Abstract A027: Loss of the Y chromosome drives basal identity and metastatic potential via epigenetic reprogramming in pancreatic cancer
Madeleine Dorsch, Felix E.G. Beaudry, Anna K. Baginska, Peihua Zao, Belen Otero-Carrasco, Mei-Ju May. Chen, Kathleen Schlüter, Maria Llamazares-Prada, Hans-Ullrich Schildhaus, Katja Steiger, Roland Schwarz, Jens T. Siveke, Alexander Schramm, Christoph Plass, Florian Rambow, Faiyaz Notta, Barbara T. Grünwald, Barbara M. GrünerAbstract
Purpose:
Loss of the Y chromosome (LOY) is a common somatic alteration in aging males and many cancer entities, yet its functional role in pancreatic ductal adenocarcinoma (PDAC) remains unclear. We sought to determine whether LOY is a recurrent, functionally consequential event in male PDAC and to define its impact on tumor biology and treatment response.
Methods:
We analyzed whole-genome sequencing data from 239 male PDAC patients across two independent cohorts (Toronto COMPASS and resected PDAC cases), integrating genomic and transcriptomic profiling. CRISPR/Cas9-mediated Y chromosome knockout was performed in male PDAC cell lines (YAPC and HuP-T3) to model LOY. Functional assays included RNA-seq, whole-genome sequencing, FISH, 2D/3D culture, anoikis resistance, subcutaneous and intravenous xenografts, and DNA methylation profiling. Single-cell RNA-seq data from PDAC patients were used to validate LOY-associated programs. A RNA-based LOY probability score (rLOY score) was applied to patient-derived models and clinical cohorts to assess treatment response and survival upon LOY stratification.
Results:
As previously reported, LOY was identified in ∼50% of male PDAC patients. Here, we demonstrate for the first time that LOY is significantly enriched in advanced-stage disease and the aggressive basal molecular subtype. LOY remains strongly associated with TP53 mutations while being independent of other large-scale genomic alterations. CRISPR-mediated Y chromosome loss induced a robust epithelial-to-mesenchymal transition (EMT), characterized by mesenchymal morphology, upregulation of mesenchymal markers, enhanced anoikis resistance, and increased lung metastatic seeding in vivo. In contrast, LOY clones exhibited impaired subcutaneous tumor formation, consistent with EMT-associated loss of epithelial tumorigenic capacity. Integrative analyses across bulk tumors, single-cell datasets, and CRISPR-engineered models converged on EMT as the dominant LOY-driven program. Mechanistically, LOY disrupted epigenetic regulation, leading to genome-wide DNA hypomethylation at EMT- and basal-defining loci, reduced chemotherapy sensitivity, and transcriptional reprogramming toward the basal subtype. Analysis of patient-derived organoids and primary cell lines confirmed that LOY is associated with resistance to gemcitabine, irinotecan, and nab-paclitaxel. In clinical cohorts, LOY correlated with progressive disease, reduced treatment response, and overall survicial, particularly in resected PDAC patients.
Conclusions:
This study establishes LOY as a causal genetic driver of PDAC progression, acting through epigenetic remodeling to promote EMT, basal subtype identity, metastasis, and therapy resistance. LOY is not a bystander but a functionally consequential alteration with direct clinical relevance. Its high prevalence, ease of detection via FISH on FFPE tissue, and strong association with aggressive disease position LOY as a clinically accessible biomarker with direct therapeutic relevance.
Citation Format:
Madeleine Dorsch, Felix E.G. Beaudry, Anna K. Baginska, Peihua Zao, Belen Otero-Carrasco, Mei-Ju May. Chen, Kathleen Schlüter, Maria Llamazares-Prada, Hans-Ullrich Schildhaus, Katja Steiger, Roland Schwarz, Jens T. Siveke, Alexander Schramm, Christoph Plass, Florian Rambow, Faiyaz Notta, Barbara T. Grünwald, Barbara M. Grüner. Loss of the Y chromosome drives basal identity and metastatic potential via epigenetic reprogramming in pancreatic cancer [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr A027.