Abstract IA013: 3D genomic analysis reveals frequent KRAS Mutations in multifocal pancreatic precancer

Abstract Pancreatic intraepithelial neoplasia (PanIN) is a precursor to pancreatic cancer and represents a critical opportunity for cancer interception. However, the number, size, shape, and connectivity of PanINs in human pancreatic tissue samples were previously unknown. To address this, we quantitatively assessed human PanINs using CODA, a novel machine-learning pipeline for 3D image analysis that generates quantifiable models of large pieces of human pancreas with single-cell resolution. Using a cohort of large slabs of grossly normal human pancreas from surgical resection specimens, we identified striking multifocality of PanINs. Extrapolating this burden to the whole pancreas suggested a median of approximately 1000 PanINs in an entire pancreas. In order to better understand the clonal relationships within and between PanINs, we developed a pipeline for CODA-guided multi-region genomic analysis of PanINs, including targeted and whole exome sequencing. Multi-region assessment of PanINs from additional human pancreatic tissue slabs revealed that almost all PanINs contained hotspot mutations in the oncogene KRAS. The majority of analyzed PanINs originated from independent clonal events, with distinct somatic mutation profiles between PanINs in the same tissue slab. A subset of PanINs contained multiple KRAS mutations despite their spatial continuity in rigorous 3D assessment. This study leverages a novel 3D genomic mapping approach to describe for the first time the spatial and genetic multifocality of human PanINs, providing important insights into the initiation and progression of pancreatic neoplasia. Citation Format: Laura D. Wood. 3D genomic analysis reveals frequent KRAS Mutations in multifocal pancreatic precancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1):Abstract nr IA013.