Distinct Progression Paths Underlie the Diversity of Pancreatic Papillary Cystic Neoplasms
- 1Universite Paris Cite, CRI, INSERM U1149
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.
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BibTeX
@misc{pignolet2026distinct,
title = {{Distinct Progression Paths Underlie the Diversity of Pancreatic Papillary Cystic Neoplasms}},
author = {C. Pignolet and L. Aguilera Munoz and L. Bourlet and T. Bourega and L. Gomes and D. Mendes and N. Theou-Anton and N. Colnot and M. Albuquerque and L. de Mestier and S. Dokmak and A. Couvelard and V. Rebours and R. Nicolle and J. Cros},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.06.757128},
url = {https://www.biorxiv.org/content/10.64898/2026.10.06.757128v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Distinct Progression Paths Underlie the Diversity of Pancreatic Papillary Cystic Neoplasms
AU - C. Pignolet
AU - L. Aguilera Munoz
AU - L. Bourlet
AU - T. Bourega
AU - L. Gomes
AU - D. Mendes
AU - N. Theou-Anton
AU - N. Colnot
AU - M. Albuquerque
AU - L. de Mestier
AU - S. Dokmak
AU - A. Couvelard
AU - V. Rebours
AU - R. Nicolle
AU - J. Cros
PY - 2026
DA - 2026/10/06
PB - bioRxiv
DO - 10.64898/2026.10.06.757128
UR - https://www.biorxiv.org/content/10.64898/2026.10.06.757128v1
AB - 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.
ER -