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@ARTICLE{Bull:287441,
      author       = {C. J. Bull and E. Hazelwood and D. N. Legge and L. J.
                      Corbin and T. G. Richardson and M. Lee and J. Yarmolinsky
                      and K. Smith-Byrne and D. A. Hughes and M. Johansson and U.
                      Peters and S. I. Berndt and H. Brenner$^*$ and A.
                      Burnett-Hartman and I. Cheng and S.-S. Kweon and L. Le
                      Marchand and L. Li and P. A. Newcomb and R. Pearlman and A.
                      McConnachie and P. Welsh and R. Taylor and M. E. J. Lean and
                      N. Sattar and N. Murphy and M. J. Gunter and N. J. Timpson
                      and E. E. Vincent},
      title        = {{I}mpact of weight loss on cancer-related proteins in
                      serum: results from a cluster randomised controlled trial of
                      individuals with type 2 diabetes.},
      journal      = {EBioMedicine},
      volume       = {100},
      issn         = {2352-3964},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier},
      reportid     = {DKFZ-2024-00244},
      pages        = {104977},
      year         = {2024},
      abstract     = {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.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.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.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.The
                      main sources of funding for this work were Diabetes UK,
                      Cancer Research UK, World Cancer Research Fund, and
                      Wellcome.},
      keywords     = {Cancer (Other) / DiRECT (Other) / Diabetes (Other) /
                      Mendelian randomization (Other) / Obesity (Other) / Weight
                      loss (Other)},
      cin          = {C070 / C120 / HD01},
      ddc          = {610},
      cid          = {I:(DE-He78)C070-20160331 / I:(DE-He78)C120-20160331 /
                      I:(DE-He78)HD01-20160331},
      pnm          = {313 - Krebsrisikofaktoren und Prävention (POF4-313)},
      pid          = {G:(DE-HGF)POF4-313},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:38290287},
      doi          = {10.1016/j.ebiom.2024.104977},
      url          = {https://inrepo02.dkfz.de/record/287441},
}