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

Abstract

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.

Oncogenic GNAS drives a gastric pylorus program in intraductal papillary mucinous neoplasms of the pancreas

“…As oncogenic GNAS mutations are largely restricted to IPMNs in humans, our finding suggests that GNAS could be driving the formation of these disease-defining cysts. These findings concur with those by Liffers et al, which show that human PanIN and gastric-type IPMN are remarkably similar at the transcriptomic level but highlight MUCL3 as a distinctive marker expressed only in gastric IPMNs 11 . Our findings show that oncogenic GNAS drives MUCL3 expression and is the likely root cause for this difference ( Figure 3 ).…”

“…In GEMMs, combined expression of both Kras and GNAS has been shown to accelerate PDAC formation through a mixed phenotype of PanIN and IPMN 10 . IPMN may be further subclassified by a combination of morphology and molecular markers including gastric foveolar (MUC6+MUC5AC+), intestinal (MUC2+MUC5AC+), and pancreatobiliary, which is widely considered to be an advanced form of gastric-type IPMN 11, 12 .…”

Modern aspects of the management of pancreatic intraductal papillary mucinous neoplasms: a narrative review

“…Pancreatic cancer may be derived from several premalignant lesions, including intraductal tubulopapillary neoplasm (ITPN) [ 19 ]. Molecular analysis of precursors of pancreatic cancer with gastric and intestinal phenotypes, such as the trefoil factor 3 (TFF3) gene, mucin 2 (MUC2) gene and mucin like 3 (MUCL3) gene, showed their molecular heterogeneity, which is possibly related to their different cell identities and etiologies [ 20 ]. The molecular mechanisms involved in the IPMN development and its subsequent progression to pancreatic cancer are mostly unknown.…”

Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of The Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential

“…In contrast, IPMNs of the intestinal and pancreato-biliary subtypes can arise in either the main or branch ducts, and usually correspond to HG IPMNs. The phylogeny of intestinal and pancreato-biliary subtypes continues to be debated, with some studies speculating that gastric IPMNs represent a common precursor to both categories of HG lesions (7,8), and others postulating that gastric and pancreato-biliary IPMNs share a developmental trajectory that is distinct from the intestinal subtype (9,10). Irrespective, the deregulated transcriptional programs that characterize the most common category of IPMNs, the gastric subtype, remain mostly an enigma.…”