Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Surgical decisions for intraductal papillary mucinous neoplasms (IPMNs), precursors of pancreatic cancer, depend on distinguishing low-from high-grade dysplasia, a distinction that molecular markers could refine. We microdissected 433 tumor regions from 135 patients and integrated transcriptomics, deep-learning histology, and KRAS/GNAS RNA-called variants. RNA programs and morphological motifs separated lesions by phenotype, intestinal versus others, rather than by dysplasia grade. Along gastric IPMN trajectories, low-grade lesions recapitulated the pit-chief polarity of normal gastric glands, whereas high-grade lesions were indistinguishable from pancreatobiliary lesions in morphology, RNA programs, and driver mutations. Intestinal IPMNs arose through two routes: a canonical GNAS -associated pathway and a KRAS -associated shift from low-grade gastric features, with lesions sharing driver mutations retaining common programs across phenotypes. Resolving these phenotypic trajectories clarified distinct progression paths and enabled phenotype-specific prediction of high-grade dysplasia in mucus aspirated from 94 resected lesions. These findings support a promising fluid-based assessment of IPMN status. Statement of significance IPMN surgery depends on distinguishing low-from high-grade dysplasia. Combining multiregion microdissected transcriptomics with deep-learning morphology across 135 patients, we resolve intestinal and gastric/pancreatobiliary trajectories supported by shared driver mutations, including a gastric-to-intestinal switch, delineating phenotype-specific progressions. These trajectories can be assessed from pancreatic fluid, which could inform surgical decisions.
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G2203820474, G2695995110, G2707798878
OpenAlex ID: W7220841348