Examination of DNA methylation patterns in pancreatic ductal adenocarcinoma

Pancreatic Ductal Adenocarcinoma (PDAC) is a deadly cancer with a 5-year survival rate of ~ 13%. PDAC treatment options are limited and are often given based on patient fitness rather than molecular characteristics. Transcriptomics analysis characterizes PDAC into molecular subtypes which could help guide patient treatment based on tumour characteristics. The consensual classical and basal-like PDAC subtypes are characterized by the expression of pancreatic developmental genes or epithelial to mesenchymal transition genes, respectively. However, while basal-like tumors are more aggressive than classical tumors, these transcriptomic signatures may not translate to ex vivo analysis and also do not reflect the continuum of phenotypes observed in vivo. In this study, we focused on DNA methylation, a heritable and stable epigenetic mark that can be used to track cell of origin. DNA methylation patterns were assessed in 62 patient-derived organoids, originating from two clinical trial studies, using a targeted analysis involving methylation arrays. The analysis confirmed hypermethylation of basal-like PDAC compared to classical PDAC and identified four DNA methylation-based clusters independent of transcriptional subtypes. Methylation profiles aligned with biological processes linked to differentiated or poorly-differentiated subtypes and was able to further characterize PDAC heterogeneity. The identification of these DNA methylation signatures may uncover unique sensitivities for treatment and possible biological mechanisms that drive PDAC biology.