Researchers at the University of Bristol’s Integrative Cancer Epidemiology Program (ICEP) have presented new evidence that how fat is distributed in people’s bodies, not just obesity, could make a difference to their risk of developing certain cancers. The study, published in the Journal of the National Cancer Institute, found that the accumulation of certain body fats—such as visceral fat and liver fat—affects the risk of 12 obesity-related cancers, independent of BMI.
“These findings support the growing consensus that BMI, while useful for population-level trends, may be too simplistic for assessing individual health risks,” said the study’s lead author Emma Hazelwood, PhD, a cancer evolution researcher at the University of Bristol. “Our results tell us that there is no ‘one-size-fits-all’ when it comes to cancer, meaning a more tailored approach to cancer prevention in people with obesity could be most effective.”
The rationale behind investigating fat distribution stems from recent developments in cardiovascular research, which have shown that certain fat types, especially visceral and liver fat, can independently raise disease risk. These findings have resulted in health organizations advocating for risk assessments not to use BMI as the primary metric for obesity’s role in disease risk. The 2024 European Association for the Study of Obesity framework and the Lancet Commission on the future of obesity have both encouraged this shift.
For their study, the ICEP researchers employed Mendelian randomization (MR), a genetic epidemiology technique, to assess five fat distribution traits: abdominal subcutaneous adipose tissue (ASAT), visceral adipose tissue (VAT), gluteofemoral adipose tissue (GFAT), liver fat, and pancreas fat. They then looked for an association between these traits and the risk of developing 12 obesity-related cancers: endometrial, ovarian, breast, colorectal, pancreatic, multiple myeloma, liver, kidney, thyroid, gallbladder, oesophageal adenocarcinoma, and meningioma.
While obesity is already known as a risk factor for developing certain cancers, “the importance of the anatomical distribution of adiposity in the obesity-cancer risk relationship is not fully understood,” the researchers wrote, noting that measures such as BMI can’t capture this variation in fat distribution and its physiological impact.
The study found that higher genetically predicted ASAT significantly increased the risks of endometrial cancer, liver cancer, and oesophageal adenocarcinoma. Conversely, higher genetically predicted GFAT was associated with decreased risks of breast cancer and meningioma. They also observed that liver fat and VAT increased the risk of liver cancer, while pancreatic fat raised the risk for endometrioid ovarian cancer.
“Our analyses provide novel insights into the relationship between adiposity distribution and cancer risk,” the researchers wrote. “These insights highlight the potential importance of adipose tissue distribution alongside maintaining a healthy weight for cancer prevention.”
Once the team had produced their risk assessments, they then looked for biological mechanisms that might explain the decreases in risk and found evidence that hormones and metabolic markers, such as bioavailable testosterone, fasting insulin, IGFBP-1, and adiponectin, could mediate the effects of specific fat deposits on cancer development. For instance, ASAT appeared to affect endometrial cancer risk via pathways involving SHBG and testosterone, while GFAT’s protective role in non-endometrioid endometrial cancer was potentially linked to higher adiponectin levels.
An important finding of the study was that while overall obesity is a risk factor, specific types of fat may be more harmful—or protective—than others. “The effects of adiposity distribution traits on cancer outcomes appear likely to vary, both by adiposity trait and cancer type,” the researchers wrote.
The findings could change how clinicians assess their patients for cancer risk based on what kind of fat, where it is in the body, and their potential risk. With further validation, fat distribution metrics could help identify individuals at higher risk of specific cancers, to allow for personalized prevention strategies, and could influence how obesity treatments, whether they are lifestyle changes or drug treatments, are used.
The research team noted that earlier observational studies had hinted at these relationships, but they exhibited limited reliability. Mendelian randomization, however, which uses genetic variants as proxies, strengthens the case for causality. Despite this, the authors noted that more research is needed, especially in non-European populations and using data with greater statistical power.
For instance, “future studies should explore potential interactions between genetically predicted adiposity and alcohol consumption in relation to cancer risk, particularly liver cancer,” the researchers wrote. Additionally, their findings could be strengthened via better data on molecular traits such as estrogen and progesterone, which were not included.
Next steps along this line of inquiry would include studies using prospective cohorts to further validate these findings and to understand how different obesity treatments influence fat distribution and cancer pathways. “It is vital to understand the biological mechanisms that underpin these associations—particularly how and why different fat depots affect cancer development,” said Hazelwood.
