Deciphering the complex interplay between pancreatic cancer, diabetes mellitus subtypes and obesity/BMI through causal inference and mediation analyses

Abstract

ObjectivesTo characterise the association between type 2 diabetes mellitus (T2DM) subtypes (new-onset T2DM (NODM) or long-standing T2DM (LSDM)) and pancreatic cancer (PC) risk, to explore the direction of causation through Mendelian randomisation (MR) analysis and to assess the mediation role of body mass index (BMI).DesignInformation about T2DM and related factors was collected from 2018 PC cases and 1540 controls from the PanGenEU (European Study into Digestive Illnesses and Genetics) study. A subset of PC cases and controls had glycated haemoglobin, C-peptide and genotype data. Multivariate logistic regression models were applied to derive ORs and 95% CIs. T2DM and PC-related single nucleotide polymorphism (SNP) were used as instrumental variables (IVs) in bidirectional MR analysis to test for two-way causal associations between PC, NODM and LSDM. Indirect and direct effects of the BMI-T2DM-PC association were further explored using mediation analysis.ResultsT2DM was associated with an increased PC risk when compared with non-T2DM (OR=2.50; 95% CI: 2.05 to 3.05), the risk being greater for NODM (OR=6.39; 95% CI: 4.18 to 9.78) and insulin users (OR=3.69; 95% CI: 2.80 to 4.86). The causal association between T2DM (57-SNP IV) and PC was not statistically significant (ORLSDM=1.08, 95% CI: 0.86 to 1.29, ORNODM=1.06, 95% CI: 0.95 to 1.17). In contrast, there was a causal association between PC (40-SNP IV) and NODM (OR=2.85; 95% CI: 2.04 to 3.98), although genetic pleiotropy was present (MR-Egger: p value=0.03). Potential mediating effects of BMI (125-SNPs as IV), particularly in terms of weight loss, were evidenced on the NODM-PC association (indirect effect for BMI in previous years=0.55).ConclusionFindings of this study do not support a causal effect of LSDM on PC, but suggest that PC causes NODM. The interplay between obesity, PC and T2DM is complex.

Plasma protein biomarkers for early detection of pancreatic ductal adenocarcinoma

“…We also collected plasma samples from 130 participants in Spain as the external validation set, including early PDAC (Stage I/II, n = 37), advanced PDAC (Stage III/IV, n = 38), chronic pancreatitis (n = 19) and healthy controls (n = 36). Those participants were randomly selected from the European Study into Digestive Illnesses and Genetics (PanGenEU), a mostly hospital‐based case‐control study of pancreatic cancer conducted in six European countries (Spain, Germany, Ireland, the United Kingdom, Italy and Sweden) 17 . Cases diagnosed or suspected of having pancreatic cancer and the corresponding controls matched by region, sex and age (± 10 years) were included from 2007 to 2014.…”

Langerhans islets induce anti-tumor immunity at the expense of glycemic control and predict chemotherapy response in pancreatic cancer

“…The interplay of T2DM to PDA is complex and, despite numerous studies, not comprehensively understood. However, strong existing evidence demonstrated that (new-onset) T2DM is likely to be a consequence of a tumor microenvironment consisting of progressively growing PDA cells 47 . We complement prior findings by showing that onset of T2DM is a potential sign of functionally shifting Langerhans islets towards shaping anti-tumor immunity via CCL27 production as a defense mechanism against PDA.…”

Translatome-based classification reveals a dual metabolic dependency of a new tumor subtype of pancreatic cancer

“…Among stromal cells, adipocytes could represent a potential source of NEAA including serine (Green et al 2016). The abundance of adipocytes in the pancreas increases in elderly, especially in the context of obesity and diabetes, which are risk factors for PDA (Molina-Montes et al 2020). M2 macrophages are the most abundant immune-related stromal cells found in PDA tumors.…”