tumor evolution. Integrative analyses across bulk tumors, single-cell datasets and CRISPR-engineered PDAC models converge on epithelial-to-mesenchymal transition (EMT) as the dominant LOY-driven program. Y-chromosome deletion alone induces EMT transcriptional states, mesenchymal morphology and enhanced metastatic ability. Mechanistically, LOY disrupts epigenetic regulation through loss of Y-linked chromatin modifiers, reshaping DNA methylation at EMT- and basal-defining loci and reducing chemotherapy sensitivity. These findings establish LOY as a causal genetic driver of PDAC progression and a clinically accessible biomarker with direct therapeutic relevance.
Authors: Madeleine Dorsch, Felix E. G. Beaudry, Anna K. Baginska, Nancy Meyer, Anne Petzold, Peihua Zhao, Belen Otero-Carrasco, Kazeera Aliar, Sebastian Urban, Julia Zummack, Jennifer Jung, Johanna M. Hölken, Ningjun Duan, Laura Godfrey, Mei-Ju May Chen, Kathleen Schlüter, Katyayni Ganesan, Florian Over, Thomas J. Y. Kono, Hans-Ulrich Schildhaus, Katja Steiger, Roland F. Schwarz, Elisabeth Hessmann, Günter Schneider, Jens T. Siveke, John P. Neoptolemos, Teresa Peccerella, Maria Llamazares-Prada, Alexander Schramm, Christoph Plass, Florian Rambow, Faiyaz Notta, Barbara T. Grünwald, Barbara M. Grüner
Institutions: Essen University Hospital, University of Duisburg-Essen, Ontario Institute for Cancer Research, University Health Network, Princess Margaret Cancer Centre, German Cancer Research Center, German Center for Lung Research, Deutsches Konsortium für Translationale Krebsforschung, Universitätsmedizin Göttingen, University Hospital Cologne, Technical University of Munich, Berlin Institute for the Foundations of Learning and Data, Stiftung Universitätsmedizin Essen, University Hospital Heidelberg, University of Toronto
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G1332297015, G3655198096, Verbundprojekt BIFOLD-BZML: Berlin Institute for the Foundations of Learning and Data, Verbund SATURN3 - Räumliche und zeitliche Auflösung der intratumoralen Heterogenität bei den drei schwer zu behandelnden Krebsarten Brustkrebs, Darmkrebs und Bauchspeicheldrüsenkrebs, Standort Universität Essen-Duisburg, Verbundprojekt BIFOLD-BBDC: Berlin Institute for the Foundations of Learning and Data, G8919811967
OpenAlex ID: W7220852187