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.