We reviewed 204 meta-analyses to evaluate the current evidence for associations between seven adiposity indices and the risk of developing or dying from 36 primary cancers and their subtypes. Twelve associations, stemming from cohort studies using continuous measures of adiposity, were supported by strong evidence, inferred by strongly statistically significant results and no suggestion of bias. These associations were primarily between body mass index and malignancies of digestive organs (oesophageal adenocarcinoma and cancers of the colorectum (in men only), biliary tract system, and pancreas), hormone related cancers (such as postmenopausal breast in women who have never used HRT), premenopausal and overall endometrial cancer, kidney cancer, and multiple myeloma. Five additional associations were supported by strong evidence when categorical measures of adiposity were used: weight gain with risk of colorectal cancer risk and body mass index with risk of gallbladder, gastric cardia, and ovarian cancer, and mortality from multiple myeloma.

The effect of obesity on the incidence and mortality of cancer is well recognised66284 and was evident in our umbrella review, with approximately 77% of the included meta-analyses reporting a nominally statistically significant summary random effects estimate. Although the reported associations are plausibly accurate and potentially causal, the risk of reporting, selection, and other inherent biases may overestimate the suggested associations, as shown in other recently published umbrella reviews in cancer epidemiology.111327 The extent to which the literature is affected by such biases is difficult to prove definitively. We used statistical tests and sensitivity analyses to look for evidence of bias. When lower P value thresholds (P<10−6) were used, the proportion of significant associations decreased to 37%. Large heterogeneity (I2 ≥50%) was observed in 37% of the meta-analyses. When we calculated the 95% prediction intervals, which further account for heterogeneity, we found that the null value was excluded in only about one third of the associations. Moreover, some meta-analyses had evidence of small study effects or excess significance bias. Most meta-analyses (53%) preserved their statistical significance with a 10% credibility ceiling, but only one in five preserved significance at a ceiling of 20%, indicating that many associations between adiposity and cancer remain uncertain.

Comparison with other studies

Our grading of the evidence largely agrees with systematic analyses of the literature performed by the World Cancer Research Fund (WCRF) and the International Agency for Research on Cancer (IARC).68485 The WCRF currently lists seven cancers for which the evidence supports a convincing causal relationship with obesity (oesophageal adenocarcinoma and cancers of the pancreas, colorectum, postmenopausal breast, endometrium, kidney, and liver). We also found strong evidence that obesity increases the risk of these cancers, except for liver cancer, for which the evidence was considered highly suggestive because of small study effects, excess significance bias, and substantial heterogeneity between studies. The association between obesity and five more malignancies (gallbladder, stomach cardia, ovarian, advanced prostate, and premenopausal breast cancer) was graded as probably causal by WCRF and received lower evidence grades in our main analysis using only continuous measures of adiposity. IARC found sufficient evidence to support the association between excess body fat and 13 of 24 cancer sites (oesophagus (adenocarcinoma), gastric cardia, colorectum, liver, gallbladder, pancreas, postmenopausal breast, endometrium, ovary, kidney, meningioma, thyroid, and multiple myeloma).84 Our results are similar to those of the IARC report for most cancers, except for gastric cardia, liver, ovarian, meningioma and thyroid cancers. These cancers received lower than strong evidence grades in our main analysis, owing to small numbers of cancer cases, very large heterogeneity between studies, or evidence of small study effects and excess significance bias. However, the associations between adiposity and risk of gastric cardia and ovarian cancer were judged to be supported with strong evidence when we evaluated categorical measures of adiposity. Similarly, evidence for an association between adiposity and risk of meningioma was considered strong when case-control studies were included in the evaluation.

Several methods exist for rating evidence, but they are inconsistent and allow some degree of arbitrariness.86 The WCRF and IARC used expert groups and criteria similar to Bradford Hill criteria to assess the association between obesity and risk of 17 and 24 primary cancers, respectively, whereas we assessed the robustness of the evidence using sensitivity analyses and statistical tests to evaluate 36 primary cancers and their subtypes, defined by anatomical location, histology, and receptor status. We also explored associations by potential effect modifiers (eg, sex, menopausal status, smoking status, and use of HRT). Our criteria for grading evidence should not be considered causal criteria, especially when used individually, but we think that they are useful for identifying biases when used together.12

Most of the associations between adiposity indices and endometrial cancer were supported by strong or highly suggestive evidence. In particular, the association between waist to hip ratio and risk of total endometrial cancer was supported by strong evidence, indicating that central obesity, which is linked to hyperinsulinaemia and type 2 diabetes, has a major role in the development of this disease. Strong evidence also supported the association between body mass index and premenopausal endometrial cancer. We found the associations between body mass index in adults or at around age 20, waist circumference, weight, and weight gain and total endometrial cancer, and between body mass index and postmenopausal type I and II endometrial cancer to be highly suggestive owing to substantial heterogeneity between studies and potential for excess significance bias. These results were in agreement with the WCRF and IARC, which did not provide separate ratings for menopausal status or histological subtype of disease.8487 The difference in evidence ratings between premenopausal and postmenopausal endometrial cancer is probably related to heterogeneity caused by use of HRT among postmenopausal women.88 We found that the associations between body mass index or weight gain and postmenopausal endometrial cancer were statistically significantly stronger in never users compared with ever users of HRT, but the relevant meta-analyses included only 2-6 studies and had fewer than 1000 cancer cases, so the evidence was deemed weak. The WCRF found that the associations between waist circumference or waist to hip ratio and total endometrial cancer were probably causal,87 which largely agreed with our findings.

We found strong evidence to support the association between weight gain in adulthood and postmenopausal breast cancer among women who have never used HRT, yielding an 11% higher risk per 5 kg of weight gain. We found highly suggestive evidence to support the positive association of body mass index with postmenopausal breast cancer, irrespective of HRT. Weight gain may be a better metric than body mass index for measuring the dynamic nature of adiposity during adulthood, when obesity becomes central and has more metabolic effects.49 Another reason for the lower grading of the evidence for body mass index was the large heterogeneity between studies,62 which could at least partially be explained by a potential interaction with HRT use. Some cohort studies have found a positive association between body mass index and postmenopausal breast cancer only among women who have never used HRT,8990 but we did not capture this potential interaction because published meta-analyses have not performed this subgroup analysis.6278 The evidence for an association between adiposity indices and premenopausal breast cancer was weaker and only reached suggestive evidence for an inverse association with body mass index in a meta-analysis of 20 cohort studies. These results largely agree with the WCRF and IARC findings of a convincing causal positive association between adiposity and postmenopausal breast cancer8491 and a probable causal inverse association for premenopausal disease.91 Two recent Mendelian randomisation studies found that a higher body mass index in adults was associated with a lower risk of postmenopausal breast cancer, contradicting the epidemiological evidence.9293 This may be due to the genetic risk score for body mass index in adults being a stronger determinant of early compared with later life body mass index; epidemiological studies have found inverse associations between body mass index in childhood and both premenopausal and postmenopausal breast cancer.9495 The positive association between body mass index in adults and postmenopausal breast cancer found in epidemiological studies may be driven by weight gain in adulthood. We found strong evidence to support the association between weight gain in adults and postmenopausal breast cancer, but weight gain is probably linked to environmental factors that are not captured by genetic risk factors.96 Moreover, some evidence exists that these associations may differ according to oestrogen and progesterone receptor status of the tumour (supplementary tables 6 and 7),6897 but large investigations in this area are lacking.

The association between body mass index and colon cancer was supported by strong evidence in men and suggestive evidence in women. Twenty four cohorts investigated the association in men, totalling a 30% higher risk of colon cancer for each 5 kg/m2 increase in body mass index. The risk was 12% higher for each 5 kg/m2 increase in body mass index among women in a meta-analysis of 20 cohorts that showed substantial heterogeneity and evidence of small study effects and excess significance bias. The association between body mass index and rectal cancer in men was supported by strong evidence, but with a summary relative risk considerably smaller than for colon cancer (1.09 v 1.30). We found no association between body mass index and rectal cancer in women. The evidence for most of the other adiposity indices was suggestive, as few studies have investigated these associations. The insulin signalling pathway is a possible mechanism underlying the association between obesity and colorectal cancer in men.98 The increased concentrations of circulating insulin induced by adiposity are higher among men than women,99 and men are more prone to abdominal fatness than women.100 Furthermore, endogenous and exogenous oestrogens have been associated with protective effects against colorectal cancer among women, which might explain why the association of adiposity with colorectal cancer is stronger in men than in women.101102 Two Mendelian randomisation studies found statistically significant positive associations between adult body mass index and colorectal cancer but did not perform analyses by sex.92103

We found that higher body mass index was associated with an increased risk of oesophageal adenocarcinoma, and this was supported by strong evidence. We found an inverse association for oesophageal squamous cell carcinoma, which was supported by highly suggestive evidence due to considerable heterogeneity between studies. Similar summary associations were found by the WCRF and IARC, which concluded that adiposity convincingly increased the risk of oesophageal adenocarcinoma.84104 A Mendelian randomisation study supports this association.105 Oesophageal squamous cell carcinoma has stronger associations with smoking and alcohol consumption than oesophageal adenocarcinoma,106 but we were unable to capture the potential residual confounding or effect modification of smoking and alcohol in the associations between adiposity and oesophageal squamous cell carcinoma because the published meta-analysis did not report these subgroup analyses.62

We found an inverse association between body mass index and lung cancer that was supported by highly suggestive evidence but had substantial heterogeneity between studies and evidence of small study effects. When we investigated this association by smoking status, we found an inverse association between body mass index and lung cancer among smokers, which was supported by suggestive evidence. We found a non-significant association among non-smokers. These results may be due to residual confounding, reverse causation, or effect modification by smoking, which led the WCRF and IARC to grade this evidence as inadequate.84107 Two recent Mendelian randomisation studies found that body mass index was statistically significantly associated with an increased risk of squamous and small cell lung cancer but had a borderline significant inverse association with lung adenocarcinoma.92108 One of the Mendelian randomisation studies found a statistically significant inverse association between body mass index and total lung cancer among never smokers and a null association in ever smokers,108 which contradicts the epidemiological evidence. However, these analyses were underpowered. Future large prospective studies should evaluate associations according to smoking status among different disease subtypes.

Furthermore, we found that the associations between body mass index and multiple myeloma and cancers of the biliary tract system, pancreas, and kidney were supported by strong evidence. The WCRF and IARC ratings were similar, except the WCRF did not study multiple myeloma.8485 The associations for less common malignancies are supported by limited data and show substantial heterogeneity between studies; we need prospective studies to better characterise these associations.