For this purpose, various precursor lesions were microdissected from tissues of more than 120 patient samples and compared with various normal pancreatic cell types on the basis of their mutation and DNA methylation patterns, their gene expression and their histology. The researchers were able to show that the epigenetic regulation differs greatly in the different lesion types. In particular, special glycoproteins, the mucins, which protect the pancreatic ductal systems from the degradation by the secreted digestive enzymes, were regulated differently.
Genetic instability leads to a higher risk that an aggressive tumour will develop more quickly from the precursor lesions. Thus, a greater proportion of amplifications and deletions ofDNA segments in the genome underpins the genetically more unstable phenotype of cystic precursor lesions (so-called IPMN) with intestinal differentiation.
The most frequent precursor lesion leading to pancreatic cancer (so-called PanIN) can so far only be distinguished from IPMN with gastric differentiation on the basis of its smaller size. In their study, the researchers were able to show that the genome-wide DNA methylation patterns of the two lesion types also show no differences. However, with MUCL3, a potential differential marker for the determination of gastric IPMNs was identified for the first time. MUCL3 is a membrane protein that exhibits both differential DNA methylation in the promoter region of the gene and significantly higher expression in gastric IPMNs than in PanIN.
The research team used the "molecular footprint" of DNA methylation, a chemical modification of DNA that has a cell type-specific distribution, to hypothesise the different cell identity of the precursor lesions. While the methylation pattern of PanIN and gastral IPMN lesions resembles that of normal ductal cells (cells of the pancreatic ductal system), the intestinal type may have originated from a rare cell subpopulation within the ductal system. The differential expression data also support this hypothesis.
Overall, the study contributes to a better understanding of PDAC tumorigenesis with its multiple molecular datasets obtained from precursor lesions in a large cohort of patients. The data suggest a different malignant potential of the individual precursor lesions thus opening up new approaches for early detection of this extremely aggressive tumour.
Sven-Thorsten Liffers, Laura Godfrey, Lisa Frohn, Lena Haeberle, Rita Vesce, Wolfgang Goering, Nickolas Stoecklein, Wolfram-Trudo Knoefel, Guenter Klöppel, Andreas Trumpp, Jens T. Siveke, Irene Esposito (corr. Author), Molecular heterogeneity and commonalities in pancreatic cancer precursors with gastric and intestinal phenotype (), http://dx.doi.org/10.1136/gutjnl-2021-326550