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Body fatness associations with cancer: evidence from recent epidemiological studies and future directions

  • Susanna C. Larsson
    Correspondence
    Corresponding author at: Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Affiliations
    Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

    Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
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  • Nikolaos Spyrou
    Affiliations
    The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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  • Christos S. Mantzoros
    Affiliations
    Department of Medicine, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA, USA

    Section of Endocrinology, VA Boston Healthcare System, Harvard Medical School, Boston, MA, USA
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Open AccessPublished:September 30, 2022DOI:https://doi.org/10.1016/j.metabol.2022.155326

      Highlights

      • Excess body fatness is causally related to increased risk of cancer at several sites.
      • Central fat accumulation leads to decreased adiponectin levels and subsequent changes in insulin and sex-hormone pathways.
      • The role of gut microbiota and gut hormones in mediating the obesity-cancer associations is currently unknown.
      • With rising prevalence of obesity, the proportion of cancer caused by obesity is expected to increase.

      Abstract

      This narrative review highlights current evidence linking greater body fatness to risk of various cancers, with focus on evidence from recent large cohort studies and pooled analyses of cohort studies as well as Mendelian randomization studies (which utilized genetic variants associated with body mass index to debrief the causal effect of higher body fatness on cancer risk). This review also provides insights into the biological mechanisms underpinning the associations. Data from both observational and Mendelian randomization studies support the associations of higher body mass index with increased risk of many cancers with the strongest evidence for digestive system cancers, including esophageal, stomach, colorectal, liver, gallbladder, and pancreatic cancer, as well as kidney, endometrial, and ovarian (weak association) cancer. Evidence from observational studies suggests that greater body fatness has contrasting effects on breast cancer risk depending on menopausal status and on prostate cancer risk depending on disease stage. Experimental and Mendelian randomization studies indicate that adiponectin, insulin, and sex hormone pathways play an important role in mediating the link between body fatness and cancer risk. The possible role of specific factors and pathways, such as other adipocytokines and hormones and the gut microbiome in mediating the associations between greater body fatness and cancer risk is yet uncertain and needs investigation in future studies. With rising prevalence of overweight and obesity worldwide, the proportion of cancer caused by excess body fatness is expected to increase. There is thus an urgent need to identify efficient ways at the individual and societal level to improve diet and physical activity patterns to reduce the burden of obesity and accompanying comorbidities, including cancer.

      Graphical abstract

      Abbreviations:

      BMI (body mass index), CI (confidence interval), CUP (Continuous Update Project), FMI (fat mass index), HR (hazard ratio), IARC (International Agency for Research on Cancer), IGF-I (insulin-like growth factor I), IGFBP (insulin-like growth factor binding protein), MR (Mendelian randomization), OR (odds ratio), WCRF (World Cancer Research Fund International), SHBG (sex-hormone binding globulin)

      Keywords

      1. Introduction

      Overweight and obesity are growing global health challenges. World Health Organization defines overweight and obesity as abnormal or excessive body fatness that may impair health [
      World Health Organization
      Fact sheet: obesity and overweight.
      ]. Body mass index (BMI) is the most frequently applied population-level measure for overall body fatness. Among adults, overweight is defined as a BMI of 25 kg/m2 or more, and obesity is defined as a BMI of 30 kg/m2 or more. Globally in 2016, over 1.9 billion adults (39 %) were estimated to be overweight of which over 650 million adults (13 %; a tripling since 1975) were classified as obese [
      World Health Organization
      Fact sheet: obesity and overweight.
      ]. Raised BMI is an important risk factor for many chronic diseases, particularly type 2 diabetes, cardiovascular diseases, non-alcoholic fatty liver disease, and multiple malignancies [
      • Guh D.P.
      • Zhang W.
      • Bansback N.
      • Amarsi Z.
      • Birmingham C.L.
      • Anis A.H.
      The incidence of co-morbidities related to obesity and overweight: a systematic review and meta-analysis.
      ,
      • Perk J.
      • De Backer G.
      • Gohlke H.
      • Graham I.
      • Reiner Z.
      • Verschuren M.
      • et al.
      European guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts).
      ,
      World Cancer Research Fund/American Institute for Cancer Research
      Diet, nutrition, physical activity and cancer: a global perspective. continuous update project expert report 2018.
      ,
      • Choi E.K.
      • Park H.B.
      • Lee K.H.
      • Park J.H.
      • Eisenhut M.
      • van der Vliet H.J.
      • et al.
      Body mass index and 20 specific cancers: re-analyses of dose-response meta-analyses of observational studies.
      ,
      • <collab>WHO Consultation on Obesity (1999: Geneva Switzerlandcollab
      World Health Organization
      Obesity: preventing and managing the global epidemic: report of a WHO consultation.
      ,
      • Lauby-Secretan B.
      • Scoccianti C.
      • Loomis D.
      • Grosse Y.
      • Bianchini F.
      • Straif K.
      • et al.
      Body fatness and cancer-viewpoint of the IARC Working Group.
      ,
      • Larsson S.C.
      • Burgess S.
      Causal role of high body mass index in multiple chronic diseases: a systematic review and meta-analysis of Mendelian randomization studies.
      ,
      • Yuan S.
      • Chen J.
      • Li X.
      • Fan R.
      • Arsenault B.
      • Gill D.
      • et al.
      Lifestyle and metabolic factors for nonalcoholic fatty liver disease: Mendelian randomization study.
      ]. It is however recognized that BMI has limitations as a marker of overall fat mass and it has been increasingly recognized that the fat accumulation outside the subcutaneous adipose tissue, namely intra-abdominally or inside the liver or muscles, is more closely associated with fat associated complications including cancer.
      Cancer is another leading and rising health burden worldwide. Globally in 2019, there were an estimated 23.6 million new cancer cases (an increase of 26.3 % since 2010) and 10.0 million cancer deaths (an increase of 20.9 % since 2010) [
      • Kocarnik J.M.
      • Compton K.
      • Dean F.E.
      • Fu W.
      • Gaw B.L.
      • et al.
      Global Burden of Disease Cancer C
      Cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life years for 29 cancer groups from 2010 to 2019: a systematic analysis for the Global Burden of Disease Study 2019.
      ]. In addition, cancer deaths as a proportion of all deaths increased from 15.7 % in 2010 to 17.7 % in 2019 [
      • Kocarnik J.M.
      • Compton K.
      • Dean F.E.
      • Fu W.
      • Gaw B.L.
      • et al.
      Global Burden of Disease Cancer C
      Cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life years for 29 cancer groups from 2010 to 2019: a systematic analysis for the Global Burden of Disease Study 2019.
      ]. Cancer was second only to cardiovascular diseases for the number of deaths, years of life lost, and disability-adjusted life years globally in 2019 [
      • Kocarnik J.M.
      • Compton K.
      • Dean F.E.
      • Fu W.
      • Gaw B.L.
      • et al.
      Global Burden of Disease Cancer C
      Cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life years for 29 cancer groups from 2010 to 2019: a systematic analysis for the Global Burden of Disease Study 2019.
      ]. In addition to the aging population, the increase in cancer incidence is likely in part driven by the rising prevalence of overweight and obesity. An analysis of results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 revealed that among 82 environmental and occupational, behavioral, and metabolic risk factors, high BMI (≥25 kg/m2) was the third leading risk factor for cancer death worldwide after smoking and alcohol use [
      Collaborators GBDCRF
      The global burden of cancer attributable to risk factors, 2010-19: a systematic analysis for the Global Burden of Disease Study 2019.
      ]. Furthermore, it was estimated that 4.6 % of cancer deaths were attributable to high BMI in 2019, whereas 3.6 % of new cancer cases were attributable to high BMI in 2012 [
      Collaborators GBDCRF
      The global burden of cancer attributable to risk factors, 2010-19: a systematic analysis for the Global Burden of Disease Study 2019.
      ].
      The purpose of this narrative review is to highlight current evidence linking greater body fatness to risk of cancer at different anatomical sites and to provide insights into the biological mechanisms behind the associations. The research question was which cancer sites are likely causally linked to body fatness?

      2. Methods

      We collected information on observational evidence on the association between BMI and site-specific cancer risk from the most recent reports by the International Agency for Research on Cancer (IARC) Working Group [
      • Lauby-Secretan B.
      • Scoccianti C.
      • Loomis D.
      • Grosse Y.
      • Bianchini F.
      • Straif K.
      • et al.
      Body fatness and cancer-viewpoint of the IARC Working Group.
      ] and World Cancer Research Fund International (WCRF) Continuous Update Project (CUP) Panel [
      World Cancer Research Fund/American Institute for Cancer Research
      Diet, nutrition, physical activity and cancer: a global perspective. continuous update project expert report 2018.
      ]. We also searched PubMed for large cohort studies and pooled analyses of cohort studies (comprising ≥100,000 participants) on BMI in relation to site-specific cancers in the general population and published since the IARC and WCRF reports. The search term used was “(body mass index OR BMI OR obesity) AND (cohort study OR prospective study OR pooled analysis) AND (cancer OR carcinoma)” and the time range was from 1 January 2018 to 15 September 2022. Estimates of the magnitude of the associations between BMI and adiposity-associated cancers were obtained from the main dose-response meta-analyses performed by the WCRF CUP Panel [
      World Cancer Research Fund/American Institute for Cancer Research
      Diet, nutrition, physical activity and cancer: a global perspective. continuous update project expert report 2018.
      ] and a recent meta-analysis of MR studies [
      • Larsson S.C.
      • Burgess S.
      Causal role of high body mass index in multiple chronic diseases: a systematic review and meta-analysis of Mendelian randomization studies.
      ]. In those meta-analyses, the overall risk estimates were obtained from random-effects and fixed-effects models, respectively, and heterogeneity among studies was assessed using the I2 statistic [
      World Cancer Research Fund/American Institute for Cancer Research
      Diet, nutrition, physical activity and cancer: a global perspective. continuous update project expert report 2018.
      ,
      • Larsson S.C.
      • Burgess S.
      Causal role of high body mass index in multiple chronic diseases: a systematic review and meta-analysis of Mendelian randomization studies.
      ]. We also report pertinent risk estimates from recent large cohort studies and pooled analyses. Where results from the same cohort were reported in more than one publication, only the most comprehensive study was included in this review. In the present review, statistical significance was defined as P < 0.05.

      3. Body fatness-cancer associations

      3.1 Previous evidence from observational studies (IARC and WCRF reports)

      Greater body fatness has been associated with an increased risk of cancer at multiple anatomical sites [
      • Guh D.P.
      • Zhang W.
      • Bansback N.
      • Amarsi Z.
      • Birmingham C.L.
      • Anis A.H.
      The incidence of co-morbidities related to obesity and overweight: a systematic review and meta-analysis.
      ,
      • Perk J.
      • De Backer G.
      • Gohlke H.
      • Graham I.
      • Reiner Z.
      • Verschuren M.
      • et al.
      European guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts).
      ,
      World Cancer Research Fund/American Institute for Cancer Research
      Diet, nutrition, physical activity and cancer: a global perspective. continuous update project expert report 2018.
      ,
      • Choi E.K.
      • Park H.B.
      • Lee K.H.
      • Park J.H.
      • Eisenhut M.
      • van der Vliet H.J.
      • et al.
      Body mass index and 20 specific cancers: re-analyses of dose-response meta-analyses of observational studies.
      ,
      • <collab>WHO Consultation on Obesity (1999: Geneva Switzerlandcollab
      World Health Organization
      Obesity: preventing and managing the global epidemic: report of a WHO consultation.
      ,
      • Lauby-Secretan B.
      • Scoccianti C.
      • Loomis D.
      • Grosse Y.
      • Bianchini F.
      • Straif K.
      • et al.
      Body fatness and cancer-viewpoint of the IARC Working Group.
      ,
      • Larsson S.C.
      • Burgess S.
      Causal role of high body mass index in multiple chronic diseases: a systematic review and meta-analysis of Mendelian randomization studies.
      ]. Based on data from conventional observational studies (i.e., case-control and cohort studies), the IARC working group [
      • Lauby-Secretan B.
      • Scoccianti C.
      • Loomis D.
      • Grosse Y.
      • Bianchini F.
      • Straif K.
      • et al.
      Body fatness and cancer-viewpoint of the IARC Working Group.
      ] and WCRF CUP Panel [
      World Cancer Research Fund/American Institute for Cancer Research
      Diet, nutrition, physical activity and cancer: a global perspective. continuous update project expert report 2018.
      ] concluded in 2016 and 2018, respectively, that there is probable or strong evidence that excess body fatness (overweight and obesity) increases the risk of cancers of the esophagus (adenocarcinoma), stomach (cardia), colon and rectum, liver, gallbladder, pancreas, kidney (renal cell), corpus uteri (endometrial cancer), ovaries, and breast (in postmenopausal women).
      In meta-analyses conducted by the WCRF CUP Panel, the relative risk per 5 kg/m2 increase in BMI was 1.48 (95 % confidence interval [CI] 1.35–1.62; I2 = 37 %; n = 9 studies) for esophageal adenocarcinoma 1.23 (95 % CI 1.07–1.40; I2 = 56 %; n = 7 studies) for gastric cardia cancer, 1.05 (95 % CI 1.03–1.07; I2 = 74 %; n = 38 studies) for colorectal cancer, 1.30 (95 % CI 1.16–1.46; I2 = 78 %; n = 12 studies) for liver cancer, 1.25 (95 % CI 1.15–1.37; I2 = 52 %; n = 8 studies) for gallbladder cancer, 1.10 (95 % CI 1.07–1.14; I2 = 23 %; n = 23 studies) for pancreatic cancer, 1.30 (95 % CI 1.25–1.36; I2 = 39 %; n = 23 studies) for kidney cancer, 1.50 (95 % CI 1.42–1.58; I2 = 86 %; n = 26 studies) for endometrial cancer, 1.06 (95 % CI 1.00–1.12; I2 = 55 %; n = 25 studies) for ovarian cancer, and 1.12 (95 % CI 1.09–1.15; I2 = 74 %; n = 56 studies) for postmenopausal breast [
      World Cancer Research Fund/American Institute for Cancer Research
      Diet, nutrition, physical activity and cancer: a global perspective. continuous update project expert report 2018.
      ] (Fig. 1). The heterogeneity between studies was largely due to the magnitude of the positive associations.
      Fig. 1
      Fig. 1Cancer sites or types convincingly or probably associated with greater body fatness in observational and MR studies*.
      *Relative risk (RR) estimates and 95 % CIs are per 5 kg/m2 increment of BMI in observational studies and per one standard deviation (~5 kg/m2) increment of BMI in MR studies. The observational estimates for esophageal and stomach cancer are for esophageal adenocarcinoma and gastric cardia specifically. The estimates for observational studies were obtained from the main dose-response meta-analysis results presented in the WCRF report
      [
      World Cancer Research Fund/American Institute for Cancer Research
      Diet, nutrition, physical activity and cancer: a global perspective. continuous update project expert report 2018.
      ]
      . Estimates for MR studies were obtained from a recent meta-analysis
      [
      • Larsson S.C.
      • Burgess S.
      Causal role of high body mass index in multiple chronic diseases: a systematic review and meta-analysis of Mendelian randomization studies.
      ]
      .
      The IARC Working Group further concluded that there was sufficient evidence that excess body fatness increases the risk of thyroid cancer and multiple myeloma as well as meningioma, and that there was limited evidence for associations between greater body fatness and increased risk of diffuse large B-cell lymphoma (the most common type of non-Hodgkin lymphoma), fatal prostate cancer, and male breast cancer [
      • Lauby-Secretan B.
      • Scoccianti C.
      • Loomis D.
      • Grosse Y.
      • Bianchini F.
      • Straif K.
      • et al.
      Body fatness and cancer-viewpoint of the IARC Working Group.
      ]. The WCRF CUP Panel added fatal and advanced prostate cancer as well as mouth, pharynx, and larynx cancers to the list of cancers probably associated with greater body fatness [
      World Cancer Research Fund/American Institute for Cancer Research
      Diet, nutrition, physical activity and cancer: a global perspective. continuous update project expert report 2018.
      ]. In a meta-analysis conducted by the WCRF CUP Panel, the relative risk of fatal prostate cancer per 5 kg/m2 increase in BMI was 1.08 (95 % CI 1.04–1.12; I2 = 19 %; n = 23 studies) [
      World Cancer Research Fund/American Institute for Cancer Research
      Diet, nutrition, physical activity and cancer: a global perspective. continuous update project expert report 2018.
      ] (Fig. 1). In contrast to the positive association between BMI and breast cancer in postmenopausal women, a consistent inverse association was found between BMI and premenopausal breast cancer risk [
      World Cancer Research Fund/American Institute for Cancer Research
      Diet, nutrition, physical activity and cancer: a global perspective. continuous update project expert report 2018.
      ,
      • Lauby-Secretan B.
      • Scoccianti C.
      • Loomis D.
      • Grosse Y.
      • Bianchini F.
      • Straif K.
      • et al.
      Body fatness and cancer-viewpoint of the IARC Working Group.
      ]. In a meta-analysis conducted by the WCRF CUP Panel, the relative risk of premenopausal breast cancer per 5 kg/m2 increment in BMI was 0.93 (95 % CI 0.90–0.97; I2 = 55 %; n = 37 studies) [
      World Cancer Research Fund/American Institute for Cancer Research
      Diet, nutrition, physical activity and cancer: a global perspective. continuous update project expert report 2018.
      ] (Fig. 1). Findings for body fatness in relation to cancer risk were generally consistent for BMI and waist circumference, for men and women, and across geographical regions [
      World Cancer Research Fund/American Institute for Cancer Research
      Diet, nutrition, physical activity and cancer: a global perspective. continuous update project expert report 2018.
      ,
      • Lauby-Secretan B.
      • Scoccianti C.
      • Loomis D.
      • Grosse Y.
      • Bianchini F.
      • Straif K.
      • et al.
      Body fatness and cancer-viewpoint of the IARC Working Group.
      ]. The IARC Working Group concluded that the evidence for an association with greater body fatness was inadequate, owing to limited data, inconsistent findings, or no data indicating an association, for cancers of the brain or spinal cord (glioma), esophagus (squamous-cell carcinoma), gastric non-cardia, extrahepatic biliary tract, testis, bladder, lung, and skin (cutaneous melanoma) [
      • Lauby-Secretan B.
      • Scoccianti C.
      • Loomis D.
      • Grosse Y.
      • Bianchini F.
      • Straif K.
      • et al.
      Body fatness and cancer-viewpoint of the IARC Working Group.
      ].

      3.2 Recent evidence from large cohort studies and pooled analyses

      A total of 10,606 articles were identified in the PubMed search. Details of relevant cohort studies and pooled analyses of cohort studies comprising >100,000 participants are provided below.

      3.2.1 Studies of BMI and several cancers

      Among cohort studies assessing the association between body fatness and cancer at several sites, a recent analysis of data from the European Prospective Investigation into Cancer and Nutrition study, including 185 361 participants, showed that each 5 kg/m2 increment in adult BMI was associated with a statistically significant 13 %, 11 %, 28 %, and 47 % increased risk of colorectal, pancreatic, kidney, and endometrial cancer, respectively, and with a non-significant 6 % increased risk of ovarian cancer [
      • Mariosa D.
      • Smith-Byrne K.
      • Richardson T.G.
      • Ferrari P.
      • Gunter M.J.
      • Papadimitriou N.
      • et al.
      Body size at different ages and risk of six cancers: a mendelian randomization and prospective cohort study.
      ]. In contrast, adult BMI was inversely associated with risk of lung cancer [
      • Mariosa D.
      • Smith-Byrne K.
      • Richardson T.G.
      • Ferrari P.
      • Gunter M.J.
      • Papadimitriou N.
      • et al.
      Body size at different ages and risk of six cancers: a mendelian randomization and prospective cohort study.
      ].
      In a population-based cohort study based on UK primary care data from the Clinical Practice Research Datalink linked to national mortality registration data (n = 3,632,674 people), obesity (BMI ≥30 kg/m2) was associated with a statistically significant increased risk of most of the studied cancers compared with a normal BMI (18.5–25 kg/m2) [
      • Bhaskaran K.
      • Dos-Santos-Silva I.
      • Leon D.A.
      • Douglas I.J.
      • Smeeth L.
      Association of BMI with overall and cause-specific mortality: a population-based cohort study of 3.6 million adults in the UK.
      ]. The relative risk increase was 19 % for esophageal cancer, 22 % for stomach cancer, 24 % for colorectal cancer, 85 % for liver cancer, 24 % for pancreatic cancer, 67 % for kidney cancer, 19 % for bladder cancer, 172 % for uterine cancer, 34 % for ovarian cancer, 30 % for breast cancer, and 13 % for hematologic cancers [
      • Bhaskaran K.
      • Dos-Santos-Silva I.
      • Leon D.A.
      • Douglas I.J.
      • Smeeth L.
      Association of BMI with overall and cause-specific mortality: a population-based cohort study of 3.6 million adults in the UK.
      ].
      In a cohort study including 437,393 participants of the UK Biobank, greater adiposity, irrespective of the adiposity marker (BMI, waist circumference, waist-to-hip ratio, and body fat percentage), was associated with a higher incidence of cancer of the stomach (cardia and non-cardia), colorectum, liver, gallbladder, pancreas, kidney, corpus uteri, and breast (in postmenopausal women) [
      • Parra-Soto S.
      • Cowley E.S.
      • Rezende L.F.M.
      • Ferreccio C.
      • Mathers J.C.
      • Pell J.P.
      • et al.
      Associations of six adiposity-related markers with incidence and mortality from 24 cancers-findings from the UK Biobank prospective cohort study.
      ]. Per one standard deviation increment in BMI, the relative risk increase was 35 % for stomach cancer, 10 % for colorectal cancer, 27 % for liver cancer, 33 % for gallbladder cancer, 12 % for pancreatic cancer, 26 % for kidney cancer, 73 % for endometrial cancer, and 10 % for postmenopausal breast cancer. At least one adiposity marker was also statistically significantly positively associated with incidence of bladder cancer and melanoma, and inversely associated with prostate cancer incidence [
      • Parra-Soto S.
      • Cowley E.S.
      • Rezende L.F.M.
      • Ferreccio C.
      • Mathers J.C.
      • Pell J.P.
      • et al.
      Associations of six adiposity-related markers with incidence and mortality from 24 cancers-findings from the UK Biobank prospective cohort study.
      ]. There was no association between any adiposity marker and risk of brain, upper esophageal, oral, thyroid, ovarian, premenopausal breast, cervical, testicular, and lung cancer or multiple myeloma, non-Hodgkin lymphoma, and leukemia [
      • Parra-Soto S.
      • Cowley E.S.
      • Rezende L.F.M.
      • Ferreccio C.
      • Mathers J.C.
      • Pell J.P.
      • et al.
      Associations of six adiposity-related markers with incidence and mortality from 24 cancers-findings from the UK Biobank prospective cohort study.
      ].
      A cohort study of 3.5 million Spanish adults with 202,837 incident cancer cases diagnosed over 8.3 years of follow-up showed that higher BMI was associated with increased risk of nine cancers in the entire cohort (including colorectal, gallbladder, kidney, endometrial, and postmenopausal breast cancer as well as multiple myeloma, leukemia, and non-Hodgkin lymphoma) and with increased risk of three additional cancers among never smokers (brain and central nervous system cancer, head and neck cancer, and Hodgkin lymphoma) [
      • Recalde M.
      • Davila-Batista V.
      • Diaz Y.
      • Leitzmann M.
      • Romieu I.
      • Freisling H.
      • et al.
      Body mass index and waist circumference in relation to the risk of 26 types of cancer: a prospective cohort study of 3.5 million adults in Spain.
      ].
      In a cohort of 135,708 Norwegian women, BMI was strongly positively associated with risk of kidney and endometrial cancer, non-significantly or borderline positively associated with risk of colorectal, pancreatic, and breast (postmenopausal) cancer, but not associated with ovarian cancer [
      • da Silva M.
      • Weiderpass E.
      • Licaj I.
      • Lissner L.
      • Rylander C.
      Excess body weight, weight gain and obesity-related cancer risk in women in Norway: the Norwegian Women and Cancer study.
      ]. A cohort study of 461,646 women (≤49 years of age) registered in the Danish Medical Birth Registry found that the risk of premenopausal ovarian cancer increased by 23 % per 5 kg/m2 increase in BMI whereas the risk of premenopausal breast cancer decreased by 10 % per 5 kg/m2 increase in BMI [
      • Urbute A.
      • Frederiksen K.
      • Kjaer S.K.
      Early adulthood overweight and obesity and risk of premenopausal ovarian cancer, and premenopausal breast cancer including receptor status: prospective cohort study of nearly 500,000 Danish women.
      ].

      3.2.2 Digestive system cancers

      In a cohort study of 226,584 Australian adults, greater BMI was statistically significantly associated with an increased risk of colon cancer but not rectal cancer [
      • Nunez C.
      • Nair-Shalliker V.
      • Egger S.
      • Sitas F.
      • Bauman A.
      Physical activity, obesity and sedentary behaviour and the risks of colon and rectal cancers in the 45 and up study.
      ]. The HR of colon cancer for BMI ≥29.4 kg/m2 versus <23.6 kg/m2 was 1.32 (95 % CI 1.08–1.63) [
      • Nunez C.
      • Nair-Shalliker V.
      • Egger S.
      • Sitas F.
      • Bauman A.
      Physical activity, obesity and sedentary behaviour and the risks of colon and rectal cancers in the 45 and up study.
      ].
      Small intestine cancer is a rare cancer with largely unknown etiology. In a recent pooled analysis including over 800,000 individuals from six European cohort studies, only 195 men and 144 women were diagnosed with small intestine cancer during a median follow-up of 16.9 years [
      • Nagel G.
      • Bjorge T.
      • Jaensch A.
      • Peter R.S.
      • Haggstrom C.
      • Lang A.
      • et al.
      Metabolic factors and the risk of small intestine cancers: pooled study of 800 000 individuals in the metabolic syndrome and cancer project.
      ]. That study found evidence of a possible association between higher BMI and an increased risk of small intestine cancer in men but not in women [
      • Nagel G.
      • Bjorge T.
      • Jaensch A.
      • Peter R.S.
      • Haggstrom C.
      • Lang A.
      • et al.
      Metabolic factors and the risk of small intestine cancers: pooled study of 800 000 individuals in the metabolic syndrome and cancer project.
      ]. Compared with lean men (mean BMI 21.8 kg/m2), the HRs were 1.53 (95 % CI 1.02–2.29) for overweight and 1.31 (95 % CI 0.86–2.00) for obese men [
      • Nagel G.
      • Bjorge T.
      • Jaensch A.
      • Peter R.S.
      • Haggstrom C.
      • Lang A.
      • et al.
      Metabolic factors and the risk of small intestine cancers: pooled study of 800 000 individuals in the metabolic syndrome and cancer project.
      ]. An earlier analysis of data from a cohort study of 498,376 US men and women, including 147 and 90 small intestine cancer cases in men and women, respectively, showed that severe obesity (BMI ≥35 kg/m2) was associated with an increased risk of small intestine cancer (HR 1.77; 95 % CI 1.11–2.82) compared with a normal BMI (<25 kg/m2) [
      • Cross A.J.
      • Hollenbeck A.R.
      • Park Y.
      A large prospective study of risk factors for adenocarcinomas and malignant carcinoid tumors of the small intestine.
      ].
      The relation between BMI in late adolescence and risk of liver (hepatocellular) cancer was investigated in a cohort of 1,220,261 Swedish men, aged 17–19 years, who were followed for a mean period of 28.5 years [
      • Hagstrom H.
      • Tynelius P.
      • Rasmussen F.
      High BMI in late adolescence predicts future severe liver disease and hepatocellular carcinoma: a national, population-based cohort study in 1.2 million men.
      ]. There was a dose-dependent association between BMI in late adolescence and incident liver cancer, with a statically significant 3.6-fold higher risk for men with BMI ≥30 versus 18–22.5 kg/m2 [
      • Hagstrom H.
      • Tynelius P.
      • Rasmussen F.
      High BMI in late adolescence predicts future severe liver disease and hepatocellular carcinoma: a national, population-based cohort study in 1.2 million men.
      ].
      The associations of anthropometric factors with risk of biliary tract cancers were examined in a pooled analysis of data from 27 cohort studies with over 2.7 million adults [
      • Jackson S.S.
      • Van Dyke A.L.
      • Zhu B.
      • Pfeiffer R.M.
      • Petrick J.L.
      • Adami H.O.
      • et al.
      Anthropometric risk factors for cancers of the biliary tract in the biliary tract cancers pooling project.
      ]. That analysis showed that for each 5 kg/m2 increase in BMI, there were risk increases for cancers of the gallbladder (hazard ratio [HR] 1.27; 95 % CI 1.19–1.36), intrahepatic bile ducts (HR 1.32; 95 % CI 1.21–1.45), and extrahepatic bile ducts (HR 1.13; 95 % CI 1.03–1.23) [
      • Jackson S.S.
      • Van Dyke A.L.
      • Zhu B.
      • Pfeiffer R.M.
      • Petrick J.L.
      • Adami H.O.
      • et al.
      Anthropometric risk factors for cancers of the biliary tract in the biliary tract cancers pooling project.
      ].
      The association between BMI and pancreatic cancer mortality was examined in the Cancer Prevention Study II, including 8354 deaths from pancreatic cancer among 963,317 adults [
      • Jacobs E.J.
      • Newton C.C.
      • Patel A.V.
      • Stevens V.L.
      • Islami F.
      • Flanders W.D.
      • et al.
      The association between body mass index and pancreatic cancer: variation by age at body mass index assessment.
      ]. This cohort study found that BMI (per 5 kg/m2 increase) before age 50 years was more strongly associated with risk of pancreatic cancer (HR 1.25; 95 % CI 1.18–1.33) than BMI at older ages at enrollment (HR 1.13; 95 % CI 1.02–1.26, in those aged 70–89 years) [
      • Jacobs E.J.
      • Newton C.C.
      • Patel A.V.
      • Stevens V.L.
      • Islami F.
      • Flanders W.D.
      • et al.
      The association between body mass index and pancreatic cancer: variation by age at body mass index assessment.
      ]. In contrast, in the US Women's Health Initiative cohort, which included 1045 pancreatic cancer cases among 156,218 women, BMI at age 50 years but not at ages 35 or 18 years was significantly positively associated with risk of pancreatic cancer [
      • Arthur R.
      • Kabat G.C.
      • Kim M.Y.
      • Ho G.Y.F.
      • Chlebowski R.T.
      • Pan K.
      • et al.
      Adiposity, history of diabetes, and risk of pancreatic cancer in postmenopausal women.
      ].

      3.2.3 Urinary tract cancers

      A recent pooled analysis of three US cohort studies found that higher BMI was associated with a substantial increased risk of kidney (renal cell) cancer [
      • Graff R.E.
      • Wilson K.M.
      • Sanchez A.
      • Chang S.L.
      • McDermott D.F.
      • Choueiri T.K.
      • et al.
      Obesity in relation to renal cell carcinoma incidence and survival in three prospective studies.
      ]. The overall HR was 2.16 (95 % CI 1.77–2.63) for BMI ≥30 versus 18–25 kg/m2 [
      • Graff R.E.
      • Wilson K.M.
      • Sanchez A.
      • Chang S.L.
      • McDermott D.F.
      • Choueiri T.K.
      • et al.
      Obesity in relation to renal cell carcinoma incidence and survival in three prospective studies.
      ].
      With respect to bladder cancer, a study based on three Swedish cohorts, including 4895 incident bladder cancer cases diagnosed among 338,910 men, BMI was positively associated with any non-muscle invasive bladder cancer (HR per 5 kg/m2 increase 1.10; 95 % CI 1.02–1.19), with a stronger association for grade 3 (corresponding HR 1.17; 95 % CI 1.01–1.34) [
      • Teleka S.
      • Jochems S.H.J.
      • Haggstrom C.
      • Wood A.M.
      • Jarvholm B.
      • Orho-Melander M.
      • et al.
      Association between blood pressure and BMI with bladder cancer risk and mortality in 340,000 men in three Swedish cohorts.
      ]. Another study including 811,633 participants from six European cohorts found that BMI was positively associated with risk of non-muscle invasive bladder cancer in men (HR per standard deviation increase 1.09; 95 % CI 1.01–1.18) but inversely associated with risk of any bladder cancer in women (HR per standard deviation increase 0.90; 95 % CI 0.82–0.99) [
      • Teleka S.
      • Haggstrom C.
      • Nagel G.
      • Bjorge T.
      • Manjer J.
      • Ulmer H.
      • et al.
      Risk of bladder cancer by disease severity in relation to metabolic factors and smoking: a prospective pooled cohort study of 800,000 men and women.
      ]. No association between BMI and overall bladder cancer risk was observed in the Janus Cohort, comprising 292,851 Norwegian adults [
      • Hektoen H.H.
      • Robsahm T.E.
      • Andreassen B.K.
      • Stenehjem J.S.
      • Axcrona K.
      • Mondul A.
      • et al.
      Lifestyle associated factors and risk of urinary bladder cancer: a prospective cohort study from Norway.
      ].

      3.2.4 Sex hormone-related cancers

      Among 108,136 postmenopausal women in the US Women's Health Initiative cohort, the risk of endometrial cancer increased with increasing BMI categories, with an over 3-fold higher risk for BMI ≥40 kg/m2 versus BMI <25 kg/m2 [
      • Arthur R.
      • Brasky T.M.
      • Crane T.E.
      • Felix A.S.
      • Kaunitz A.M.
      • Shadyab A.H.
      • et al.
      Associations of a healthy lifestyle index with the risks of endometrial and ovarian cancer among women in the Women's Health Initiative study.
      ]. There was a corresponding non-significant 29 % increased relative risk of ovarian cancer [
      • Arthur R.
      • Brasky T.M.
      • Crane T.E.
      • Felix A.S.
      • Kaunitz A.M.
      • Shadyab A.H.
      • et al.
      Associations of a healthy lifestyle index with the risks of endometrial and ovarian cancer among women in the Women's Health Initiative study.
      ].
      In a recent pooled analysis of 20 cohort studies, including 36,297 breast cancer cases among 1,061,915 women, BMI at cohort baseline was strongly inversely associated with risk of premenopausal breast cancer and strongly positively and nonlinearly associated with risk of postmenopausal breast cancer, particularly among women who had never used postmenopausal hormone therapy [
      • van den Brandt P.A.
      • Ziegler R.G.
      • Wang M.
      • Hou T.
      • Li R.
      • Adami H.O.
      • et al.
      Body size and weight change over adulthood and risk of breast cancer by menopausal and hormone receptor status: a pooled analysis of 20 prospective cohort studies.
      ]. These associations were mainly observed for receptor-positive tumor subtypes. Early adult BMI (at 18–20 years) was inversely associated with both premenopausal and postmenopausal breast cancer risk (21 % and 11 % risk reduction, respectively, per 5 kg/m2 increment of BMI) with stronger associations for receptor-negative tumor subtypes [
      • van den Brandt P.A.
      • Ziegler R.G.
      • Wang M.
      • Hou T.
      • Li R.
      • Adami H.O.
      • et al.
      Body size and weight change over adulthood and risk of breast cancer by menopausal and hormone receptor status: a pooled analysis of 20 prospective cohort studies.
      ].
      For prostate cancer mortality, a recent meta-analysis of 19 cohort studies found a combined HR of dying from prostate cancer (19,633 prostate cancer deaths) of 1.10 (95 % CI 1.07–1.12) for each 5 kg/m2 increment of BMI [
      • Perez-Cornago A.
      • Dunneram Y.
      • Watts E.L.
      • Key T.J.
      • Travis R.C.
      Adiposity and risk of prostate cancer death: a prospective analysis in UK biobank and meta-analysis of published studies.
      ]. Weaker associations were found for other adiposity markers [
      • Perez-Cornago A.
      • Dunneram Y.
      • Watts E.L.
      • Key T.J.
      • Travis R.C.
      Adiposity and risk of prostate cancer death: a prospective analysis in UK biobank and meta-analysis of published studies.
      ].

      3.2.5 Hematologic cancers

      A couple of recent pooled analyses of six US cohort studies have reported results on the association between body fatness and risk of multiple myeloma and non-Hodgkin's lymphoma [
      • Bertrand K.A.
      • Teras L.R.
      • Deubler E.L.
      • Chao C.R.
      • Rosner B.A.
      • Wang K.
      • et al.
      Anthropometric traits and risk of multiple myeloma: a pooled prospective analysis.
      ,
      • Teras L.R.
      • Bertrand K.A.
      • Deubler E.L.
      • Chao C.R.
      • Lacey Jr., J.V.
      • Patel A.V.
      • et al.
      Body size and risk of non-Hodgkin lymphoma by subtype: a pooled analysis from six prospective cohorts in the United States.
      ]. In a pooled analysis with 2756 incident multiple myeloma cases diagnosed among 544,016 US adults, each 5 kg/m2 increment in adult BMI was associated with a statistically significant 10 % increased risk of multiple myeloma [
      • Bertrand K.A.
      • Teras L.R.
      • Deubler E.L.
      • Chao C.R.
      • Rosner B.A.
      • Wang K.
      • et al.
      Anthropometric traits and risk of multiple myeloma: a pooled prospective analysis.
      ]. Another pooled analysis with 11,263 incident non-Hodgkin's lymphoma cases diagnosed among 568,717 US adults found no dose-response relationship between usual adult BMI and risk of non-Hodgkin's lymphoma (HR per 5 kg/m2 increase in BMI 1.01; 95 % CI 0.99–1.03) but found a statistically significant 20 % increased risk in those with severe obesity (BMI ≥40 kg/m2) compared with normal-weight adults (BMI 18.5–22.9 kg/m2) [
      • Teras L.R.
      • Bertrand K.A.
      • Deubler E.L.
      • Chao C.R.
      • Lacey Jr., J.V.
      • Patel A.V.
      • et al.
      Body size and risk of non-Hodgkin lymphoma by subtype: a pooled analysis from six prospective cohorts in the United States.
      ]. Moreover, BMI in young adulthood was associated with a statistically significant 14 % increased risk of non-Hodgkin's lymphoma per 5 kg/m2 increment in BMI [
      • Teras L.R.
      • Bertrand K.A.
      • Deubler E.L.
      • Chao C.R.
      • Lacey Jr., J.V.
      • Patel A.V.
      • et al.
      Body size and risk of non-Hodgkin lymphoma by subtype: a pooled analysis from six prospective cohorts in the United States.
      ].
      The association between BMI and leukemia risk was investigated in the Cancer Prevention Study II, which included 387 acute myeloid leukemias, 100 chronic myeloid leukemias, and 170 myelodysplastic syndromes diagnosed among 152,090 US adults over 21 years of follow-up [
      • Teras L.R.
      • Patel A.V.
      • Carter B.D.
      • Rees-Punia E.
      • McCullough M.L.
      • Gapstur S.M.
      Anthropometric factors and risk of myeloid leukaemias and myelodysplastic syndromes: a prospective study and meta-analysis.
      ]. No significant associations were observed [
      • Teras L.R.
      • Patel A.V.
      • Carter B.D.
      • Rees-Punia E.
      • McCullough M.L.
      • Gapstur S.M.
      Anthropometric factors and risk of myeloid leukaemias and myelodysplastic syndromes: a prospective study and meta-analysis.
      ].
      A cohort study based on primary care data from the United Kingdom's Clinical Practice Research Datalink, including 5.8 million adults of whom 927 developed Hodgkin's lymphoma during 41.6 million years of follow-up, found that each 5 kg/m2 increase in BMI was associated with a statistically significant 10 % increase in Hodgkin's lymphoma risk [
      • Strongman H.
      • Brown A.
      • Smeeth L.
      • Bhaskaran K.
      Body mass index and Hodgkin's lymphoma: UK population-based cohort study of 5.8 million individuals.
      ]. The non-linear analysis suggested a J-shaped association, with risk increasing at BMI above 24.2 kg/m2 [
      • Strongman H.
      • Brown A.
      • Smeeth L.
      • Bhaskaran K.
      Body mass index and Hodgkin's lymphoma: UK population-based cohort study of 5.8 million individuals.
      ].

      3.2.6 Other cancers

      A population-based cohort study consisting of 1.7 million Norwegian adults identified 857 primary tumors of the spinal cord, spinal meninges, spinal and peripheral nerves during 49 million person-years of follow-up [
      • Gheorghiu A.
      • Brunborg C.
      • Johannesen T.B.
      • Helseth E.
      • Zwart J.A.
      • Wiedmann M.K.H.
      The impact of body mass index and height on risk for primary tumours of the spinal cord, spinal meninges, spinal and peripheral nerves in 1.7 million Norwegian women and men: a prospective cohort study.
      ]. This study did not identify overweight and obesity as risk factors for primary tumors of the spinal cord, spinal meninges, spinal and peripheral nerves in women or men [
      • Gheorghiu A.
      • Brunborg C.
      • Johannesen T.B.
      • Helseth E.
      • Zwart J.A.
      • Wiedmann M.K.H.
      The impact of body mass index and height on risk for primary tumours of the spinal cord, spinal meninges, spinal and peripheral nerves in 1.7 million Norwegian women and men: a prospective cohort study.
      ].
      In a pooled analysis of cohort studies involving 1.6 million Americans, Europeans, and Asians of which 23,732 were diagnosed with lung cancer, BMI was inversely associated with lung cancer risk after removing the first five years of follow-up [
      • Yu D.
      • Zheng W.
      • Johansson M.
      • Lan Q.
      • Park Y.
      • White E.
      • et al.
      Overall and central obesity and risk of lung cancer: a pooled analysis.
      ]. The HRs per 5 kg/m2 increment in BMI were 0.95 (95 % CI 0.90–1.00) in never smokers, 0.92 (95 % CI 0.89–0.95) in former smokers, and 0.89 (95 % CI 0.86–0.91) and current smokers [
      • Yu D.
      • Zheng W.
      • Johansson M.
      • Lan Q.
      • Park Y.
      • White E.
      • et al.
      Overall and central obesity and risk of lung cancer: a pooled analysis.
      ].

      3.2.7 BMI and cancer in Asian populations

      Results from the Asia Cohort Consortium, including several cohort studies with over a half a million adults from southern and eastern Asia, showed U-shaped associations of BMI with esophageal cancer mortality [
      • Lee S.
      • Jang J.
      • Abe S.K.
      • Rahman S.
      • Saito E.
      • Islam R.
      • et al.
      Association between body mass index and oesophageal cancer mortality: a pooled analysis of prospective cohort studies with >800 000 individuals in the Asia Cohort Consortium.
      ] and stomach cancer incidence [
      • Jang J.
      • Lee S.
      • Ko K.P.
      • Abe S.K.
      • Rahman M.S.
      • Saito E.
      • et al.
      Association between body mass index and risk of gastric cancer by anatomical and histological subtypes in over 500,000 east and southeast Asian cohort participants.
      ]. In the same consortium, a dose-dependent association between BMI and multiple myeloma mortality was observed; the HR for BMI ≥30 kg/m2 versus 25–29.9 kg/m2 was 1.61 (95 % CI 0.99–2.64) [
      • Ugai T.
      • Ito H.
      • Oze I.
      • Saito E.
      • Rahman M.S.
      • Boffetta P.
      • et al.
      Association of BMI, smoking, and alcohol with multiple myeloma mortality in Asians: a pooled analysis of more than 800,000 participants in the Asia Cohort Consortium.
      ]. Other studies based on the Asia Cohort Consortium showed a linear association between BMI and thyroid cancer incidence in men (HR per 5 kg/m2 increase 1.25; 95 % CI 1.10–1.55) but not in women (corresponding HR 1.07; 95 % CI 0.97–1.18) [
      • Shin A.
      • Cho S.
      • Jang D.
      • Abe S.K.
      • Saito E.
      • Rahman M.S.
      • et al.
      Body mass index and thyroid cancer risk: a pooled analysis of half a million men and women in the Asia Cohort Consortium.
      ], and no clear association between BMI and mortality from pancreatic [
      • Lin Y.
      • Fu R.
      • Grant E.
      • Chen Y.
      • Lee J.E.
      • Gupta P.C.
      • et al.
      Association of body mass index and risk of death from pancreas cancer in Asians: findings from the Asia Cohort Consortium.
      ] and prostate cancer [
      • Fowke J.H.
      • McLerran D.F.
      • Gupta P.C.
      • He J.
      • Shu X.O.
      • Ramadas K.
      • et al.
      Associations of body mass index, smoking, and alcohol consumption with prostate cancer mortality in the Asia Cohort Consortium.
      ].
      The association between body fatness and risk of 15 major cancers were examined in the China Kadoorie Biobank study, which included half a million adults with a mean BMI of 23.7 kg/m2 [
      • Wang L.
      • Jin G.
      • Yu C.
      • Lv J.
      • Guo Y.
      • Bian Z.
      • et al.
      Cancer incidence in relation to body fatness among 0.5 million men and women: findings from the China Kadoorie Biobank.
      ]. Each 5 kg/m2 increase in BMI was associated with increased risk of colorectal (HR 1.17; 95 % CI 1.10–1.25), endometrial (HR 2.01; 95 % CI 1.72–2.35), postmenopausal breast (HR 1.29; 95 % CI 1.18–1.40), and cervical (HR, 1.15; 95 % CI, 1.03–1.29) cancer, whereas it was associated with a reduced risk of esophageal (HR 0.73; 95 % CI 0.67–0.79), gastric (HR 0.88; 95 % CI 0.82–0.94), liver (HR 0.85; 95 % CI 0.79–0.92), and lung (HR 0.78; 95 % CI 0.74–0.82) cancer [
      • Wang L.
      • Jin G.
      • Yu C.
      • Lv J.
      • Guo Y.
      • Bian Z.
      • et al.
      Cancer incidence in relation to body fatness among 0.5 million men and women: findings from the China Kadoorie Biobank.
      ]. In the same cohort, no association was observed between BMI and small intestine cancer (HR per standard deviation increase 1.06; 95 % CI 0.89–1.25) [
      • Pang Y.
      • Kartsonaki C.
      • Guo Y.
      • Chen Y.
      • Yang L.
      • Bian Z.
      • et al.
      Adiposity and risks of colorectal and small intestine cancer in Chinese adults: a prospective study of 0.5 million people.
      ].
      The associations between BMI and risk of stomach, liver (hepatocellular), pancreatic, and kidney cancer have been examined in studies based on the Korean National Health Insurance database, which included between 2.6 million [
      • Lim J.H.
      • Shin C.M.
      • Han K.D.
      • Lee S.W.
      • Jin E.H.
      • Choi Y.J.
      • et al.
      Association between the persistence of obesity and the risk of gastric cancer: a nationwide population-based study.
      ] to 23.3 million adults [
      • Nam G.E.
      • Cho K.H.
      • Han K.
      • Kim C.M.
      • Han B.
      • Cho S.J.
      • et al.
      Obesity, abdominal obesity and subsequent risk of kidney cancer: a cohort study of 23.3 million east Asians.
      ]. These studies found statistically significant associations; compared with normal-weight individuals, the risk of stomach cancer (n = 13,441 cases) was 20 % higher in those with BMI ≥25 kg/m2, liver cancer (n = 47,308 cases) risk was over 2-fold higher in those with BMI ≥31 kg/m2 [
      • Jun B.G.
      • Kim M.
      • Shin H.S.
      • Yi J.J.
      • Yi S.W.
      Impact of overweight and obesity on the risk of hepatocellular carcinoma: a prospective cohort study in 14.3 million Koreans.
      ], pancreatic cancer (n = 22,543 cases) risk was 16 % higher in those with BMI ≥28kg/m2 [
      • Park B.K.
      • Seo J.H.
      • Chung J.B.
      • Choi J.K.
      Lifestyle, body mass index, diabetes, and the risk of pancreatic cancer in a nationwide population-based cohort study with 7.4 million Korean subjects.
      ], and kidney cancer (n = 18,036 cases) risk was 77 % higher in those with BMI ≥30 kg/m2 [
      • Nam G.E.
      • Cho K.H.
      • Han K.
      • Kim C.M.
      • Han B.
      • Cho S.J.
      • et al.
      Obesity, abdominal obesity and subsequent risk of kidney cancer: a cohort study of 23.3 million east Asians.
      ]. Another report based on this database showed an over 2-fold increased risk of kidney cancer in those with prolonged obesity [
      • Park Y.H.
      • Moon H.W.
      • Cho H.J.
      • Ha U.S.
      • Hong S.H.
      • Lee J.Y.
      • et al.
      Cumulative obesity exposure increases the risk of kidney cancer: a longitudinal nationwide cohort study.
      ]. Moreover, data from the same database found that compared with BMI 18.5–23 kg/m2, low BMI (<18.5 kg/m2), but not overweight or obesity, was associated with a statistically significant increased risk of head and neck cancers [
      • Kim C.S.
      • Park J.O.
      • Nam I.C.
      • Park S.J.
      • Lee D.H.
      • Kim H.B.
      • et al.
      Associations of body mass index and waist circumference with the risk of head and neck cancer: a national population-based study.
      ]. In another Korean cohort, including 255,051 adults, BMI ≥25 kg/m2 versus BMI 18.5–22.9 kg/m2 was associated with a statistically significant increased risk of thyroid cancer in both metabolic healthy and metabolic unhealthy men and with risk of thyroid cancer in metabolic unhealthy women [
      • Kwon H.
      • Chang Y.
      • Cho A.
      • Ahn J.
      • Park S.E.
      • Park C.Y.
      • et al.
      Metabolic obesity phenotypes and thyroid cancer risk: a cohort study.
      ].

      3.3 Evidence from Mendelian randomization studies

      The associations of genetically predicted BMI, as a proxy for lifelong BMI, in relation to cancer risk have been investigated in several MR studies published during the last few years. In MR analysis, genetic variants that are reliably associated with the exposure (e.g., BMI) are used as instrumental variables to decipher whether the exposure has a causal relationship with the outcome (e.g., cancer) [
      • Davey Smith G.
      • Hemani G.
      Mendelian randomization: genetic anchors for causal inference in epidemiological studies.
      ,
      • Larsson S.C.
      Mendelian randomization as a tool for causal inference in human nutrition and metabolism.
      ]. People who inherit genetic alleles that associate with higher BMI will on average have higher BMI than people who inherit alleles that associate with lower BMI. As genetic alleles are normally passed from parents to offspring independently of environmental factors and are largely unchanged by disease development (except for mutations in specific cancer genes), the MR design diminishes biases that are common in conventional observational studies, such as confounding and reverse causation bias [
      • Davey Smith G.
      • Hemani G.
      Mendelian randomization: genetic anchors for causal inference in epidemiological studies.
      ,
      • Larsson S.C.
      Mendelian randomization as a tool for causal inference in human nutrition and metabolism.
      ].
      MR studies of the association of genetically predicted BMI with site-specific cancers have confirmed the association between higher BMI and increased risk of cancer at several sites [
      • Larsson S.C.
      • Burgess S.
      Causal role of high body mass index in multiple chronic diseases: a systematic review and meta-analysis of Mendelian randomization studies.
      ]. Specifically, a meta-analysis of MR studies showed that genetically predicted higher BMI was associated with an increased risk of digestive system cancers (including esophageal, stomach, colorectal, liver, gallbladder, and pancreatic cancers) as well as cancers of the kidney, corpus uteri, and ovaries [
      • Larsson S.C.
      • Burgess S.
      Causal role of high body mass index in multiple chronic diseases: a systematic review and meta-analysis of Mendelian randomization studies.
      ] (Fig. 1). The odds ratio (OR) per one standard deviation increment in BMI (~5 kg/m2) was 1.75 (95 % CI 1.26–2.44; I2 = 14 %; n = 3 studies) for esophageal cancer, 1.09 (95 % CI 1.04–1.15; I2 = 83 %; n = 3 studies) for stomach cancer, 1.08 (95 % CI 1.05–1.12; I2 = 0 %; n = 5 studies) for colorectal cancer, 1.62 (95 % CI 1.19–2.21; I2 = 0 %; n = 3 studies) for liver cancer, 1.50 (95 % CI 1.06–2.13; I2 = 4 %; n = 3 studies) for gallbladder cancer, 1.36 (95 % CI 1.20–1.55; I2 = 0 %; n = 3 studies) for pancreatic cancer, 1.49 (95 % CI 1.38–1.60; I2 = 64 %; n = 4 studies) for kidney cancer, 1.49 (95 % CI 1.38–1.61; I2 = 90 %; n = 3 studies) for endometrial cancer, and 1.09 (95 % CI 1.00–1.18; I2 = 32 %; n = 4 studies) for ovarian cancer (Fig. 1). The moderate to strong heterogeneity in the analyses of stomach, kidney, and endometrial cancer was caused by different magnitude of the positive association. The overall evidence from MR studies suggests possible associations between higher BMI and increased risk of multiple myeloma (OR 1.10; 95 % CI 0.99–1.21; n = 3 studies; heterogeneity: I2 = 0 %), non-Hodgkin's lymphoma (OR 1.15; 95 % CI 0.99–1.33; n = 2 studies; heterogeneity: I2 = 0 %), and lung cancer (OR 1.09; 95 % CI 0.99–1.15; n = 4 studies; heterogeneity: I2 = 90 %). There were also positive associations between genetically predicted BMI and risk of cervical (OR 1.13; 95 % CI 1.01–1.27; I2 = 90 %; n = 3 studies) and urinary bladder cancer (OR 1.27; 95 % CI 1.03–1.50; I2 = 78 %; n = 3 studies) but these associations were driven by a single study (the FinnGen Study) [
      • Larsson S.C.
      • Burgess S.
      Causal role of high body mass index in multiple chronic diseases: a systematic review and meta-analysis of Mendelian randomization studies.
      ]. Genetically predicted higher BMI was associated with a decreased risk of total breast and prostate cancer, with ORs of 0.87 (95 % CI 0.82–0.92; I2 = 57 %; n = 5 studies) and 0.90 (95 % CI 0.84–0.96; I2 = 1 %; n = 4 studies), respectively [
      • Larsson S.C.
      • Burgess S.
      Causal role of high body mass index in multiple chronic diseases: a systematic review and meta-analysis of Mendelian randomization studies.
      ] (Fig. 1). For breast cancer, genetically predicted higher BMI was associated with a reduced risk of both estrogen receptor positive and estrogen receptor negative tumors [
      • Vithayathil M.
      • Carter P.
      • Kar S.
      • Mason A.M.
      • Burgess S.
      • Larsson S.C.
      Body size and composition and risk of site-specific cancers in the UK Biobank and large international consortia: a mendelian randomisation study.
      ]. There was also an inverse association between genetically predicted BMI and non-melanoma skin cancer (OR 0.86 (95 % CI 0.77–0.95); I2 = 0 %; n = 2 studies) [
      • Larsson S.C.
      • Burgess S.
      Causal role of high body mass index in multiple chronic diseases: a systematic review and meta-analysis of Mendelian randomization studies.
      ]. Meta-analysis results of two MR studies, including a total of 586,353 UK and Finnish individuals, showed no association of genetically predicted BMI with risk of head and neck cancer (OR 0.96; 95 % CI 0.77–1.19; I2 = 82 %), thyroid cancer (OR 0.96; 95 % CI 0.73–1.27; I2 = 0 %), and leukemia (OR 1.14; 95 % CI 0.95–1.39; I2 = 54 %), or with testicular cancer (OR 0.96; 95 % CI 0.68–1.34; I2 = 0 %) among 263,949 UK and Finnish men [
      • Larsson S.C.
      • Burgess S.
      Causal role of high body mass index in multiple chronic diseases: a systematic review and meta-analysis of Mendelian randomization studies.
      ]. A recent MR study found no association between BMI and glioma risk [
      • Saunders C.N.
      • Cornish A.J.
      • Kinnersley B.
      • Law P.J.
      • Claus E.B.
      • Il'yasova D.
      • et al.
      Lack of association between modifiable exposures and glioma risk: a mendelian randomization analysis.
      ].

      4. Biological mechanisms

      Excess body fatness is associated with considerable metabolic and endocrine aberrations that can contribute to cancer development and progression. There are several connected pathways whereby excess body fatness may increase cancer risk. The most credible biological mechanisms are via alterations in circulating levels of adiponectin and other adipocytokines and chronic low-grade inflammation; elevated levels of insulin and insulin-like growth factor I (IGF-I); and increased levels and bioavailability of sex hormones. Other emerging yet unestablished biological mechanisms that might contribute to the obesity-cancer relations include alterations in the gut microbiome and gut hormones.

      4.1 Adipocytokines and low-grade inflammation

      Obesity and more specifically central obesity is related to chronic low-grade inflammation [
      • Ouchi N.
      • Parker J.L.
      • Lugus J.J.
      • Walsh K.
      Adipokines in inflammation and metabolic disease.
      ], which is an important hallmark of cancer development and progression [
      • Colotta F.
      • Allavena P.
      • Sica A.
      • Garlanda C.
      • Mantovani A.
      Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability.
      ,
      • Crusz S.M.
      • Balkwill F.R.
      Inflammation and cancer: advances and new agents.
      ]. Adipose tissue is an active endocrine organ that secretes many adipocytokines (also called adipokines), a collective term for hormones and cytokines that are mainly albeit not exclusively derived from the adipose tissue [
      • Ouchi N.
      • Parker J.L.
      • Lugus J.J.
      • Walsh K.
      Adipokines in inflammation and metabolic disease.
      ,
      • Tilg H.
      • Moschen A.R.
      Adipocytokines: mediators linking adipose tissue, inflammation and immunity.
      ,
      • Waki H.
      • Tontonoz P.
      Endocrine functions of adipose tissue.
      ]. Adiponectin is the most abundant and most widely studied adipocytokine that along with other adipocytokines are thought to provide a key link between obesity, insulin resistance, and related inflammatory disorders [
      • Ouchi N.
      • Parker J.L.
      • Lugus J.J.
      • Walsh K.
      Adipokines in inflammation and metabolic disease.
      ,
      • Tilg H.
      • Moschen A.R.
      Adipocytokines: mediators linking adipose tissue, inflammation and immunity.
      ,
      • Boutari C.
      • Mantzoros C.S.
      Inflammation: a key player linking obesity with malignancies.
      ]. Adiponectin, a 30kDa cytokine and member of the C1q/TNF superfamily, was first described by several groups in the mid-1990s [
      • Straub L.G.
      • Scherer P.E.
      Metabolic messengers: adiponectin.
      ]. It exerts a multitude of effects on numerous tissues, including the liver, kidney, pancreas, blood vessels, nervous system, bone and immune cells and is subsequently cleared by the liver [
      • Straub L.G.
      • Scherer P.E.
      Metabolic messengers: adiponectin.
      ]. Adiponectin effects are mediated by adiponectin receptor 1 and 2 (AdipoR1, AdipoR2) and T-cadherin [
      • Wang Y.
      • Lam K.S.L.
      • Xu J.Y.
      • Lu G.
      • Xu L.Y.
      • Cooper G.J.S.
      • et al.
      Adiponectin inhibits cell proliferation by interacting with several growth factors in an oligomerization-dependent manner*.
      ,
      • Yamauchi T.
      • Kamon J.
      • Ito Y.
      • Tsuchida A.
      • Yokomizo T.
      • Kita S.
      • et al.
      Cloning of adiponectin receptors that mediate antidiabetic metabolic effects.
      ]. Adiponectin receptors are ubiquitously expressed in healthy tissues as well as in malignant cells [
      • Dalamaga M.
      • Diakopoulos K.N.
      • Mantzoros C.S.
      The role of adiponectin in cancer: a review of current evidence.
      ].
      Although adiponectin is primarily produced in adipose tissue, it stands out from the other adipocytokines as it circulates in very high levels in relation to other adipocytokines and is inversely correlated with fat mass, especially central obesity [
      • Arita Y.
      • Kihara S.
      • Ouchi N.
      • Takahashi M.
      • Maeda K.
      • Miyagawa J.
      • et al.
      Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity.
      ,
      • Cnop M.
      • Havel P.J.
      • Utzschneider K.M.
      • Carr D.B.
      • Sinha M.K.
      • Boyko E.J.
      • et al.
      Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex.
      ,
      • Goudswaard L.J.
      • Bell J.A.
      • Hughes D.A.
      • Corbin L.J.
      • Walter K.
      • Davey Smith G.
      • et al.
      Effects of adiposity on the human plasma proteome: observational and mendelian randomisation estimates.
      ]. Normally, adiponectin is produced by the fat tissue and facilitates energy expenditure and tissue insulin sensitivity. In the setting of obesity, intrabdominal and ectopic fat distribution, tissue hypoxia induces a body wide chronic inflammatory state that perturbs the physiologic adipokine secretion leading to lower adiponectin levels [
      • Tarasiuk A.
      • Mosińska P.
      • Fichna J.
      The mechanisms linking obesity to colon cancer: an overview.
      ]. Serum adiponectin levels are inversely associated with body fatness and are not affected by acute fasting [
      • Gavrila A.
      • Chan J.L.
      • Yiannakouris N.
      • Kontogianni M.
      • Miller L.C.
      • Orlova C.
      • et al.
      Serum adiponectin levels are inversely associated with overall and central fat distribution but are not directly regulated by acute fasting or leptin administration in humans: cross-sectional and interventional studies.
      ]. Hypoadiponectinemia results in dysregulation of IGFs, chronic low-grade inflammation, sex hormone imbalance, and ultimately promotion of malignant transformation [
      • Dalamaga M.
      • Diakopoulos K.N.
      • Mantzoros C.S.
      The role of adiponectin in cancer: a review of current evidence.
      ,
      • Barb D.
      • Pazaitou-Panayiotou K.
      • Mantzoros C.S.
      Adiponectin: a link between obesity and cancer.
      ]. Evidence from observational studies links hypoadiponectinemia with increased risk of several obesity-related malignancies, including colorectal [
      • Wei E.K.
      • Giovannucci E.
      • Fuchs C.S.
      • Willett W.C.
      • Mantzoros C.S.
      Low plasma adiponectin levels and risk of colorectal cancer in men: a prospective study.
      ,
      • Otani K.
      • Ishihara S.
      • Yamaguchi H.
      • Murono K.
      • Yasuda K.
      • Nishikawa T.
      • et al.
      Adiponectin and colorectal cancer.
      ,
      • Wei E.K.
      • Giovannucci E.
      • Fuchs C.S.
      • Willett W.C.
      • Mantzoros C.S.
      Low plasma adiponectin levels and risk of colorectal cancer in men: a prospective study.
      ], stomach [
      • Ishikawa M.
      • Kitayama J.
      • Kazama S.
      • Hiramatsu T.
      • Hatano K.
      • Nagawa H.
      Plasma adiponectin and gastric cancer.
      ], liver [
      • Zhang L.
      • Yuan Q.
      • Li M.
      • Chai D.
      • Deng W.
      • Wang W.
      The association of leptin and adiponectin with hepatocellular carcinoma risk and prognosis: a combination of traditional, survival, and dose-response meta-analysis.
      ], kidney [
      • Spyridopoulos T.N.
      • Petridou E.T.
      • Skalkidou A.
      • Dessypris N.
      • Chrousos G.P.
      • Mantzoros C.S.
      Low adiponectin levels are associated with renal cell carcinoma: a case-control study.
      ,
      • Fang J.
      • Xu X.
      • Mao Q.
      • Ying Y.
      • Zhang X.
      • Xie L.
      Lower circulating adiponectin is associated with higher risk of renal cell carcinoma: a meta-analysis.
      ,
      • Yap N.Y.
      • Yap F.N.
      • Perumal K.
      • Rajandram R.
      Circulating adiponectin as a biomarker in renal cell carcinoma: a systematic review and meta-analysis.
      ], endometrial [
      • Petridou E.
      • Mantzoros C.
      • Dessypris N.
      • Koukoulomatis P.
      • Addy C.
      • Voulgaris Z.
      • et al.
      Plasma adiponectin concentrations in relation to endometrial cancer: a case-control study in Greece.
      ,
      • Dal Maso L.
      • Augustin L.S.
      • Karalis A.
      • Talamini R.
      • Franceschi S.
      • Trichopoulos D.
      • et al.
      Circulating adiponectin and endometrial cancer risk.
      ,
      • Zeng F.
      • Shi J.
      • Long Y.
      • Tian H.
      • Li X.
      • Zhao A.Z.
      • et al.
      Adiponectin and endometrial cancer: a systematic review and meta-analysis.
      ], ovarian [
      • Li H.
      • Sun L.
      • Chen L.
      • Kang Z.
      • Hao G.
      • Bai F.
      Effects of adiponectin, plasma D-dimer, inflammation and tumor markers on clinical characteristics and prognosis of patients with ovarian cancer.
      ], and breast cancer [
      • Körner A.
      • Pazaitou-Panayiotou K.
      • Kelesidis T.
      • Kelesidis I.
      • Williams C.J.
      • Kaprara A.
      • et al.
      Total and high-molecular-weight adiponectin in breast cancer: in vitro and in vivo studies.
      ,
      • Gu L.
      • Cao C.
      • Fu J.
      • Li Q.
      • Li D.H.
      • Chen M.Y.
      Serum adiponectin in breast cancer: a meta-analysis.
      ,
      • Dalamaga M.
      • Karmaniolas K.
      • Papadavid E.
      • Pelekanos N.
      • Sotiropoulos G.
      • Lekka A.
      Elevated serum visfatin/nicotinamide phosphoribosyl-transferase levels are associated with risk of postmenopausal breast cancer independently from adiponectin, leptin, and anthropometric and metabolic parameters.
      ]. Adiponectin has been inversely associated with postmenopausal but not premenopausal breast cancer, independently of BMI or other known breast cancer risk factors [
      • Mantzoros C.
      • Petridou E.
      • Dessypris N.
      • Chavelas C.
      • Dalamaga M.
      • Alexe D.M.
      • et al.
      Adiponectin and breast cancer risk.
      ]. Interestingly, AdipoR1 has been found to be higher expressed in breast tumor tissue than adjacent and control tissues [
      • Körner A.
      • Pazaitou-Panayiotou K.
      • Kelesidis T.
      • Kelesidis I.
      • Williams C.J.
      • Kaprara A.
      • et al.
      Total and high-molecular-weight adiponectin in breast cancer: in vitro and in vivo studies.
      ]. Higher breast cancer risk has also been associated with genetic variants of the AdipoR1 that confer decreased adiponectin signaling [
      • Kaklamani V.G.
      • Sadim M.
      • Hsi A.
      • Offit K.
      • Oddoux C.
      • Ostrer H.
      • et al.
      Variants of the adiponectin and adiponectin receptor 1 genes and breast cancer risk.
      ]. Besides high risk for malignancy, low serum adiponectin has been linked to increased numbers and size of tumor foci in colorectal cancer [
      • Otake S.
      • Takeda H.
      • Fujishima S.
      • Fukui T.
      • Orii T.
      • Sato T.
      • et al.
      Decreased levels of plasma adiponectin associated with increased risk of colorectal cancer.
      ], increased malignancy stage in stomach cancer [
      • Ishikawa M.
      • Kitayama J.
      • Kazama S.
      • Hiramatsu T.
      • Hatano K.
      • Nagawa H.
      Plasma adiponectin and gastric cancer.
      ], and more aggressive phenotype in breast cancer [
      • Dalamaga M.
      • Diakopoulos K.N.
      • Mantzoros C.S.
      The role of adiponectin in cancer: a review of current evidence.
      ].
      Adiponectin can influence cancer tissues through its receptors that have been shown to be widely in several cancers linked to obesity. Colorectal carcinoma cell lines display growth inhibition in the presence of adiponectin, and this effect is potentiated by glucose deprivation [
      • Świerczyński M.
      • Szymaszkiewicz A.
      • Fichna J.
      • Zielińska M.
      New insights into molecular pathways in colorectal cancer: adiponectin, interleukin-6 and opioid signaling.
      ,
      • Nigro E.
      • Schettino P.
      • Polito R.
      • Scudiero O.
      • Monaco M.L.
      • De Palma G.D.
      • et al.
      Adiponectin and colon cancer: evidence for inhibitory effects on viability and migration of human colorectal cell lines.
      ]. Adiponectin has been shown to exert in vitro antitumor effects in esophageal [
      • Konturek P.C.
      • Burnat G.
      • Rau T.
      • Hahn E.G.
      • Konturek S.
      Effect of adiponectin and ghrelin on apoptosis of Barrett adenocarcinoma cell line.
      ,
      • Schlottmann F.
      • Dreifuss N.H.
      • Patti M.G.
      Obesity and esophageal cancer: GERD, Barrett's esophagus, and molecular carcinogenic pathways.
      ,
      • Beales I.L.P.
      • Garcia-Morales C.
      • Ogunwobi O.O.
      • Mutungi G.
      Adiponectin inhibits leptin-induced oncogenic signalling in oesophageal cancer cells by activation of PTP1B.
      ], stomach [
      • Ishikawa M.
      • Kitayama J.
      • Yamauchi T.
      • Kadowaki T.
      • Maki T.
      • Miyato H.
      • et al.
      Adiponectin inhibits the growth and peritoneal metastasis of gastric cancer through its specific membrane receptors AdipoR1 and AdipoR2.
      ], hepatocellular [
      • Saxena N.K.
      • Fu P.P.
      • Nagalingam A.
      • Wang J.
      • Handy J.
      • Cohen C.
      • et al.
      Adiponectin modulates C-jun N-terminal kinase and mammalian target of rapamycin and inhibits hepatocellular carcinoma.
      ], endometrial [
      • Cong L.
      • Gasser J.
      • Zhao J.
      • Yang B.
      • Li F.
      • Zhao A.Z.
      Human adiponectin inhibits cell growth and induces apoptosis in human endometrial carcinoma cells, HEC-1-a and RL95 2.
      ,
      • Zhang L.
      • Wen K.
      • Han X.
      • Liu R.
      • Qu Q.
      Adiponectin mediates antiproliferative and apoptotic responses in endometrial carcinoma by the AdipoRs/AMPK pathway.
      ], and prostate cancer [
      • Lu J.P.
      • Hou Z.F.
      • Duivenvoorden W.C.
      • Whelan K.
      • Honig A.
      • Pinthus J.H.
      Adiponectin inhibits oxidative stress in human prostate carcinoma cells.
      ]. Data have been inconsistent in breast cancer where the anticarcinogenic effect of adiponectin appears to be modified by estrogen receptor expression [
      • Jardé T.
      • Perrier S.
      • Vasson M.P.
      • Caldefie-Chézet F.
      Molecular mechanisms of leptin and adiponectin in breast cancer.
      ,
      • Naimo G.D.
      • Gelsomino L.
      • Catalano S.
      • Mauro L.
      • Andò S.
      Interfering role of ERα on adiponectin action in breast cancer.
      ]. Besides suppression of tumorigenicity, adiponectin can reduces the metastatic potential of cancer cells, a phenomenon reported for hepatocellular [
      • Man K.
      • Ng K.T.
      • Xu A.
      • Cheng Q.
      • Lo C.M.
      • Xiao J.W.
      • et al.
      Suppression of liver tumor growth and metastasis by adiponectin in nude mice through inhibition of tumor angiogenesis and downregulation of rho kinase/IFN-inducible protein 10/matrix metalloproteinase 9 signaling.
      ] and breast [
      • Kim K.Y.
      • Baek A.
      • Hwang J.E.
      • Choi Y.A.
      • Jeong J.
      • Lee M.S.
      • et al.
      Adiponectin-activated AMPK stimulates dephosphorylation of AKT through protein phosphatase 2A activation.
      ] cancer cells.
      The adipose tissue also secretes a number of other molecules, including certain cytokines, such as interleukin-6 (IL-6), IL-1 receptor antagonist, IL-18, tumor-necrosis factor α (TNF-α), pre-B cell colony-enhancing factor (also known as visfatin), and monocyte chemoattractant protein-1 (also known as chemokine C-C motif ligand 2); fatty acid-binding protein-4; retinol binding protein 4; mediators of the clotting process, such as plasminogen-activator inhibitor-1; growth factors, such as vascular endothelial growth factor and angiopoietin-like protein-4; and some complement factors [
      • Ouchi N.
      • Parker J.L.
      • Lugus J.J.
      • Walsh K.
      Adipokines in inflammation and metabolic disease.
      ,
      • Tilg H.
      • Moschen A.R.
      Adipocytokines: mediators linking adipose tissue, inflammation and immunity.
      ,
      • Waki H.
      • Tontonoz P.
      Endocrine functions of adipose tissue.
      ,
      • Goudswaard L.J.
      • Bell J.A.
      • Hughes D.A.
      • Corbin L.J.
      • Walter K.
      • Davey Smith G.
      • et al.
      Effects of adiposity on the human plasma proteome: observational and mendelian randomisation estimates.
      ,
      • Juge-Aubry C.E.
      • Somm E.
      • Giusti V.
      • Pernin A.
      • Chicheportiche R.
      • Verdumo C.
      • et al.
      Adipose tissue is a major source of interleukin-1 receptor antagonist: upregulation in obesity and inflammation.
      ]. Circulating levels of several inflammatory biomarkers, such as C-reactive protein (an acute phase reactant) [
      • Goudswaard L.J.
      • Bell J.A.
      • Hughes D.A.
      • Corbin L.J.
      • Walter K.
      • Davey Smith G.
      • et al.
      Effects of adiposity on the human plasma proteome: observational and mendelian randomisation estimates.
      ,
      • Holmes M.V.
      • Lange L.A.
      • Palmer T.
      • Lanktree M.B.
      • North K.E.
      • Almoguera B.
      • et al.
      Causal effects of body mass index on cardiometabolic traits and events: a mendelian randomization analysis.
      ,
      • Visser M.
      • Bouter L.M.
      • McQuillan G.M.
      • Wener M.H.
      • Harris T.B.
      Elevated C-reactive protein levels in overweight and obese adults.
      ], IL-6 [
      • Holmes M.V.
      • Lange L.A.
      • Palmer T.
      • Lanktree M.B.
      • North K.E.
      • Almoguera B.
      • et al.
      Causal effects of body mass index on cardiometabolic traits and events: a mendelian randomization analysis.
      ], IL-18 [
      • Ouchi N.
      • Parker J.L.
      • Lugus J.J.
      • Walsh K.
      Adipokines in inflammation and metabolic disease.
      ], and TNF-α [
      • Goudswaard L.J.
      • Bell J.A.
      • Hughes D.A.
      • Corbin L.J.
      • Walter K.
      • Davey Smith G.
      • et al.
      Effects of adiposity on the human plasma proteome: observational and mendelian randomisation estimates.
      ], as well as plasminogen-activator inhibitor-1 [
      • Goudswaard L.J.
      • Bell J.A.
      • Hughes D.A.
      • Corbin L.J.
      • Walter K.
      • Davey Smith G.
      • et al.
      Effects of adiposity on the human plasma proteome: observational and mendelian randomisation estimates.
      ] increase with increasing BMI and decline following weight loss [
      • Ouchi N.
      • Parker J.L.
      • Lugus J.J.
      • Walsh K.
      Adipokines in inflammation and metabolic disease.
      ,
      • Esposito K.
      • Pontillo A.
      • Di Palo C.
      • Giugliano G.
      • Masella M.
      • Marfella R.
      • et al.
      Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a randomized trial.
      ]. MR studies have not supported a causal role of higher C-reactive protein or IL-6 levels in the development of colorectal, endometrial, ovarian, breast, and prostate cancer [
      • Allin K.H.
      • Nordestgaard B.G.
      • Zacho J.
      • Tybjaerg-Hansen A.
      • Bojesen S.E.
      C-reactive protein and the risk of cancer: a mendelian randomization study.
      ,
      • Hazelwood E.
      • Sanderson E.
      • Tan V.Y.
      • Ruth K.S.
      • Frayling T.M.
      • Dimou N.
      • et al.
      Identifying molecular mediators of the relationship between body mass index and endometrial cancer risk: a Mendelian randomization analysis.
      ,
      • Wang X.
      • Dai J.Y.
      • Albanes D.
      • Arndt V.
      • Berndt S.I.
      • Bezieau S.
      • et al.
      Mendelian randomization analysis of C-reactive protein on colorectal cancer risk.
      ,
      • Bouras E.
      • Karhunen V.
      • Gill D.
      • Huang J.
      • Haycock P.C.
      • Gunter M.J.
      • et al.
      Circulating inflammatory cytokines and risk of five cancers: a mendelian randomization analysis.
      ,
      • He C.
      • Qian Y.
      • Liu B.
      • Yang S.
      • Ye D.
      • Sun X.
      • et al.
      Genetically predicted circulating level of C-reactive protein is not associated with prostate cancer risk.
      ,
      • Robinson T.
      • Martin R.M.
      • Yarmolinsky J.
      Mendelian randomisation analysis of circulating adipokines and C-reactive protein on breast cancer risk.
      ]. Genetically predicted circulating TNF-α levels have been reported to be significantly or suggestively inversely associated with risk of colorectal, endometrial, breast, and lung cancer [
      • Yuan S.
      • Carter P.
      • Bruzelius M.
      • Vithayathil M.
      • Kar S.
      • Mason A.M.
      • et al.
      Effects of tumour necrosis factor on cardiovascular disease and cancer: a two-sample Mendelian randomization study.
      ].
      Some adipocytokines modulate angiogenesis, which is essential in cancer development and progression. For example, adiponectin may inhibit angiogenesis, whereas leptin acts in synergy with vascular endothelial growth factor to promote angiogenesis [
      • Cao Y.
      Angiogenesis and vascular functions in modulation of obesity, adipose metabolism, and insulin sensitivity.
      ].

      4.2 Insulin and IGF-I

      Circulating insulin and insulin like growth factor levels are frequently elevated in overweight and obese individuals as a consequence of reduced insulin sensitivity driven, at least partly, by alterations in adiponectin levels. MR studies have provided evidence of strong causal associations of greater BMI, waist-to-hip ratio, and fat mass with increased insulin resistance [
      • Zeng H.
      • Lin C.
      • Wang S.
      • Zheng Y.
      • Gao X.
      Genetically predicted body composition in relation to cardiometabolic traits: a Mendelian randomization study.
      ,
      • Xu H.
      • Jin C.
      • Guan Q.
      Causal effects of overall and abdominal obesity on insulin resistance and the risk of type 2 diabetes mellitus: a two-sample mendelian randomization study.
      ,
      • Song Q.
      • Huang T.
      • Song J.
      • Meng X.
      • Li C.
      • Wang Y.
      • et al.
      Causal associations of body mass index and waist-to-hip ratio with cardiometabolic traits among Chinese children: a Mendelian randomization study.
      ,
      • Mantzoros C.S.
      • Flier J.S.
      Insulin resistance: the clinical spectrum.
      ] and fasting insulin levels [
      • Holmes M.V.
      • Lange L.A.
      • Palmer T.
      • Lanktree M.B.
      • North K.E.
      • Almoguera B.
      • et al.
      Causal effects of body mass index on cardiometabolic traits and events: a mendelian randomization analysis.
      ,
      • Zeng H.
      • Lin C.
      • Wang S.
      • Zheng Y.
      • Gao X.
      Genetically predicted body composition in relation to cardiometabolic traits: a Mendelian randomization study.
      ,
      • Xu H.
      • Jin C.
      • Guan Q.
      Causal effects of overall and abdominal obesity on insulin resistance and the risk of type 2 diabetes mellitus: a two-sample mendelian randomization study.
      ,
      • Song Q.
      • Huang T.
      • Song J.
      • Meng X.
      • Li C.
      • Wang Y.
      • et al.
      Causal associations of body mass index and waist-to-hip ratio with cardiometabolic traits among Chinese children: a Mendelian randomization study.
      ]. It has been estimated that each 1 kg/m2 elevation in genetically predicted BMI increases fasting insulin levels by 8.5 % [
      • Holmes M.V.
      • Lange L.A.
      • Palmer T.
      • Lanktree M.B.
      • North K.E.
      • Almoguera B.
      • et al.
      Causal effects of body mass index on cardiometabolic traits and events: a mendelian randomization analysis.
      ].
      Observational and MR studies have demonstrated that elevated circulating levels of insulin or C-peptide (a marker of insulin secretion) are associated with several obesity-related cancers, including colorectal [
      • Zhang H.
      • Li D.
      • Liu X.
      • Wan Z.
      • Yu Z.
      • Wang Y.
      • et al.
      Fasting insulin and risk of overall and 14 site-specific cancers: evidence from genetic data.
      ,
      • Murphy N.
      • Song M.
      • Papadimitriou N.
      • Carreras-Torres R.
      • Langenberg C.
      • Martin R.M.
      • et al.
      Associations between glycemic traits and colorectal cancer: a Mendelian randomization analysis.
      ,
      • Xu J.
      • Ye Y.
      • Wu H.
      • Duerksen-Hughes P.
      • Zhang H.
      • Li P.
      • et al.
      Association between markers of glucose metabolism and risk of colorectal cancer.
      ], stomach [
      • Hidaka A.
      • Sasazuki S.
      • Goto A.
      • Sawada N.
      • Shimazu T.
      • Yamaji T.
      • et al.
      Plasma insulin, C-peptide and blood glucose and the risk of gastric cancer: the Japan Public Health Center-based prospective study.
      ], liver [
      • Loftfield E.
      • Freedman N.D.
      • Lai G.Y.
      • Weinstein S.J.
      • McGlynn K.A.
      • Taylor P.R.
      • et al.
      Higher glucose and insulin levels are associated with risk of liver cancer and chronic liver disease mortality among men without a history of diabetes.
      ,
      • Aleksandrova K.
      • Boeing H.
      • Nothlings U.
      • Jenab M.
      • Fedirko V.
      • Kaaks R.
      • et al.
      Inflammatory and metabolic biomarkers and risk of liver and biliary tract cancer.
      ], pancreatic [
      • Carreras-Torres R.
      • Johansson M.
      • Gaborieau V.
      • Haycock P.C.
      • Wade K.H.
      • Relton C.L.
      • et al.
      The role of obesity, type 2 diabetes, and metabolic factors in pancreatic cancer: a mendelian randomization study.
      ,
      • Lu Y.
      • Gentiluomo M.
      • Lorenzo-Bermejo J.
      • Morelli L.
      • Obazee O.
      • Campa D.
      • et al.
      Mendelian randomisation study of the effects of known and putative risk factors on pancreatic cancer.
      ,
      • Yuan S.
      • Kar S.
      • Carter P.
      • Vithayathil M.
      • Mason A.M.
      • Burgess S.
      • et al.
      Is type 2 diabetes causally associated with cancer risk? Evidence from a two-sample Mendelian randomization study.
      ,
      • Michaud D.S.
      • Wolpin B.
      • Giovannucci E.
      • Liu S.
      • Cochrane B.
      • Manson J.E.
      • et al.
      Prediagnostic plasma C-peptide and pancreatic cancer risk in men and women.
      ,
      • Wolpin B.M.
      • Bao Y.
      • Qian Z.R.
      • Wu C.
      • Kraft P.
      • Ogino S.
      • et al.
      Hyperglycemia, insulin resistance, impaired pancreatic beta-cell function, and risk of pancreatic cancer.
      ], kidney [
      • Yuan S.
      • Kar S.
      • Carter P.
      • Vithayathil M.
      • Mason A.M.
      • Burgess S.
      • et al.
      Is type 2 diabetes causally associated with cancer risk? Evidence from a two-sample Mendelian randomization study.
      ,
      • Johansson M.
      • Carreras-Torres R.
      • Scelo G.
      • Purdue M.P.
      • Mariosa D.
      • Muller D.C.
      • et al.
      The influence of obesity-related factors in the etiology of renal cell carcinoma-a Mendelian randomization study.
      ], and endometrial cancer [
      • Hazelwood E.
      • Sanderson E.
      • Tan V.Y.
      • Ruth K.S.
      • Frayling T.M.
      • Dimou N.
      • et al.
      Identifying molecular mediators of the relationship between body mass index and endometrial cancer risk: a Mendelian randomization analysis.
      ,
      • Zhang H.
      • Li D.
      • Liu X.
      • Wan Z.
      • Yu Z.
      • Wang Y.
      • et al.
      Fasting insulin and risk of overall and 14 site-specific cancers: evidence from genetic data.
      ,
      • Yuan S.
      • Kar S.
      • Carter P.
      • Vithayathil M.
      • Mason A.M.
      • Burgess S.
      • et al.
      Is type 2 diabetes causally associated with cancer risk? Evidence from a two-sample Mendelian randomization study.
      ,
      • Nead K.T.
      • Sharp S.J.
      • Thompson D.J.
      • Painter J.N.
      • Savage D.B.
      • Semple R.K.
      • et al.
      Evidence of a causal association between insulinemia and endometrial cancer: a Mendelian randomization analysis.
      ,
      • Gunter M.J.
      • Hoover D.R.
      • Yu H.
      • Wassertheil-Smoller S.
      • Manson J.E.
      • Li J.
      • et al.
      A prospective evaluation of insulin and insulin-like growth factor-I as risk factors for endometrial cancer.
      ]. Moreover, insulin therapy among diabetes patients is associated with increased risk of colorectal [
      • Karlstad O.
      • Starup-Linde J.
      • Vestergaard P.
      • Hjellvik V.
      • Bazelier M.T.
      • Schmidt M.K.
      • et al.
      Use of insulin and insulin analogs and risk of cancer - systematic review and meta-analysis of observational studies.
      ,
      • Bu W.J.
      • Song L.
      • Zhao D.Y.
      • Guo B.
      • Liu J.
      Insulin therapy and the risk of colorectal cancer in patients with type 2 diabetes: a meta-analysis of observational studies.
      ], stomach [
      • Karlstad O.
      • Starup-Linde J.
      • Vestergaard P.
      • Hjellvik V.
      • Bazelier M.T.
      • Schmidt M.K.
      • et al.
      Use of insulin and insulin analogs and risk of cancer - systematic review and meta-analysis of observational studies.
      ], liver [
      • Karlstad O.
      • Starup-Linde J.
      • Vestergaard P.
      • Hjellvik V.
      • Bazelier M.T.
      • Schmidt M.K.
      • et al.
      Use of insulin and insulin analogs and risk of cancer - systematic review and meta-analysis of observational studies.
      ,
      • Liu X.L.
      • Wu H.
      • Zhao L.G.
      • Xu H.L.
      • Zhang W.
      • Xiang Y.B.
      Association between insulin therapy and risk of liver cancer among diabetics: a meta-analysis of epidemiological studies.
      ], pancreatic [
      • Karlstad O.
      • Starup-Linde J.
      • Vestergaard P.
      • Hjellvik V.
      • Bazelier M.T.
      • Schmidt M.K.
      • et al.
      Use of insulin and insulin analogs and risk of cancer - systematic review and meta-analysis of observational studies.
      ], and kidney cancer [
      • Karlstad O.
      • Starup-Linde J.
      • Vestergaard P.
      • Hjellvik V.
      • Bazelier M.T.
      • Schmidt M.K.
      • et al.
      Use of insulin and insulin analogs and risk of cancer - systematic review and meta-analysis of observational studies.
      ]. A recent MR study estimated that fasting insulin mediated 19 % of the relationship between genetically predicted BMI and endometrial cancer risk [
      • Hazelwood E.
      • Sanderson E.
      • Tan V.Y.
      • Ruth K.S.
      • Frayling T.M.
      • Dimou N.
      • et al.
      Identifying molecular mediators of the relationship between body mass index and endometrial cancer risk: a Mendelian randomization analysis.
      ].
      IGF-I is a peptide hormone that is primarily synthesized by the liver under the regulation of growth hormone (GH) but is also produced locally by most tissues where it functions in an autocrine or paracrine manner [
      • Le Roith D.
      Seminars in medicine of the Beth Israel Deaconess Medical Center. Insulin-like growth factors.
      ,
      • Bach L.A.
      IGF-binding proteins.
      ,
      • Moschos S.J.
      • Mantzoros C.S.
      The role of the IGF system in cancer: from basic to clinical studies and clinical applications.
      ]. In addition to being a mediator of GH-stimulated somatic growth, IGF-I exerts GH-independent anabolic effects in many cells and tissues via activation of the IGF-1 receptor. The totality of evidence from observational and MR studies indicates that elevated circulating IGF-I levels modestly increase the risk of epithelial cancers including colorectal [
      • Murphy N.
      • Carreras-Torres R.
      • Song M.
      • Chan A.T.
      • Martin R.M.
      • Papadimitriou N.
      • et al.
      Circulating levels of insulin-like growth factor 1 and insulin-like growth factor binding protein 3 associate with risk of colorectal cancer based on serologic and Mendelian randomization analyses.
      ,
      • Larsson S.C.
      • Carter P.
      • Vithayathil M.
      • Kar S.
      • Mason A.M.
      • Burgess S.
      Insulin-like growth factor-1 and site-specific cancers: a Mendelian randomization study.
      ,
      • Rinaldi S.
      • Cleveland R.
      • Norat T.
      • Biessy C.
      • Rohrmann S.
      • Linseisen J.
      • et al.
      Serum levels of IGF-I, IGFBP-3 and colorectal cancer risk: results from the EPIC cohort, plus a meta-analysis of prospective studies.
      ], prostate [
      • Murphy N.
      • Carreras-Torres R.
      • Song M.
      • Chan A.T.
      • Martin R.M.
      • Papadimitriou N.
      • et al.
      Circulating levels of insulin-like growth factor 1 and insulin-like growth factor binding protein 3 associate with risk of colorectal cancer based on serologic and Mendelian randomization analyses.
      ,
      • Larsson S.C.
      • Carter P.
      • Vithayathil M.
      • Kar S.
      • Mason A.M.
      • Burgess S.
      Insulin-like growth factor-1 and site-specific cancers: a Mendelian randomization study.
      ,
      • Watts E.L.
      • Perez-Cornago A.
      • Fensom G.K.
      • Smith-Byrne K.
      • Noor U.
      • Andrews C.D.
      • et al.
      Circulating insulin-like growth factors and risks of overall, aggressive and early-onset prostate cancer: a collaborative analysis of 20 prospective studies and Mendelian randomization analysis.
      ,
      • Wolk A.
      • Mantzoros C.S.
      • Andersson S.-O.
      • Bergström R.
      • Signorello L.B.
      • Lagiou P.
      • et al.
      Insulin-like growth factor 1 and prostate cancer risk: a population-based, case-control study.
      ], and breast cancer [
      • Murphy N.
      • Carreras-Torres R.
      • Song M.
      • Chan A.T.
      • Martin R.M.
      • Papadimitriou N.
      • et al.
      Circulating levels of insulin-like growth factor 1 and insulin-like growth factor binding protein 3 associate with risk of colorectal cancer based on serologic and Mendelian randomization analyses.
      ,
      • Larsson S.C.
      • Carter P.
      • Vithayathil M.
      • Kar S.
      • Mason A.M.
      • Burgess S.
      Insulin-like growth factor-1 and site-specific cancers: a Mendelian randomization study.
      ,
      • Murphy N.
      • Knuppel A.
      • Papadimitriou N.
      • Martin R.M.
      • Tsilidis K.K.
      • Smith-Byrne K.
      • et al.
      Insulin-like growth factor-1, insulin-like growth factor-binding protein-3, and breast cancer risk: observational and Mendelian randomization analyses with approximately 430 000 women.
      ]. In the bloodstream, over 99 % of IGF-1 is attached to one of six binding proteins (IGFBPs) that modulate IGF-I activity [
      • Bach L.A.
      IGF-binding proteins.
      ]. The vast majority of serum IGF-I (75–85 %) is complexed with IGFBP-3 and a glycoprotein, while the remaining 20–25 % is complexed with one of the other IGFBPs [
      • Allard J.B.
      • Duan C.
      IGF-binding proteins: why do they exist and why are there so many?.
      ]. Despite low GH secretion [
      • Frystyk J.
      • Brick D.J.
      • Gerweck A.V.
      • Utz A.L.
      • Miller K.K.
      Bioactive insulin-like growth factor-I in obesity.
      ] and decreasing IGFBP-1 and IGFBP-2 levels with increasing adiposity and insulin levels [
      • Goudswaard L.J.
      • Bell J.A.
      • Hughes D.A.
      • Corbin L.J.
      • Walter K.
      • Davey Smith G.
      • et al.
      Effects of adiposity on the human plasma proteome: observational and mendelian randomisation estimates.
      ,
      • Brismar K.
      • Fernqvist-Forbes E.
      • Wahren J.
      • Hall K.
      Effect of insulin on the hepatic production of insulin-like growth factor-binding protein-1 (IGFBP-1), IGFBP-3, and IGF-I in insulin-dependent diabetes.
      ,
      • Wolk K.
      • Larsson S.C.
      • Vessby B.
      • Wolk A.
      • Brismar K.
      Metabolic, anthropometric, and nutritional factors as predictors of circulating insulin-like growth factor binding protein-1 levels in middle-aged and elderly men.
      ,
      • Cotterill A.M.
      • Holly J.M.
      • Wass J.A.
      The regulation of insulin-like growth factor binding protein (IGFBP)-1 during prolonged fasting.
      ,
      • Lee P.D.
      • Giudice L.C.
      • Conover C.A.
      • Powell D.R.
      Insulin-like growth factor binding protein-1: recent findings and new directions.
      ], no consistent association has been observed between BMI and total or bioavailable IGF-I levels [
      • Frystyk J.
      • Brick D.J.
      • Gerweck A.V.
      • Utz A.L.
      • Miller K.K.
      Bioactive insulin-like growth factor-I in obesity.
      ].

      4.3 Signaling pathways linking adiponectin, insulin, and cancer growth

      Adiponectin exerts its tumor suppressing effects mainly through the interconnected 5´AMP-activated protein kinase (AMPK) and mammalian homologue of target of rapamycin (mTOR) intracellular signaling pathways [
      • Parida S.
      • Siddharth S.
      • Sharma D.
      Adiponectin, obesity, and cancer: clash of the bigwigs in health and disease.
      ,
      • Kelesidis I.
      • Kelesidis T.
      • Mantzoros C.S.
      Adiponectin and cancer: a systematic review.
      ]. Adiponectin activates AMPK, a key regulator of cellular energy. After adiponectin binds to AdipoR1/R2 the Ser/Thr liver kinase B1, it is transferred from the nucleus to the cytoplasm where it recruits the adaptor protein APPL1 and phosphorylates AMPK [
      • Deepa S.S.
      • Dong L.Q.
      APPL1: role in adiponectin signaling and beyond.
      ]. Under cellular stress, adiponectin activates AMPK and inhibits growth promoting and proliferative pathways, while upregulating catabolic pathways to increase energy production [
      • Kahn B.B.
      • Alquier T.
      • Carling D.
      • Hardie D.G.
      AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism.
      ]. Moreover, AMPK interacts with a variety of signaling pathways to stimulate β-oxidation of free fatty acids, inhibits lipid biogenesis, effects that have been linked to tumor growth inhibition [
      • Chajès V.
      • Cambot M.
      • Moreau K.
      • Lenoir G.M.
      • Joulin V.
      Acetyl-CoA carboxylase alpha is essential to breast cancer cell survival.
      ,
      • Zhan Y.
      • Ginanni N.
      • Tota M.R.
      • Wu M.
      • Bays N.W.
      • Richon V.M.
      • et al.
      Control of cell growth and survival by enzymes of the fatty acid synthesis pathway in HCT-116 colon cancer cells.
      ]. Activated AMPK also stimulates the expression of p21 and p53 and phosphorylates p53 to further suppress cancer cell proliferation and induce apoptosis [
      • Jones R.G.
      • Plas D.R.
      • Kubek S.
      • Buzzai M.
      • Mu J.
      • Xu Y.
      • et al.
      AMP-activated protein kinase induces a p53-dependent metabolic checkpoint.
      ].
      Adiponectin can indirectly inhibit neoplastic activity by interfering with the insulin intracellular signaling [
      • Ziemke F.
      • Mantzoros C.S.
      Adiponectin in insulin resistance: lessons from translational research.
      ]. Low adiponectin levels have been correlated with insulin resistance and elevated insulin levels [
      • Kadowaki T.
      • Yamauchi T.
      • Kubota N.
      • Hara K.
      • Ueki K.
      • Tobe K.
      Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome.
      ]. Moreover, AdipoR2 mRNA expression in fatty tissue has been negatively associated with insulin resistance and several metabolic parameters independently of body fatness [
      • Blüher M.
      • Williams C.J.
      • Klöting N.
      • Hsi A.
      • Ruschke K.
      • Oberbach A.
      • et al.
      Gene expression of adiponectin receptors in human visceral and subcutaneous adipose tissue is related to insulin resistance and metabolic parameters and is altered in response to physical training.
      ]. The insulin receptor protein kinase activates the mTOR pathway through phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT) [
      • He Y.
      • Sun M.M.
      • Zhang G.G.
      • Yang J.
      • Chen K.S.
      • Xu W.W.
      • et al.
      Targeting PI3K/Akt signal transduction for cancer therapy.
      ,
      • Norton L.
      • Shannon C.
      • Gastaldelli A.
      • DeFronzo R.A.
      Insulin: the master regulator of glucose metabolism.
      ]. It is well established that alterations in PI3K/AKT/mTOR signaling underpin tumorigenesis [
      • He Y.
      • Sun M.M.
      • Zhang G.G.
      • Yang J.
      • Chen K.S.
      • Xu W.W.
      • et al.
      Targeting PI3K/Akt signal transduction for cancer therapy.
      ]. Adiponectin inhibits the PI3K/AKT/mTOR axis hindering cancer cell growth imposed by insulin and other growth factors [
      • Sengupta S.
      • Peterson T.R.
      • Sabatini D.M.
      Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress.
      ,
      • Murugan A.K.
      mTOR: role in cancer, metastasis and drug resistance.
      ].

      4.4 Sex hormones

      In premenopausal women, estrogens are synthesized primarily in the ovaries, whereas in postmenopausal women and men, the primary site for estrogen synthesis is adipose tissue. Obesity and resulting hyperinsulinemia are related to decreased levels of sex hormone binding globulin (SHBG) [
      • Goudswaard L.J.
      • Bell J.A.
      • Hughes D.A.
      • Corbin L.J.
      • Walter K.
      • Davey Smith G.
      • et al.
      Effects of adiposity on the human plasma proteome: observational and mendelian randomisation estimates.
      ,
      • Weinberg M.E.
      • Manson J.E.
      • Buring J.E.
      • Cook N.R.
      • Seely E.W.
      • Ridker P.M.
      • et al.
      Low sex hormone-binding globulin is associated with the metabolic syndrome in postmenopausal women.
      ], which binds estradiol and testosterone with high affinity. In peri- and postmenopausal women, high BMI associates with higher levels of bioavailable estradiol [
      • Weinberg M.E.
      • Manson J.E.
      • Buring J.E.
      • Cook N.R.
      • Seely E.W.
      • Ridker P.M.
      • et al.
      Low sex hormone-binding globulin is associated with the metabolic syndrome in postmenopausal women.
      ] and testosterone [
      • Weinberg M.E.
      • Manson J.E.
      • Buring J.E.
      • Cook N.R.
      • Seely E.W.
      • Ridker P.M.
      • et al.
      Low sex hormone-binding globulin is associated with the metabolic syndrome in postmenopausal women.
      ,
      • Maturana M.A.
      • Spritzer P.M.
      Association between hyperinsulinemia and endogenous androgen levels in peri- and postmenopausal women.
      ,
      • Grasa M.D.M.
      • Gulfo J.
      • Camps N.
      • Alcala R.
      • Monserrat L.
      • Moreno-Navarrete J.M.
      • et al.
      Modulation of SHBG binding to testosterone and estradiol by sex and morbid obesity.
      ], whereas in men, high BMI associates with lower testosterone levels [
      • Grasa M.D.M.
      • Gulfo J.
      • Camps N.
      • Alcala R.
      • Monserrat L.
      • Moreno-Navarrete J.M.
      • et al.
      Modulation of SHBG binding to testosterone and estradiol by sex and morbid obesity.
      ,
      • Eriksson J.
      • Haring R.
      • Grarup N.
      • Vandenput L.
      • Wallaschofski H.
      • Lorentzen E.
      • et al.
      Causal relationship between obesity and serum testosterone status in men: a bi-directional Mendelian randomization analysis.
      ,
      • Mintziori G.
      • Nigdelis M.P.
      • Mathew H.
      • Mousiolis A.
      • Goulis D.G.
      • Mantzoros C.S.
      The effect of excess body fat on female and male reproduction.
      ]. Obese men commonly present with hypogonadotropic hypogonadism [
      • Mintziori G.
      • Nigdelis M.P.
      • Mathew H.
      • Mousiolis A.
      • Goulis D.G.
      • Mantzoros C.S.
      The effect of excess body fat on female and male reproduction.
      ].
      MR studies have provided evidence of causal relationships of higher circulating SHBG levels with decreased risk of endometrial cancer [
      • Hazelwood E.
      • Sanderson E.
      • Tan V.Y.
      • Ruth K.S.
      • Frayling T.M.
      • Dimou N.
      • et al.
      Identifying molecular mediators of the relationship between body mass index and endometrial cancer risk: a Mendelian randomization analysis.
      ] and of higher endogenous levels of total estradiol (proxied by a single genetic variant in the CYP19A gene, which encodes aromatase) with increased risk of cancers of the corpus uteri (particularly the endometroid subtype) [
      • Hazelwood E.
      • Sanderson E.
      • Tan V.Y.
      • Ruth K.S.
      • Frayling T.M.
      • Dimou N.
      • et al.
      Identifying molecular mediators of the relationship between body mass index and endometrial cancer risk: a Mendelian randomization analysis.
      ,
      • Larsson S.C.
      • Kar S.
      • Perry J.R.B.
      • Carter P.
      • Vithayathil M.
      • Mason A.M.
      • et al.
      Serum estradiol and 20 site-specific cancers in women: Mendelian randomization study.
      ] and breast (particularly estrogen receptor positive tumors) and possibly ovarian cancer of the endometrioid subtype as well as stomach cancer in women [
      • Larsson S.C.
      • Kar S.
      • Perry J.R.B.
      • Carter P.
      • Vithayathil M.
      • Mason A.M.
      • et al.
      Serum estradiol and 20 site-specific cancers in women: Mendelian randomization study.
      ]. Furthermore, MR studies have reported that genetically predicted higher endogenous levels of total and bioavailable testosterone are associated with increased risk of cancers of the corpus uteri [
      • Hazelwood E.
      • Sanderson E.
      • Tan V.Y.
      • Ruth K.S.
      • Frayling T.M.
      • Dimou N.
      • et al.
      Identifying molecular mediators of the relationship between body mass index and endometrial cancer risk: a Mendelian randomization analysis.
      ,
      • Ruth K.S.
      • Day F.R.
      • Tyrrell J.
      • Thompson D.J.
      • Wood A.R.
      • Mahajan A.
      • et al.
      Using human genetics to understand the disease impacts of testosterone in men and women.
      ] and breast (estrogen receptor positive tumors) [
      • Ruth K.S.
      • Day F.R.
      • Tyrrell J.
      • Thompson D.J.
      • Wood A.R.
      • Mahajan A.
      • et al.
      Using human genetics to understand the disease impacts of testosterone in men and women.
      ], and that genetically predicted higher free and bioavailable testosterone endogenous levels are related to an increased risk of prostate cancer [
      • Ruth K.S.
      • Day F.R.
      • Tyrrell J.
      • Thompson D.J.
      • Wood A.R.
      • Mahajan A.
      • et al.
      Using human genetics to understand the disease impacts of testosterone in men and women.
      ,
      • Watts E.L.
      • Perez-Cornago A.
      • Fensom G.K.
      • Smith-Byrne K.
      • Noor U.
      • Andrews C.D.
      • et al.
      Circulating free testosterone and risk of aggressive prostate cancer: prospective and mendelian randomisation analyses in international consortia.
      ]. Thus, the observed positive associations between BMI and risk of cancers of the corpus uteri, breast (postmenopausal), ovaries (endometrioid subtype), and stomach may in part be mediated by higher sex hormone levels in women. A recent MR study estimated that bioavailable testosterone and SHBG mediated 15 % and 7 %, respectively, of the association between BMI and endometrial cancer risk [
      • Hazelwood E.
      • Sanderson E.
      • Tan V.Y.
      • Ruth K.S.
      • Frayling T.M.
      • Dimou N.
      • et al.
      Identifying molecular mediators of the relationship between body mass index and endometrial cancer risk: a Mendelian randomization analysis.
      ]. The mediating effect of bioavailable estradiol could not be tested due to the lack of reliable genetic instruments [
      • Hazelwood E.
      • Sanderson E.
      • Tan V.Y.
      • Ruth K.S.
      • Frayling T.M.
      • Dimou N.
      • et al.
      Identifying molecular mediators of the relationship between body mass index and endometrial cancer risk: a Mendelian randomization analysis.
      ].
      In obese men, the low testosterone environment might contribute to an increased risk of advanced or fatal prostate cancer but possibly to lower risk of non-advanced prostate cancer [
      • Giovannucci E.
      • Michaud D.
      The role of obesity and related metabolic disturbances in cancers of the colon, prostate, and pancreas.
      ]. The biological mechanism behind the association between obesity and decreased risk of breast cancer in premenopausal women is unclear, but oligo- and anovulation, which is more frequently observed in overweight and obese women than in normal weight women [
      • Mintziori G.
      • Nigdelis M.P.
      • Mathew H.
      • Mousiolis A.
      • Goulis D.G.
      • Mantzoros C.S.
      The effect of excess body fat on female and male reproduction.
      ], and alterations in related hormones might be involved.

      4.5 Emerging mechanisms

      Evidence indicates that there is a mutual relationship between obesity and gut microbiota. In humans, obesity is associated with alterations in the gut microbiota composition as well as decreased bacterial diversity [
      • Ley R.E.
      • Turnbaugh P.J.
      • Klein S.
      • Gordon J.I.
      Microbial ecology: human gut microbes associated with obesity.
      ,
      • Bell D.S.
      Changes seen in gut bacteria content and distribution with obesity: causation or association?.
      ,
      • Turnbaugh P.J.
      • Hamady M.
      • Yatsunenko T.
      • Cantarel B.L.
      • Duncan A.
      • Ley R.E.
      • et al.
      A core gut microbiome in obese and lean twins.
      ]. Low-calorie diets (fat- or carbohydrate-restricted) and weight loss has been revealed to change the relative abundance of major gut phyla (increased levels of Bacteroidetes and decreased levels of Firmicutes) in obese individuals [
      • Ley R.E.
      • Turnbaugh P.J.
      • Klein S.
      • Gordon J.I.
      Microbial ecology: human gut microbes associated with obesity.
      ]. Studies in mice have shown that obese-associated microbiome is associated with increased capacity to harvest energy from the diet [
      • Turnbaugh P.J.
      • Ley R.E.
      • Mahowald M.A.
      • Magrini V.
      • Mardis E.R.
      • Gordon J.I.
      An obesity-associated gut microbiome with increased capacity for energy harvest.
      ] and weight gain [
      • Goodrich J.K.
      • Waters J.L.
      • Poole A.C.
      • Sutter J.L.
      • Koren O.
      • Blekhman R.
      • et al.
      Human genetics shape the gut microbiome.
      ]. Evidence from MR studies further indicates that certain gut microbiota taxa modify BMI and fat mass [
      • Hughes D.A.
      • Bacigalupe R.
      • Wang J.
      • Ruhlemann M.C.
      • Tito R.Y.
      • Falony G.
      • et al.
      Genome-wide associations of human gut microbiome variation and implications for causal inference analyses.
      ,
      • Kurilshikov A.
      • Medina-Gomez C.
      • Bacigalupe R.
      • Radjabzadeh D.
      • Wang J.
      • Demirkan A.
      • et al.
      Large-scale association analyses identify host factors influencing human gut microbiome composition.
      ]. For example, a genetic variant in the LCT locus that predisposes individuals to lactose intolerance and is related to the abundances of Bifidobacterium is associated with adiposity-related phenotypes, such as BMI, waist circumference, and fat mass [
      • Kurilshikov A.
      • Medina-Gomez C.
      • Bacigalupe R.
      • Radjabzadeh D.
      • Wang J.
      • Demirkan A.
      • et al.
      Large-scale association analyses identify host factors influencing human gut microbiome composition.
      ]. Nevertheless, little is known about the possible causal effect of gut microbiome on cancer risk, but a recent phenome-wide association MR study provided no evidence of any strong association between microbiome-related genetic variants and cancer outcomes [
      • Groot H.E.
      • van de Vegte Y.J.
      • Verweij N.
      • Lipsic E.
      • Karper J.C.
      • van der Harst P.
      Human genetic determinants of the gut microbiome and their associations with health and disease: a phenome-wide association study.
      ].
      There are several obesity-associated gut hormones (e.g., ghrelin, glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide, peptideYY, neurotensin, vasoactive intestinal peptide, and somatostatin) that have not yet been studied adequately but have been proposed to have either a protective role against cancer or increase cancer cell growth and proliferation [
      • Guzzardi M.A.
      • Pugliese G.
      • Bottiglieri F.
      • Pelosini C.
      • Muscogiuri G.
      • Barrea L.
      • et al.
      Obesity-related gut hormones and cancer: novel insight into the pathophysiology.
      ]. Ghrelin is a peptide hormone produced primarily by the stomach and stimulates appetite and GH release and has diabetogenic and lipogenic effects [
      • Higgins S.C.
      • Gueorguiev M.
      • Korbonits M.
      Ghrelin, the peripheral hunger hormone.
      ]. Circulating ghrelin levels are decreased in obesity [
      • Higgins S.C.
      • Gueorguiev M.
      • Korbonits M.
      Ghrelin, the peripheral hunger hormone.
      ]. The ghrelin system is thought to be involved in the regulation of several important processes of digestive system cancer progression, although the exact roles of ghrelin in cancer are unestablished [
      • Kasprzak A.
      Role of the ghrelin system in colorectal cancer.
      ,
      • Kotta A.S.
      • Kelling A.S.
      • Corleto K.A.
      • Sun Y.
      • Giles E.D.
      Ghrelin and cancer: examining the roles of the ghrelin axis in tumor growth and progression.
      ]. Observational studies have reported that low circulating ghrelin levels are associated with an increased risk of stomach cancer [
      • Murphy G.
      • Kamangar F.
      • Dawsey S.M.
      • Stanczyk F.Z.
      • Weinstein S.J.
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      • et al.
      The relationship between serum ghrelin and the risk of gastric and esophagogastric junctional adenocarcinomas.
      ,
      • Pritchett N.R.
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      • Kamangar F.
      • Dawsey S.M.
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      Serum ghrelin and esophageal and gastric cancer in two cohorts in China.
      ,
      • Sadjadi A.
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      • Boreiri M.
      • Samadi F.
      • Alizadeh B.Z.
      • et al.
      Serum ghrelin; a new surrogate marker of gastric mucosal alterations in upper gastrointestinal carcinogenesis.
      ]. Moreover, low ghrelin levels were associated with a higher risk of esophageal squamous cell carcinoma in two observational studies [
      • Sadjadi A.
      • Yazdanbod A.
      • Lee Y.Y.
      • Boreiri M.
      • Samadi F.
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      • et al.
      Serum ghrelin; a new surrogate marker of gastric mucosal alterations in upper gastrointestinal carcinogenesis.
      ,
      • Murphy G.
      • Kamangar F.
      • Albanes D.
      • Stanczyk F.Z.
      • Weinstein S.J.
      • Taylor P.R.
      • et al.
      Serum ghrelin is inversely associated with risk of subsequent oesophageal squamous cell carcinoma.
      ], but with a lower risk of this cancer type in another study [
      • Pritchett N.R.
      • Maziarz M.
      • Shu X.O.
      • Kamangar F.
      • Dawsey S.M.
      • Fan J.H.
      • et al.
      Serum ghrelin and esophageal and gastric cancer in two cohorts in China.
      ]. With regard to colorectal cancer, one study found that low ghrelin levels were strongly associated with an increased colorectal cancer risk in the years approaching diagnosis [
      • Murphy G.
      • Cross A.J.
      • Dawsey S.M.
      • Stanczyk F.Z.
      • Kamangar F.
      • Weinstein S.J.
      • et al.
      Serum ghrelin is associated with risk of colorectal adenocarcinomas in the ATBC study.
      ], but this association was not replicated in another study [
      • Sundkvist A.
      • Myte R.
      • Palmqvist R.
      • Harlid S.
      • Van Guelpen B.
      Plasma ghrelin is probably not a useful biomarker for risk prediction or early detection of colorectal cancer.
      ]. Studies of ghrelin in relation to other obesity-related cancers are scarce or lacking. Likewise, the possible role of other gut hormones in cancer development in humans remains to be determined.

      5. Discussion

      A large body of evidence from both conventional observational studies and MR studies supports the association between greater body fatness and increased risk of a plurality of cancers, with the most consistent evidence for digestive system cancers, including esophageal, stomach, colorectal, liver, gallbladder, and pancreatic cancer, as well as kidney, endometrial and ovarian (weak association) cancer. Data from observational studies indicates that greater body fatness has contrasting effects on breast cancer risk depending on menopausal status (inverse association in premenopausal women and positive association in postmenopausal women) and on prostate cancer risk depending on disease stage (positive association for advanced prostate cancer only). In MR studies, genetically predicted higher BMI is associated with a reduced risk of overall breast cancer (possibly driven by the inverse association in premenopausal women) and overall prostate cancer. For cancers at other sites, including meningioma, head and neck, thyroid, small intestine, biliary tract, bladder, testicular, cervical, lung, skin, and hematologic cancers, the magnitude of the association with body fatness is weak or modest and data inconclusive.
      With respect to biological mechanisms, data from experimental and MR studies indicate that adiponectin, insulin, and sex hormone pathways play an important role in mediating the association between excess body fatness and risk of cancer. The potential causal associations of the gut microbiome and gut hormones with cancer risk and their possible roles in mediating the adiposity-cancer associations warrant investigation in future studies.
      BMI is the most used measure of body fatness in epidemiological studies but is not the best marker of fat mass, which is physiologically of higher relevance in cancer development. BMI is not designed to distinguish between adipose tissue and lean mass, which widely vary depending on gender, age, and ethnicity [
      • Bandera E.V.
      • Fay S.H.
      • Giovannucci E.
      • Leitzmann M.F.
      • Marklew R.
      • McTiernan A.
      • et al.
      The use and interpretation of anthropometric measures in cancer epidemiology: a perspective from the world cancer research fund international continuous update project.
      ]. The associations of overall fat mass, visceral fat (also known as organ fat or intra-abdominal fat), and waist-to-hip ratio (as a measure of central obesity) with cancer risk have been reported in many studies. Data from two large US cohorts showed that BMI was merely as good predictor of colorectal cancer risk as predicted body fat percentage in a relatively healthy population [
      • Hanyuda A.
      • Lee D.H.
      • Ogino S.
      • Wu K.
      • Giovannucci E.L.
      Long-term status of predicted body fat percentage, body mass index and other anthropometric factors with risk of colorectal carcinoma: two large prospective cohort studies in the US.
      ]. In an MR study on different body composition measures (BMI, fat mass index [FMI], and fat-free mass index) in relation to 22 site-specific cancers, the magnitude of the associations with cancer risk was substantially stronger for FMI than for BMI per 1 kg/m2 increase in the adiposity measure [
      • Vithayathil M.
      • Carter P.
      • Kar S.
      • Mason A.M.
      • Burgess S.
      • Larsson S.C.
      Body size and composition and risk of site-specific cancers in the UK Biobank and large international consortia: a mendelian randomisation study.
      ]. In that study, genetically predicted FMI was significantly positively associated with cancers of the liver (OR per 1 kg/m2 increase in FMI 2.40; 95 % CI 1.02–5.65), pancreas (OR 1.68; 95 % CI 1.06–2.66), and lung (OR 1.57; 95 % CI 1.16–2.13) and inversely associated with melanoma (OR 0.68; 95 % CI 0.51–0.91) and prostate cancer (OR 0.77; 95 % CI 0.61–0.97) [
      • Vithayathil M.
      • Carter P.
      • Kar S.
      • Mason A.M.
      • Burgess S.
      • Larsson S.C.
      Body size and composition and risk of site-specific cancers in the UK Biobank and large international consortia: a mendelian randomisation study.
      ]. There were also strong albeit nonsignificant positive associations between FMI and cancers of the esophagus (OR 1.66; 95 % CI 0.97–2.83), biliary tract (OR 2.02; 95 % CI 0.94–4.30), and corpus uteri (OR 1.35; 95 % CI 0.92–1.98) [
      • Vithayathil M.
      • Carter P.
      • Kar S.
      • Mason A.M.
      • Burgess S.
      • Larsson S.C.
      Body size and composition and risk of site-specific cancers in the UK Biobank and large international consortia: a mendelian randomisation study.
      ]. The association of genetically predicted visceral adiposity with cancer at six sites, including colorectal, pancreatic, ovarian, lung, breast, and prostate cancer, was assessed in a recent MR study which found evidence of causal associations of greater visceral fat mass with risk of pancreatic, endometroid ovarian, and squamous-cell lung cancer but no strong association with colorectal, breast, and prostate cancer [
      • Lu Y.
      • Tang H.
      • Huang P.
      • Wang J.
      • Deng P.
      • Li Y.
      • et al.
      Assessment of causal effects of visceral adipose tissue on risk of cancers: a Mendelian randomization study.
      ]. In other MR studies, genetically predicted BMI but not waist-to-hip ratio was significantly positively associated with risk of colorectal [
      • Gao C.
      • Patel C.J.
      • Michailidou K.
      • Peters U.
      • Gong J.
      • Schildkraut J.
      • et al.
      Mendelian randomization study of adiposity-related traits and risk of breast, ovarian, prostate, lung and colorectal cancer.
      ], pancreatic [
      • Langdon R.J.
      • Richmond R.C.
      • Hemani G.
      • Zheng J.
      • Wade K.H.
      • Carreras-Torres R.
      • et al.
      A phenome-wide Mendelian randomization study of pancreatic cancer using summary genetic data.
      ], endometrial [
      • Painter J.N.
      • O'Mara T.A.
      • Marquart L.
      • Webb P.M.
      • Attia J.
      • Medland S.E.
      • et al.
      Genetic risk score Mendelian randomization shows that obesity measured as body mass index, but not waist: hip ratio, is causal for endometrial cancer.
      ], ovarian [
      • Gao C.
      • Patel C.J.
      • Michailidou K.
      • Peters U.
      • Gong J.
      • Schildkraut J.
      • et al.
      Mendelian randomization study of adiposity-related traits and risk of breast, ovarian, prostate, lung and colorectal cancer.
      ], and lung cancer [
      • Gao C.
      • Patel C.J.
      • Michailidou K.
      • Peters U.
      • Gong J.
      • Schildkraut J.
      • et al.
      Mendelian randomization study of adiposity-related traits and risk of breast, ovarian, prostate, lung and colorectal cancer.
      ]. Thus, overall and visceral fat mass, but not waist-to-hip ratio, appears to be a somewhat better predictor of cancer risk than BMI. This is potentially due to the fact that waist-to-hip ratio is also affected by subcutaneous adipose tissue and does not fully reflect visceral adiposity [
      • Renehan A.G.
      • Zwahlen M.
      • Egger M.
      Adiposity and cancer risk: new mechanistic insights from epidemiology.
      ].
      The most important preventive measures for obesity-associated cancers are based on weight loss interventions like bariatric surgery and medical nutrition. Bariatric surgery is a widely accepted option for long-term weight loss and reduction of comorbidities of morbidly obese patients [
      • de la Cruz-Muñoz N.
      • Xie L.
      • Quiroz H.J.
      • Kutlu O.C.
      • Atem F.
      • Lipshultz S.E.
      • et al.
      Long-term outcomes after adolescent bariatric surgery.
      ]. Interestingly, bariatric surgery has been shown to decrease the risk for several obesity-associated cancers such as colorectal [
      • Almazeedi S.
      • El-Abd R.
      • Al-Khamis A.
      • Albatineh A.N.
      • Al-Sabah S.
      Role of bariatric surgery in reducing the risk of colorectal cancer: a meta-analysis.
      ,
      • Schauer D.P.
      • Feigelson H.S.
      • Koebnick C.
      • Caan B.
      • Weinmann S.
      • Leonard A.C.
      • et al.
      Bariatric surgery and the risk of cancer in a large multisite cohort.
      ,
      • Rustgi V.K.
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      • Gupta K.
      • Minacapelli C.D.
      • Bhurwal A.
      • Catalano C.
      • et al.
      Bariatric surgery reduces cancer risk in adults with nonalcoholic fatty liver disease and severe obesity.
      ], liver [
      • Ramai D.
      • Singh J.
      • Lester J.
      • Khan S.R.
      • Chandan S.
      • Tartaglia N.
      • et al.
      Systematic review with meta-analysis: bariatric surgery reduces the incidence of hepatocellular carcinoma.
      ], pancreatic [
      • Schauer D.P.
      • Feigelson H.S.
      • Koebnick C.
      • Caan B.
      • Weinmann S.
      • Leonard A.C.
      • et al.
      Bariatric surgery and the risk of cancer in a large multisite cohort.
      ,
      • Rustgi V.K.
      • Li Y.
      • Gupta K.
      • Minacapelli C.D.
      • Bhurwal A.
      • Catalano C.
      • et al.
      Bariatric surgery reduces cancer risk in adults with nonalcoholic fatty liver disease and severe obesity.
      ], endometrial [
      • Schauer D.P.
      • Feigelson H.S.
      • Koebnick C.
      • Caan B.
      • Weinmann S.
      • Leonard A.C.
      • et al.
      Bariatric surgery and the risk of cancer in a large multisite cohort.
      ,
      • Rustgi V.K.
      • Li Y.
      • Gupta K.
      • Minacapelli C.D.
      • Bhurwal A.
      • Catalano C.
      • et al.
      Bariatric surgery reduces cancer risk in adults with nonalcoholic fatty liver disease and severe obesity.
      ,
      • Aminian A.
      • Wilson R.
      • Al-Kurd A.
      • Tu C.
      • Milinovich A.
      • Kroh M.
      • et al.
      Association of bariatric surgery with cancer risk and mortality in adults with obesity.
      ,
      • Lazzati A.
      • Epaud S.
      • Ortala M.
      • Katsahian S.
      • Lanoy E.
      Effect of bariatric surgery on cancer risk: results from an emulated target trial using population-based data.
      ,
      • Ishihara B.P.
      • Farah D.
      • Fonseca M.C.M.
      • Nazario A.
      The risk of developing breast, ovarian, and endometrial cancer in obese women submitted to bariatric surgery: a meta-analysis.
      ], ovarian [
      • Lazzati A.
      • Epaud S.
      • Ortala M.
      • Katsahian S.
      • Lanoy E.
      Effect of bariatric surgery on cancer risk: results from an emulated target trial using population-based data.
      ,
      • Ishihara B.P.
      • Farah D.
      • Fonseca M.C.M.
      • Nazario A.
      The risk of developing breast, ovarian, and endometrial cancer in obese women submitted to bariatric surgery: a meta-analysis.
      ], and postmenopausal breast [
      • Schauer D.P.
      • Feigelson H.S.
      • Koebnick C.
      • Caan B.
      • Weinmann S.
      • Leonard A.C.
      • et al.
      Bariatric surgery and the risk of cancer in a large multisite cohort.
      ] cancer. Additionally, bariatric surgery can decrease cancer specific mortality by 40–50 % across the spectrum of malignancies a [
      • Aminian A.
      • Wilson R.
      • Al-Kurd A.
      • Tu C.
      • Milinovich A.
      • Kroh M.
      • et al.
      Association of bariatric surgery with cancer risk and mortality in adults with obesity.
      ,
      • Adams T.D.
      • Stroup A.M.
      • Gress R.E.
      • Adams K.F.
      • Calle E.E.
      • Smith S.C.
      • et al.
      Cancer incidence and mortality after gastric bypass surgery.
      ]. Recent evidence from secondary analyses of the randomized controlled Look AHEAD trial suggests that intensive lifestyle modifications aimed at weight loss can lead to reduction of obesity-related cancers in overweight or obese adult patients [
      • Yeh H.C.
      • Bantle J.P.
      • Cassidy-Begay M.
      • Blackburn G.
      • Bray G.A.
      • Byers T.
      • et al.
      Intensive weight loss intervention and cancer risk in adults with type 2 diabetes: analysis of the look AHEAD randomized clinical trial.
      ].

      6. Conclusion

      With rising prevalence of overweight and obesity globally, the proportion of cancer caused by excess body fatness is expected to increase. There is thus an urgent need to identify efficient ways at the individual and societal level to improve diet and physical activity patterns to reduce the burden of excess adiposity and accompanying diseases, including cancer. We believe that the role of modified peptide analogues of one or more than of these hormones in unimolecular forms or other formulations will play instrumental roles in limiting cancer prevalence and progression in the future via their major effects in decreasing body weight. This will be a major topic for future research efforts.

      CRediT authorship contribution statement

      SCL conducted the literature search, created the figures, and wrote the first draft of the paper. NS and CSM contributed to the drafting and revision of the paper.

      Declaration of competing interest

      The authors declare no competing interests.

      Acknowledgement

      None.

      Funding

      This work was supported by funding from the Swedish Cancer Society (Cancerfonden).

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