Down‐regulation of metabolic pathways could offset the poor prognosis conferred by co‐existent diabetes mellitus in pancreatic (head) adenocarcinoma. Issue 11 (13th September 2021)

• Record Type: Journal Article
• Authors: Gardi, Nilesh; Ketkar, Madhura; McKinnon, Ross A.; Pandol, Stephen J.; Dutt, Shilpee; Barreto, Savio G.
• Is Part Of: ANZ journal of surgery. Volume 91:Issue 11(2021)
• Page Start: 2466
• Page End: 2474
• Publication Date: 2021-09-13
• Subjects: general surgery -- genetics -- glucagon -- hepatopancreaticobiliary surgery -- insulin -- pancreas -- transcriptome; Surgery -- Periodicals; 617.005
• DOI: 10.1111/ans.17194
• Languages: English
• ISSNs: 1445-1433

Abstract

Abstract: Background: Pancreatic ductal adenocarcinoma (PDAC) patients with diabetes mellitus (DM) have poor overall survival. Underlying mechanisms have not been fully clarified. This presents an opportunity for precision‐oncology for which we systematically analysed publicly‐available PDAC transcriptome data. Methods: PDAC TCGA RNASeq data were used. Analyses were restricted to only 'high purity' and 'head' as anatomical site. Patients were characterised by: (1) Gene expression classification, and (2) Weighted gene correlation network analysis (WGCNA) to identify co‐expression patterns of genes. Newly identified gene signature subclasses of pancreatic head PDAC were associated with clinical and functional characteristics of patients. Results: Consensus clustering identified two patient subclasses within PDAC involving pancreatic head. WGCNA identified 11 distinct networks of gene expression patterns across two sub‐classes. Class 1 patients demonstrated a significant upregulation of Module 5 and Module 6 gene expression compared to Class 2. Class 1 predominantly expressed the acinar, ductal and islet cell gene signatures. There were significantly less patients with DM in Class 1 subclass compared to Class 2 ( p < 0.037). Patients with DM had significant downregulation of pathways involved in cellular metabolism, hormone secretion and paucity of islet cell markers with no reduced survival compared with non‐diabetics. Conclusions: A significant proportion of patients with PDAC of pancreatic head and DM exhibit downregulation of pathways involved in cellular metabolism, hormone secretion and signalling accompanied by a paucity of islet expression. Investigating the relationship between DM and gene expression profiles in patients with PDAC presents opportunities to improve overall survival in diabetics with PDAC. Abstract : Consensus cluster and Co‐expression network analysis using WGCNA identified 2 head subclasses (a) Consensus clustering approach to identify classes within head PDAC samples. (b) Heatmap representing top 500 differentially expressed genes between head subclass 1 and 2. FDR<0.05. (c) Kaplan‐Meier plot depicting overall survival of all the 55 head PDAC patients classified as subclasses. (d) Heatmap of 11 modules distinguished between Class 1 and 2 ('M') based on a high Correlation value between module eigengene and expression profile across patients, plotted against molecular classes (vertically). Red color indicates upregulation and green color indicates downregulation.