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Adiposity and cancer risk: new mechanistic insights from epidemiology

Key Points

  • A large volume of epidemiological evidence points to an association between body mass index (BMI) and increased risk of several cancer types. Proposed mechanisms for the adiposity–cancer link need to account for the observed specificities of associations by gender, site, histological subtype and molecular phenotype.

  • Underlying the above associations, three mainly 'hormonal' mechanisms have been proposed: altered sex hormone metabolism; increased insulin levels and bioavailability of insulin-like growth factor I (IGF1); and adipokine pathophysiology. Additionally, newer hypotheses have been suggested, including as systemic inflammation and microbiome effects. These hypotheses generally fail to capture the specificity of associations.

  • Intentional weight loss might lead to changes of obesity-associated intermediary biomarkers, which in turn might indicate causal pathways to the development of obesity-associated cancer. However, there are many inconsistencies, particularly for changes in inflammatory markers and circulating IGF measurements.

  • Ectopic fat deposition is of two main types: systemic (such as visceral adipose tissue) and local (such as breast fat and hepatic steatosis). The concept of local ectopic fat is relatively new in the field of cancer, but it has been implicated in the development of cardiovascular disease. This concept confers specificity of association for cancer risk and could pave the way to more-targeted preventive interventions in the future.

Abstract

Excess body adiposity, commonly expressed as body mass index (BMI), is a risk factor for many common adult cancers. Over the past decade, epidemiological data have shown that adiposity–cancer risk associations are specific for gender, site, geographical population, histological subtype and molecular phenotype. The biological mechanisms underpinning these associations are incompletely understood but need to take account of the specificities observed in epidemiology to better inform future prevention strategies.

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Figure 1: Biological mechanism hypotheses.
Figure 2: The roles of ectopic fat.
Figure 3: Hypothesized steatosis–hepatocellular carcinoma pathway.

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Acknowledgements

The authors acknowledge the many colleagues and other researchers around the world who have shared with them, over many years, their thoughts, experiences and methodological insights into the details and concepts described in this Review.

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FURTHER INFORMATION

Health Survey for England

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Supplementary information

41568_2015_BFnrc3967_MOESM207_ESM.pdf

Supplementary information S1 (table) | Summary of findings from epidemiological studies (2006 to 2012) that report associations between serum adiponectin levels and risk of different types of cancer, condensed from Dalamaga et al. review.1 (PDF 74 kb)

Supplementary information S2 (table) | Measures of abdominal adiposity, BMI and cancer risk (PDF 243 kb)

Supplementary information S3 (table) | Causal structure and diagrams

(PDF 112 kb)

Glossary

Body mass index

(BMI). An anthropometric measure of body adiposity defined as the body mass (in kilograms) divided by the square of the body height (in metres).

Intermediary biomarkers

Biomarkers that predict the development of a disease and thought to be on the causal pathway to the development of that disease.

Sex hormone

A family of hormones that share a basic chemical (steroidal) structure. These hormones include androgens, oestrogens and progesterone, and they have important effects on sexual development and reproductive functions.

Bioavailability

The proportion of a substance that can be used physiologically by target tissues.

Cohort studies

Studies in which a group of individuals is investigated prospectively over time. This is the preferred epidemiological study method for evaluating anthropometric measures and cancer risk.

Relative risk

The risk of cancer (or other disease) in a group of exposed persons divided by the risk in a group of unexposed persons. Relative risk is a commonly used measure of association in epidemiological studies.

Effect modification

Also known as effect interaction. When the association of an exposure with the risk of disease differs in the presence of another exposure.

Anthropometric measures

Measurements of the size or proportions of the human body: for example, weight, height and waist circumference.

Summary risk estimates

The weighted summations of collections of study-level risks derived from meta-analyses of studies. These estimates are typically reported as risk or point estimates with 95% confidence intervals.

Confounding

The association or lack of association with an exposure that is actually due to another factor that determines the occurrence of a disease but that is also associated with the exposure.

Anovulation

A menstrual cycle that is not accompanied by the discharge of an egg from the ovary.

Attributable risk

In epidemiology, this is the difference in the rate of a condition between an exposed population and an unexposed population.

Peripheral adipose tissue

Fat stores other than intra-abdominal fat (mainly subcutaneous fat).

Hyperinsulinaemia

A pathophysiological state characterized by elevated levels of insulin in the circulation.

Reporting bias

A scenario in which investigators fail to report outcomes in studies, often because these associations are not significant.

Visceral adipose tissue

(VAT). Adipose tissue arising in the abdominal cavity — namely, the omentum, mesenteric and retro-peritoneal fat stores — but excluding within-viscera fat, such as intrahepatic and intrapancreatic fat.

Biomarkers

Characteristics that are objectively measured and evaluated as indicators of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention.

Central adiposity

The storage of adipose tissue preferentially in adipocytes within the trunk rather than the extremities.

Steatosis

The accumulation of intracellular fats, mainly triglycerides. Used typically to describe fat deposition within the liver (hepatic steatosis) but may equally apply to fat accumulation in other organs.

White adipose tissue

(WAT). A type of body fat. Mammals have three types of body fat: white, brown and beige. The main function of WAT is metabolism.

Bias

A systematic deviation of a result from a true value.

Structural equation modelling

A family of statistical modelling techniques that combine latent variables through regression equations.

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Renehan, A., Zwahlen, M. & Egger, M. Adiposity and cancer risk: new mechanistic insights from epidemiology. Nat Rev Cancer 15, 484–498 (2015). https://doi.org/10.1038/nrc3967

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