Abstract 41: Integrative analysis of genomic and transcriptomic data informs precancer progression in the pancreas.

Abstract Pancreatic ductal adenocarcinoma (PDAC) arises from heterogeneous precursor lesions, including intraductal papillary mucinous neoplasms (IPMNs), but the features distinguishing indolent from progressive lesions remain unclear. We performed an integrative analysis of transcriptomic, genomic, and microenvironmental profiles of IPMNs to define multi-omic phenotypes. Using transfer learning, we projected IPMN-derived transcriptional programs onto spatial transcriptomic datasets from IPMNs and pancreatic intraepithelial neoplasias (PanINs). We identified two major phenotypes: one associated with cancer-associated fibroblasts and epithelial-to-mesenchymal transition, shared across IPMN, PanIN, and PDAC; and a second, glycolysis-enriched phenotype with a unique somatic variant profile specific to IPMN. Spatial mapping further revealed grade-specific enrichment of transcriptional programs and distinct interactions with stromal and immune subtypes, underscoring the role of the precancer microenvironment in progression. These findings establish multi-omic phenotypes that unify genetic, transcriptional, and microenvironmental heterogeneity, providing a framework for distinguishing progressive from indolent precancers and a web-based public atlas for future exploration of these data and transcriptional phenotypes. Citation Format: Kathleen Noller, Jiaying Lai, Daniel Lesperance, Ricky S. Adkins, Ahmed M. Elhossiny, Paola A. Guerrera, Kimal Rajapakshe, Anirban Maitra, Anup Mahurkar, Owen White, Marina Pasca Di Magliano, Michael Ochs, Luciane Tsukamoto Kagohara, Laura Wood, Rachel Karchin, Elana Judith Fertig. Integrative analysis of genomic and transcriptomic data informs precancer progression in the pancreas abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 41.