Loss of the Y chromosome drives basal identity and metastatic potential via epigenetic reprogramming in pancreatic cancer

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.