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Lookup NU author(s): Professor Roy Taylor
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2024 The Author(s)Background: Type 2 diabetes is associated with higher risk of several cancer types. However, the biological intermediates driving this relationship are not fully understood. As novel interventions for treating and managing type 2 diabetes become increasingly available, whether they also disrupt the pathways leading to increased cancer risk is currently unknown. We investigated the effect of a type 2 diabetes intervention, in the form of intentional weight loss, on circulating proteins associated with cancer risk to gain insight into potential mechanisms linking type 2 diabetes and adiposity with cancer development. Methods: Fasting serum samples from participants with diabetes enrolled in the Diabetes Remission Clinical Trial (DiRECT) receiving the Counterweight-Plus weight-loss programme (intervention, N = 117, mean weight-loss 10 kg, 46% diabetes remission) or best-practice care by guidelines (control, N = 143, mean weight-loss 1 kg, 4% diabetes remission) were subject to proteomic analysis using the Olink Oncology-II platform (48% of participants were female; 52% male). To identify proteins which may be altered by the weight-loss intervention, the difference in protein levels between groups at baseline and 1 year was examined using linear regression. Mendelian randomization (MR) was performed to extend these results to evaluate cancer risk and elucidate possible biological mechanisms linking type 2 diabetes and cancer development. MR analyses were conducted using independent datasets, including large cancer meta-analyses, UK Biobank, and FinnGen, to estimate potential causal relationships between proteins modified during intentional weight loss and the risk of colorectal, breast, endometrial, gallbladder, liver, and pancreatic cancers. Findings: Nine proteins were modified by the intervention: glycoprotein Nmb; furin; Wnt inhibitory factor 1; toll-like receptor 3; pancreatic prohormone; erb-b2 receptor tyrosine kinase 2; hepatocyte growth factor; endothelial cell specific molecule 1 and Ret proto-oncogene (Holm corrected P-value <0.05). Mendelian randomization analyses indicated a causal relationship between predicted circulating furin and glycoprotein Nmb on breast cancer risk (odds ratio (OR) = 0.81, 95% confidence interval (CI) = 0.67–0.99, P-value = 0.03; and OR = 0.88, 95% CI = 0.78–0.99, P-value = 0.04 respectively), though these results were not supported in sensitivity analyses examining violations of MR assumptions. Interpretation: Intentional weight loss among individuals with recently diagnosed diabetes may modify levels of cancer-related proteins in serum. Further evaluation of the proteins identified in this analysis could reveal molecular pathways that mediate the effect of adiposity and type 2 diabetes on cancer risk. Funding: The main sources of funding for this work were Diabetes UK, Cancer Research UK, World Cancer Research Fund, and Wellcome.
Author(s): Bull CJ, Hazelwood E, Legge DN, Corbin LJ, Richardson TG, Lee M, Yarmolinsky J, Smith-Byrne K, Hughes DA, Johansson M, Peters U, Berndt SI, Brenner H, Burnett-Hartman A, Cheng I, Kweon S-S, Le Marchand L, Li L, Newcomb PA, Pearlman R, McConnachie A, Welsh P, Taylor R, Lean MEJ, Sattar N, Murphy N, Gunter MJ, Timpson NJ, Vincent EE
Publication type: Article
Publication status: Published
Journal: eBioMedicine
Year: 2024
Volume: 100
Print publication date: 01/02/2024
Online publication date: 29/01/2024
Acceptance date: 09/01/2024
Date deposited: 20/02/2024
ISSN (electronic): 2352-3964
Publisher: Elsevier B.V.
URL: https://doi.org/10.1016/j.ebiom.2024.104977
DOI: 10.1016/j.ebiom.2024.104977
Data Access Statement: Due to the sensitive nature of the data used in this study, requests to access the data should be made to the Principal Investigators of the DiRECT trial via https://www.directclinicaltrial.org.uk/DiRectStudyTeam.html. Summary statistics used for MR analyses were obtained from the reference GWAS. R scripts used in this study have been made publicly available on GitHub at: https://github.com/cb12104/direct_olink_oncology. All analyses were performed in R version 4.0.3.
PubMed id: 38290287
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