Impact of weight loss on cancer-related proteins in serum: results from a cluster randomised controlled trial of individuals with type 2 diabetesResearch in context
Caroline J. Bull,
Emma Hazelwood,
Danny N. Legge,
Laura J. Corbin,
Tom G. Richardson,
Matthew Lee,
James Yarmolinsky,
Karl Smith-Byrne,
David A. Hughes,
Mattias Johansson,
Ulrike Peters,
Sonja I. Berndt,
Hermann Brenner,
Andrea Burnett-Hartman,
Iona Cheng,
Sun-Seog Kweon,
Loic Le Marchand,
Li Li,
Polly A. Newcomb,
Rachel Pearlman,
Alex McConnachie,
Paul Welsh,
Roy Taylor,
Mike E.J. Lean,
Naveed Sattar,
Neil Murphy,
Marc J. Gunter,
Nicholas J. Timpson,
Emma E. Vincent
Affiliations
Caroline J. Bull
MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; School of Translational Health Sciences, Dorothy Hodgkin Building, University of Bristol, Bristol, UK
Emma Hazelwood
MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
Danny N. Legge
School of Translational Health Sciences, Dorothy Hodgkin Building, University of Bristol, Bristol, UK
Laura J. Corbin
MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
Tom G. Richardson
MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
Matthew Lee
Section of Nutrition and Metabolism, International Agency for Research on Cancer, WHO, Lyon, France
James Yarmolinsky
MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
Karl Smith-Byrne
Cancer Epidemiology Unit, Oxford Population Health, University of Oxford, UK
David A. Hughes
MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
Mattias Johansson
Section of Nutrition and Metabolism, International Agency for Research on Cancer, WHO, Lyon, France
Ulrike Peters
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Sonja I. Berndt
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Hermann Brenner
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
Andrea Burnett-Hartman
Institute for Health Research, Kaiser Permanente Colorado, Denver, CO, USA
Iona Cheng
Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
Sun-Seog Kweon
Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, Korea; Jeonnam Regional Cancer Center, Chonnam National University Hwasun Hospital, Hwasun, Korea
Loic Le Marchand
University of Hawaii Cancer Center, Honolulu, HI, USA
Li Li
Department of Family Medicine, University of Virginia, Charlottesville, VA, USA
Polly A. Newcomb
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; School of Public Health, University of Washington, Seattle, WA, USA
Rachel Pearlman
Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
Alex McConnachie
Robertson Centre for Biostatistics, Institute of Health and Wellbeing, University of Glasgow, Glasgow, G12 8QQ, UK
Paul Welsh
School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK
Roy Taylor
Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
Mike E.J. Lean
Human Nutrition, School of Medicine, Dentistry and Nursing, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, UK
Naveed Sattar
School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK
Neil Murphy
Section of Nutrition and Metabolism, International Agency for Research on Cancer, WHO, Lyon, France
Marc J. Gunter
Section of Nutrition and Metabolism, International Agency for Research on Cancer, WHO, Lyon, France; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, UK
Nicholas J. Timpson
MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
Emma E. Vincent
MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; School of Translational Health Sciences, Dorothy Hodgkin Building, University of Bristol, Bristol, UK; Corresponding author. MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.
Summary: 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.
