Abstract
Intraductal papillary mucinous neoplasms (IPMNs) are critical precursors to pancreatic ductal adenocarcinoma, a highly lethal cancer characterized by late detection and rapid progression. Here we integrate multi-region whole-genome and transcriptome sequencing to trace the evolution of IPMN, constructing detailed phylogenetic trees to provide insights into subclonal architectures and progression pathways. Our analysis identifies two distinct evolutionary trajectories: one driven by a single ancestral clone, and another involving multiple independent ancestral clones. We further explore the roles of mutational signatures and structural variants in promoting clonal evolution and the emergence of new subclones. Complementing these genomic findings, our transcriptomic analysis reveals unique gene expression profiles and variations in the immune landscape that correlate with different progression stages of IPMN. These insights reveal the complex molecular dynamics of IPMN heterogeneity and progression, highlighting the need to refine early detection and treatment strategies.
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Data availability
Whole-genome sequencing (WGS) and RNA-seq raw data have been deposited in the European Genome-phenome Archive (EGA) under accession numbers EGAS50000001182 and EGAS50000001540 respectively. Processed datasets supporting the findings of this study are available at the following repositories: https://github.com/Wedge-lab/IPMNPDACpaperArchive/tree/main/IPMNPDAC_WGS/Data, https://github.com/Wedge-lab/IPMNPDACpaperArchive/tree/main/IPMNPDAC_WGS/Data/sigDPC, https://github.com/Wedge-lab/IPMNPDACpaperArchive/tree/main/IPMNPDAC_WGS/Data/svDriverCluster, https://github.com/Wedge-lab/IPMNPDACpaperArchive/tree/main/IPMNPDAC_WGS/Data/cnvDriverCluster Source data are provided with this paper.
Code availability
The Code and data used for the analysis are available at: https://gitfront.io/r/xtgitfhe2/8f2rTdyZs1S9/IPMNPDACpaperArchive/ [gitfront.io].
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Acknowledgements
This work was performed under the frame of the Scottish Genome Partnership. This study was funded by the Scottish Genome Partnership and, in part, by Associazione Italiana Ricerca Cancro (AIRC IG n. 26343), Italian Ministry of Health through Fondazione Italiana Malattie Pancreas (FIMP_CUP J37G22000230001), Fondazione Cariverona: Oncology Biobank Project “Antonio Schiavi” (prot. 203885/2017), European Union - NextGenerationEU through the Italian Ministry of University and Research under PNRR - M4C2-I1.3 Project PE_00000019 “HEAL ITALIA” CUP: B33C22001030006, European Union - NextGenerationEU through Italian Ministry of Health, PNRR HUB Diagnostica Avanzata PNC-E3-2022-23683266 PNCHLS-DA. DCW carried out this research at the National Institute for Health and Care Research (NIHR) Manchester Biomedical Research Centre (BRC) (NIHR203308). XH was funded by Cancer Research UK RadNet Manchester (C1994/A28701).
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A.P. and D.K.C. designed the study. A.P., R.U.G., C.L., S.D., F.D., N.B.J., C.J.M., E.D., S.R., P.P., N.S., R.T.L., R.S., and A.S. analyzed tissue samples. A.P., R.U.G., C.L., S.D., F.D., N.B.J., C.J.M., E.D., S.R., P.P., N.S., R.T.L., R.S., A.S., and D.K.C. acquired data. A.P., X.H., R.U.G., C.L., L.P.S.S., A.V.B., D.C.W., and D.K.C. analyzed data. A.P., X.H., R.U.G., C.L., L.P.S.S., A.PU., F.E.M.F., M.M., R.S., A.S., A.V.B., D.C.W., and D.K.C. interpreted data. A.P., X.H., D.C.W., and D.K.C. wrote the paper. All authors approved the final version of the manuscript.
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D.K.C. has received consulting and lecture fees from Immodulon Therapeutics and Mylan, research funding from Astrazeneca, BMS GmbH & Co. KG, Merck, and Immodulon Therapeutics. MM reports honoraria from AstraZeneca, MSD Oncology, Ipsen, Hippocrates, Viatris, and Servier, and reports consulting or advisory role for AstraZeneca, MSD Oncology, and Janssen Oncology; research funding from Roche and other relationships (participation to protocol Steering Committees and Independent Data Monitoring Committee) with Novartis and OncoSil. FEMF has received research funding from Astrazeneca and Sierra Oncology, speakers fees from Servier Oncology, Viatris travel support from Viatris, and is in the advisory board of Astellas and Abbott. NBJ has received honorariums and delivered talks for Nanostring, 10x genomics, APkoya, and is the scientific advisory board for Galvani. C.L. has received funds from NTP (scientific advisor), MSD (speaker bureau), and Medica srl (speaker bureau). No potential conflicts of interest were disclosed by the other authors.
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Pea, A., He, X., Upstill-Goddard, R. et al. Clonal evolutionary analysis reveals patterns of malignant transformation of Intraductal Papillary Mucinous Neoplasms of the pancreas. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69762-w
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DOI: https://doi.org/10.1038/s41467-026-69762-w
