Mucinous cystic neoplasms and simple mucinous cysts are two distinct precursors of pancreatic cancer: clinicopathological, genomic, and transcriptomic characterization

Mucinous cystic neoplasms (MCNs) of the pancreas are macroscopic precursors of pancreatic cancer. A similar cystic lesion but lacking the ovarian-type subepithelial stroma has been recently defined as a simple mucinous cyst (SMC); however, its nature remains unclear. This study aims to define the clinicopathological and molecular profiles of a cohort of MCNs and SMCs of the pancreas and their associated invasive carcinoma. Overall, 23 cases were identified, comprising 19 MCNs and 4 SMCs with co-occurring invasive carcinoma. A multiregional (two samples from each cystic lesion and one from the adenocarcinoma) DNA and RNA sequencing approach was used. The key findings can be summarized as follows: (1) Molecular association: In 22/23 cases (95.7%), the concomitant mucinous cyst and invasive carcinoma shared specific genomic alterations, establishing for the first time that SMC is a true precursor of pancreatic cancer. (2) Clinical behavior: carcinomas arising from SMC appeared to be more aggressive than those arising from MCN. (3) Mutational profile: both cyst types showed significant similarities to conventional pancreatic ductal adenocarcinoma (PDAC), with KRAS and TP53 the most commonly altered genes. (4) Intracystic heterogeneity: while most molecular alterations were present in both analyzed cystic areas, RNF43 showed the highest heterogeneity. (5) CDKN2A: its alterations were predominantly restricted to the invasive component, suggesting a role in driving the invasion in a subset of cases. CNKN2A may also serve as a potential biomarker for identifying high-risk cysts. (6) RNAseq: most cases showed a switch from the classical to the basal transcriptome subtype during the progression from cystic neoplasms to invasive cancers. These findings establish SMCs as new precursors of pancreatic cancer and provide critical insights into the tumorigenesis of MCNs, with potential immediate implications for tumor taxonomy and clinical management. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Authors

Institutions

Publication Details

Journal
The Journal of Pathology
Published
2025-05-15
DOI
https://doi.org/10.1002/path.6437
Citations
12
Primary Topic
Pancreatic and Hepatic Oncology Research
Type
article
Field-Weighted Citation Impact
12.54

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Mucinous cystic neoplasms and simple mucinous cysts are two distinct precursors of pancreatic cancer: clinicopathological, genomic, and transcriptomic characterization

Riccardo De Robertis, Aldo Scarpa, Michele Simbolo, Concetta Sciammarella et al.
12 citations
The Journal of Pathology
Pancreatic and Hepatic Oncology Research
12.54
article

Mucinous cystic neoplasms and simple mucinous cysts are two distinct precursors of pancreatic cancer: clinicopathological, genomic, and transcriptomic characterization

Riccardo De Robertis, Aldo Scarpa, Michele Simbolo, Concetta Sciammarella, Antonio Pea, David K. Chang, Andrea Mafficini, Serena Pedron, Jaswinder Singh Samra, Levy Aniceto Santana, Stela Golovco, Mirko D’Onofrio, Vincenzo Corbo, Giuseppe Malleo, Αναστάσιος Γκουντάκος, Anthony James Gill, Paola Mattiolo, Amber L. Johns, Lodewijk A.A. Brosens, Laura DeLong Wood, Kohei Fujikura, Rita T. Lawlor, Joanne Verheij, Manuela Villanova, Michele Stanislaw Milella, Claudio Luchini, Davide Pasini, Martijn W.J. Stommel, Francesca Masetto, Nicola Sperandio, Roberto Salvia, Michele Bevere, Mahsa Ahadi, Calogero Ciulla, Denise Fiorini, Aldo Mombello, Hjalmar C. van Santvoort, Carlotta Franzina
article en
12 citations

Abstract

Mucinous cystic neoplasms (MCNs) of the pancreas are macroscopic precursors of pancreatic cancer. A similar cystic lesion but lacking the ovarian-type subepithelial stroma has been recently defined as a simple mucinous cyst (SMC); however, its nature remains unclear. This study aims to define the clinicopathological and molecular profiles of a cohort of MCNs and SMCs of the pancreas and their associated invasive carcinoma. Overall, 23 cases were identified, comprising 19 MCNs and 4 SMCs with co-occurring invasive carcinoma. A multiregional (two samples from each cystic lesion and one from the adenocarcinoma) DNA and RNA sequencing approach was used. The key findings can be summarized as follows: (1) Molecular association: In 22/23 cases (95.7%), the concomitant mucinous cyst and invasive carcinoma shared specific genomic alterations, establishing for the first time that SMC is a true precursor of pancreatic cancer. (2) Clinical behavior: carcinomas arising from SMC appeared to be more aggressive than those arising from MCN. (3) Mutational profile: both cyst types showed significant similarities to conventional pancreatic ductal adenocarcinoma (PDAC), with KRAS and TP53 the most commonly altered genes. (4) Intracystic heterogeneity: while most molecular alterations were present in both analyzed cystic areas, RNF43 showed the highest heterogeneity. (5) CDKN2A: its alterations were predominantly restricted to the invasive component, suggesting a role in driving the invasion in a subset of cases. CNKN2A may also serve as a potential biomarker for identifying high-risk cysts. (6) RNAseq: most cases showed a switch from the classical to the basal transcriptome subtype during the progression from cystic neoplasms to invasive cancers. These findings establish SMCs as new precursors of pancreatic cancer and provide critical insights into the tumorigenesis of MCNs, with potential immediate implications for tumor taxonomy and clinical management. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

The Journal of PathologyVol. 266(4-5)
University of Verona (IT), The University of Sydney (AU), Garvan Institute of Medical Research (AU), Johns Hopkins University (US), Radboud University Nijmegen (NL), Utrecht University (NL), Royal North Shore Hospital (AU), Glasgow Royal Infirmary (GB), Radboud University Medical Center (NL), University Medical Center Utrecht (NL), St. Antonius Ziekenhuis (NL), Cancer Research Center (US), Amsterdam University Medical Centers (NL), The Kinghorn Cancer Centre (AU), Sidney Kimmel Comprehensive Cancer Center (US), University of Glasgow (GB), University of Amsterdam (NL)
Fondazione Italiana per la ricerca sulle Malattie del Pancreas, Associazione Italiana per la Ricerca sul Cancro, Fondazione Cassa di Risparmio di Verona Vicenza Belluno e Ancona
Good health and well-being
Openalex Percentile: Top 1%
Pancreatic and Hepatic Oncology Research
12.54
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.