Whole genome and transcriptome analysis and the link between insulin receptor aberration and diabetes in PDAC.

Abstract

743 Background: Pancreatic ductal adenocarcinoma’s (PDAC) association with diabetes development remains poorly understood. The insulin receptor ( INSR) can divert insulin signaling from metabolic to oncogenic pathway activation through alternative splicing of INSR in several cancer types. Methods: 54 treatment naïve patients with metastatic PDAC underwent fresh tumour biopsy in the BC Cancer Personalized Oncogenomics (POG) and PanGen studies (NCT02155621, NCT02869802) for whole genome (WGA) and transcriptome analysis (RNASeq). Copy status and expression of INSR were correlated with T2DM status, Moffitt subtypes, and overall survival (OS). The findings were then correlated with 92 resected PDAC from the International Cancer Genome Consortium (ICGC). Results: 13/54 (24%) had confirmed T2DM at enrollment, and had poorer OS compared to non-diabetic PDAC patients, independent of Moffitt subtype, HR 3.2 (1.5-6.5), p =0.001. Diabetics were more likely to have hypertension (64 v 11%, p <0.001), dyslipidemia (57 v 16%, p=0.013), and to be older (61.5 v 58 years, p=0.014) and smokers (71.4 v 21.6%, p=0.015). WGA revealed significant enrichment of heterozygous INSR copy loss in T2DM (69%) compared to all other patients (24%; p=0.03) and an enrichment of INSR copy loss for metastatic PDAC relative to resected PDAC in ICGC (35 v 18%, p=0.03). Heterozygous INSR copy loss (n = 17/54) was an independent predictor of worse OS (10.8 v 15.1 months, HR 2.29 (1.20-4.36), p=0.012), and it interacted with diabetes status (p=0.023). Moffitt basal (vs. classical) subtype (n = 17/54, of which 8/17 have INSR copy loss) was also an independent predictor of OS with HR 4.3 (2.1-8.7), p<0.001. Whilst there was no interaction between INSR status and Moffitt subtype on OS (p=0.727), INSR expression is lower in basal subtype, p<0.001. Conclusions: Presence of T2DM in our cohort is an independent predictor of worse OS, consistent with published literature. Alteration in the insulin signalling pathway with heterozygous copy loss of INSR was associated with poorer prognosis, diabetes development and overlapped with Moffitt basal subtype.