Our group previously identified three subtypes of human PDAC based on gene expression (PDAassigner, classical, quasi-mesenchymal (QM) and exocrine-like subtypes). Recently Bailey et al. published four subtypes that were concordant with our three subtypes except that their immunogenic subtype (enriched for immune genes) is a sub-subtype of the classical subtype. Here we applied our published prognostic/predictive colorectal cancer gene expression subtype classifier (CRCassigner) to PDAC patient samples to establish if these subtypes existed in PDAC and if they could be used to further refine our original PDAC subtypes.
CRCassigner signatures were used to classify 123 PDAC patient samples. Comparisons between different subtype classifications were performed using hypergeometric test. Patient survival analysis were performed using Kaplan-Meier plots and log-rank test. Pathway enrichment analysis was performed using gene set enrichment analysis (GSEA) on RNAseq expression profiles.
We confirmed the existence of the five CRCassigner subtypes – enterocyte, goblet-like, inflammatory, stem-like and transit-amplifying (TA) - in PDAC. These subtypes were found to be sub-groups of original three PDAssigner subtypes. By combining our subtype classification with Bailey et al.’s we classified PDAC into six sub-subgroups of three published subtypes – classical (pancreatic progenitors and immunogenic); QM/squamous (stem-like and inflammatory) and exocrine-like/ADEX (TA and enterocyte). Interestingly, we observed differences in the distribution of immune cells between Bailey’s immunogenic and our inflammatory subtypes. We noted a significant increase in the expression of most of the immune regulatory genes in the inflammatory (n = 7) subtype compared to the immunogenic subtype (n = 13).
This study further refines our published PDAC subtypes. The data reveals a new subgroups with a different immune and stromal profiles associated with different overall survival in this small data set. Further validation of these results is warranted to determine if subtype classifier can stratify patient samples for treatment with immunotherapy or immunotherapy combinations in PDAC.
Clinical trial identification
Legal entity responsible for the study
The Institute of Cancer Research
National institute for health research
A. Scarpa: Associazione Italiana Ricerca Cancro (grant. 12182) Fondazione Italiana Malattie Pancreas – Ministero Salute (CUP_J33G13000210001) European Community Grant FP7 Cam-Pac Cam-Pac, Grant agreement no: 602783 A. Sadanandam: Entitled to a share of royalties received by the licensor for a patent patent number PCT/IB2013/060416. Received research funding from Bristol-Myers Squibb for pancreatic cancer. All other authors have declared no conflicts of interest.