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. 2025 Dec 1;117(12):2621-2642.
doi: 10.1093/jnci/djaf201.

Adiposity distribution and risks of 12 obesity-related cancers: a Mendelian randomization analysis

Emma Hazelwood  1   2 , Lucy J Goudswaard  1   2 , Matthew A Lee  3 , Marina Vabistsevits  1   2   4 , Dimitri J Pournaras  5 , Hermann Brenner  6   7   8 , Daniel D Buchanan  9   10   11 , Stephen B Gruber  12 , Andrea Gsur  13 , Li Li  14 , Ludmila Vodickova  15   16 , Robert C Grant  17 , N Jewel Samadder  18 , Nicholas J Timpson  1   2 , Marc J Gunter  3   19 , Benjamin Schuster-Böckler  20 , James Yarmolinsky  19 , Tom G Richardson  1   2 , Heinz Freisling  3 , Neil Murphy  3 , Emma E Vincent  1   2   21
Affiliations

Adiposity distribution and risks of 12 obesity-related cancers: a Mendelian randomization analysis

Emma Hazelwood et al. J Natl Cancer Inst. .

Abstract

Introduction: There is convincing evidence that overall adiposity increases the risks of several cancers. Whether the distribution of adiposity plays a similar role is unclear.

Methods: We used 2-sample Mendelian randomization (MR) to examine causal relationships of 5 adiposity distribution traits (abdominal subcutaneous adipose tissue (ASAT); visceral adipose tissue (VAT); gluteofemoral adipose tissue (GFAT); liver fat; and pancreas fat) with the risks of 12 obesity-related cancers (endometrial, ovarian, breast, colorectal, pancreas, multiple myeloma, liver, kidney (renal cell), thyroid, gallbladder, esophageal adenocarcinoma, and meningioma).

Results: Sample size across all genome-wide association studies (GWAS) ranged from 8407 to 728 896 (median: 57 249). We found evidence that higher genetically predicted ASAT increased the risks of endometrial cancer, liver cancer, and esophageal adenocarcinoma (odds ratios (OR) and 95% confidence intervals (CI) per standard deviation (SD) higher ASAT = 1.79 (1.18 to 2.71), 3.83 (1.39 to 10.53), and 2.34 (1.15 to 4.78), respectively). Conversely, we found evidence that higher genetically predicted GFAT decreased the risks of breast cancer and meningioma (ORs and 95% CIs per SD higher genetically predicted GFAT = 0.77 (0.62 to 0.97) and 0.53 (0.32 to 0.90), respectively). We also found evidence for an effect of higher genetically predicted VAT and liver fat on increased liver cancer risk (ORs and 95% CIs per SD higher genetically predicted adiposity trait = 4.29 (1.41 to 13.07) and 4.09 (2.29 to 7.28), respectively).

Discussion: Our analyses provide novel insights into the relationship between adiposity distribution and cancer risk. These insights highlight the potential importance of adipose tissue distribution alongside maintaining a healthy weight for cancer prevention.

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Conflict of interest statement

Tom G. Richardson is employed full-time by GlaxoSmithKline outside of the research presented in this article. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article, and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/World Health Organization. This article is the result of the scientific work of Neil Murphy while he was affiliated at IARC. Robert C. Grant received a graduate scholarship from Pfizer and provided consulting or advisory roles for AstraZeneca, Tempus, Eisai, Incyte, Knight Therapeutics, Guardant Health, and Ipsen. Dimitri J. Pournaras has been funded by the Royal College of Surgeons of England. He receives consulting fees from Johnson & Johnson, Novo Nordisk, GSK, Sandoz, and Pfizer and payments for lectures, presentations, and educational events from Johnson & Johnson, Medtronic, and Novo Nordisk.

Figures

Figure 1.
Figure 1.
Flowchart detailing analysis plan.
Figure 2.
Figure 2.
Univariable MR results examining the effect of measures of adiposity on risk of obesity-related cancers, A) overall and B) by subtypes. Odds ratios shown are given as 1 SD increase in adiposity measure. Open/closed circles indicate the P-value did not/did meet the multiple testing-corrected evidence threshold (P < .05/12 cancer types), respectively. Abbreviations: ASAT = adipose subcutaneous adipose tissue; BMI = body mass index; GFAT = gluteofemoral adipose tissue; VAT = visceral adipose tissue.
Figure 3.
Figure 3.
Univariable MR results examining the effect of measures of adiposity on potential molecular mediators of the effect of adiposity on cancer risk. Betas shown are given as 1 SD increase in adiposity measure and inverse-normal transformed nmol/L total testosterone; natural log transformed nmol/L bioavailable testosterone; inverse rank normal transformed SD SHBG; natural log transformed pmol/L fasting insulin; nmol/L IGF-1; SD IGF-2; SD IGFBP-1; SD IGFBP-3; SD MCP-1; SD CXCL-8; SD IL-1B; SD IL-6; SD TNF-a; mg/L CRP; SD IFN-a; SD IFN-B; SD PAI-1; SD triglycerides; SD FASN; SD (0.38 mmol/L) HDL cholesterol; SD leptin; SD visfatin; SD resistin; SD adiponectin. Open/closed circles indicate the P-value did not/did meet the multiple testing-corrected evidence threshold (P < .05/24 molecular traits), respectively. Abbreviations: ASAT = adipose subcutaneous adipose tissue; CRP = C-reactive protein; CXCL = C-X-C motif chemokine ligand; FASN = fatty acid synthase; GFAT = gluteofemoral adipose tissue; HDL = high-density lipoprotein; IFN = interferon; IGF = insulin-like growth factor; IGFBP = IGF binding protein; IL = interleukin; MCP = monocyte chemotactic protein; PAI = plasminogen activator inhibitor; SHBG = sex hormone-binding globulin; TNF = tumor necrosis factor; VAT = visceral adipose tissue.
Figure 4.
Figure 4.
Univariable MR results examining the effect of potential molecular mediators of the effect of adiposity distribution on cancer risk. A) Molecular traits and cancers that were found to be affected by ASAT in earlier MR analyses; B) molecular traits and cancers that were found to be affected by GFAT in earlier MR analyses; C) molecular traits and cancers that were found to be affected by liver fat in earlier MR analyses; D) molecular traits and cancers that were found to be affected by pancreas fat in earlier MR analyses. Odds ratios shown are given as increase of one inverse-normal transformed nmol/L total testosterone; inverse rank normal transformed SD SHBG; natural log transformed pmol/L fasting insulin; nmol/L IGF-1; SD IGFBP-1; SD resistin; SD adiponectin; SD PAI-1; SD CXCL-8; SD (0.38 mmol/L) HDL cholesterol; SD triglycerides; natural log transformed nmol/L bioavailable testosterone. Open/closed circles indicate the P-value did not/did meet the multiple testing-corrected evidence threshold (P < .05/21 unique adiposity-cancer pairs), respectively. Abbreviations: ASAT = adipose subcutaneous adipose tissue; CXCL = C-X-C motif chemokine ligand; GFAT = gluteofemoral adipose tissue; HDL = high-density lipoprotein; IGF = insulin-like growth factor; IGFBP = IGF binding protein; PAI = plasminogen activator inhibitor; SHBG = sex hormone-binding globulin; VAT = visceral adipose tissue.
Figure 5.
Figure 5.
Schematic showing the results from MR analyses of adiposity measures on molecular traits, and molecular traits on cancer risks (overall only, ie, not including cancer subtypes/subsites). Purple molecular traits are sex hormones and related traits; yellow molecular traits are insulin-related traits; orange molecular traits are inflammation-related adipokines; green molecular traits are lipid-related traits; gray traits are chemokine traits. Red arrows represent analyses with evidence for a causal effect that increases molecular trait levels or cancer risk; blue arrows represent analyses with evidence for a causal effect that decreases molecular trait levels or cancer risk. Solid arrows represent analyses for which there was some evidence (P < .05) for a mediating effect of the molecular trait in multivariable MR analyses; dotted arrows represent analyses where there was evidence (P < .05) in univariable MR analyses only. Note that no molecular trait evaluated was estimated to mediate 100% of the effects of adiposity measures on cancer risks, so other as yet unknown biological pathways presumably exist but are not shown. A) MR results from analyses relating to ASAT. B) MR results from analyses relating to VAT. C) MR results from analyses relating to GFAT. D) MR results from analyses relating to pancreas fat. E) MR results from analyses relating to liver fat.
Figure 5.
Figure 5.
Schematic showing the results from MR analyses of adiposity measures on molecular traits, and molecular traits on cancer risks (overall only, ie, not including cancer subtypes/subsites). Purple molecular traits are sex hormones and related traits; yellow molecular traits are insulin-related traits; orange molecular traits are inflammation-related adipokines; green molecular traits are lipid-related traits; gray traits are chemokine traits. Red arrows represent analyses with evidence for a causal effect that increases molecular trait levels or cancer risk; blue arrows represent analyses with evidence for a causal effect that decreases molecular trait levels or cancer risk. Solid arrows represent analyses for which there was some evidence (P < .05) for a mediating effect of the molecular trait in multivariable MR analyses; dotted arrows represent analyses where there was evidence (P < .05) in univariable MR analyses only. Note that no molecular trait evaluated was estimated to mediate 100% of the effects of adiposity measures on cancer risks, so other as yet unknown biological pathways presumably exist but are not shown. A) MR results from analyses relating to ASAT. B) MR results from analyses relating to VAT. C) MR results from analyses relating to GFAT. D) MR results from analyses relating to pancreas fat. E) MR results from analyses relating to liver fat.
Figure 5.
Figure 5.
Schematic showing the results from MR analyses of adiposity measures on molecular traits, and molecular traits on cancer risks (overall only, ie, not including cancer subtypes/subsites). Purple molecular traits are sex hormones and related traits; yellow molecular traits are insulin-related traits; orange molecular traits are inflammation-related adipokines; green molecular traits are lipid-related traits; gray traits are chemokine traits. Red arrows represent analyses with evidence for a causal effect that increases molecular trait levels or cancer risk; blue arrows represent analyses with evidence for a causal effect that decreases molecular trait levels or cancer risk. Solid arrows represent analyses for which there was some evidence (P < .05) for a mediating effect of the molecular trait in multivariable MR analyses; dotted arrows represent analyses where there was evidence (P < .05) in univariable MR analyses only. Note that no molecular trait evaluated was estimated to mediate 100% of the effects of adiposity measures on cancer risks, so other as yet unknown biological pathways presumably exist but are not shown. A) MR results from analyses relating to ASAT. B) MR results from analyses relating to VAT. C) MR results from analyses relating to GFAT. D) MR results from analyses relating to pancreas fat. E) MR results from analyses relating to liver fat.
Figure 6.
Figure 6.
Schematic showing the results from MR analyses of adiposity measures on molecular traits, and molecular traits on subtype/subsite-specific cancer risks. Purple molecular traits are sex hormones and related traits; yellow molecular traits are insulin-related traits; orange molecular traits are inflammation-related adipokines; green molecular traits are lipid-related traits; gray traits are chemokine traits. Red arrows represent analyses with evidence for a causal effect that increases molecular trait levels or cancer risk; blue arrows represent analyses with evidence for a causal effect that decreases molecular trait levels or cancer risk. Solid arrows represent analyses for which there was evidence (P < .05) for a mediating effect of the molecular trait in multivariable MR analyses; dotted arrows represent analyses where there was evidence (P < .05) in univariable MR analyses only. Note that no molecular trait evaluated was estimated to mediate 100% of the effects of adiposity measures on cancer risks, so other as yet unknown biological pathways presumably exist but are not shown. A) MR results from analyses relating to ASAT. B) MR results from analyses relating to VAT. C) MR results from analyses relating to GFAT. D) MR results from analyses relating to pancreas fat.
Figure 6.
Figure 6.
Schematic showing the results from MR analyses of adiposity measures on molecular traits, and molecular traits on subtype/subsite-specific cancer risks. Purple molecular traits are sex hormones and related traits; yellow molecular traits are insulin-related traits; orange molecular traits are inflammation-related adipokines; green molecular traits are lipid-related traits; gray traits are chemokine traits. Red arrows represent analyses with evidence for a causal effect that increases molecular trait levels or cancer risk; blue arrows represent analyses with evidence for a causal effect that decreases molecular trait levels or cancer risk. Solid arrows represent analyses for which there was evidence (P < .05) for a mediating effect of the molecular trait in multivariable MR analyses; dotted arrows represent analyses where there was evidence (P < .05) in univariable MR analyses only. Note that no molecular trait evaluated was estimated to mediate 100% of the effects of adiposity measures on cancer risks, so other as yet unknown biological pathways presumably exist but are not shown. A) MR results from analyses relating to ASAT. B) MR results from analyses relating to VAT. C) MR results from analyses relating to GFAT. D) MR results from analyses relating to pancreas fat.
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