Journal Article

Molecular heterogeneity and commonalities in pancreatic cancer precursors with gastric and intestinal phenotype

Opitz, Friederike V, Goering, Wolfgang, Klöppel, Guenter, Frohn, Lisa, Esposito, Irene, Schlitter, Anna Melissa, Vesce, Rita, Espinet, Elisa, Haeberle, Lena, Stoecklein, Nickolas, Liffers, Sven-Thorsten, Trumpp, Andreas, Yavas, Aslihan, Godfrey, Laura, Knoefel, Wolfram Trudo, Siveke, Jens T

2023

Overview

ObjectiveDue to the limited number of modifiable risk factors, secondary prevention strategies based on early diagnosis represent the preferred route to improve the prognosis of pancreatic ductal adenocarcinoma (PDAC). Here, we provide a comparative morphogenetic analysis of PDAC precursors aiming at dissecting the process of carcinogenesis and tackling the heterogeneity of preinvasive lesions.DesignTargeted and whole-genome low-coverage sequencing, genome-wide methylation and transcriptome analyses were applied on a final collective of 122 morphologically well-characterised low-grade and high-grade PDAC precursors, including intestinal and gastric intraductal papillary mucinous neoplasms (IPMN) and pancreatic intraepithelial neoplasias (PanIN).ResultsEpigenetic regulation of mucin genes determines the phenotype of PDAC precursors. PanIN and gastric IPMN display a ductal molecular profile and numerous similarly regulated pathways, including the Notch pathway, but can be distinguished by recurrent deletions and differential methylation and, in part, by the expression of mucin-like 3. Intestinal IPMN are clearly distinct lesions at the molecular level with a more instable genotype and are possibly related to a different ductal cell compartment.ConclusionsPDAC precursors with gastric and intestinal phenotype are heterogeneous in terms of morphology, genetic and epigenetic profile. This heterogeneity is related to a different cell identity and, possibly, to a different aetiology.

• Publisher: BMJ Publishing Group Ltd and British Society of Gastroenterology,BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Adenocarcinoma / Carcinogenesis / Carcinoma, Pancreatic Ductal - pathology / Disease prevention / DNA methylation / Epigenesis, Genetic / Epigenetics / Evolution & development / gene expression / gene mutation / Gene regulation / Genomes / Genotypes / Humans / Intestine / Morphology / Mucin / Mucins - metabolism / Mutation / Pancreas / Pancreatic cancer / Pancreatic Intraductal Neoplasms - genetics / Pancreatic Neoplasms / Pancreatic Neoplasms - pathology / pancreatic pathology / pancreatic tumours / Pathology / Phenotype / Phenotypes / pre-malignancy - GI tract / Risk factors / Transcriptomes / Tumors