Obesity has been previously linked to an increased risk of cancer, but most studies have not differentiated the risks between male and female patients. A prospective study of more than 400,000 UK Biobank participants, carried out by researchers at Uppsala University, has now found that both overall fat accumulation and fat distribution in different parts of the body confer different cancer risks depending on sex. Additionally, the study indicated that such risks vary across cancer types, like colorectal, esophageal, and liver cancer.

Åsa Johansson PhD, and colleagues reported on their study in Cancer Cell, in a paper titled “Adiposity and sex-specific cancer risk.” In their report they concluded, “In this study, we report that fat accumulation and distribution influence the risk of many different types of cancer and some effects differ between sexes. Our results show that there is a strong effect of adiposity on cancer risk in general, which is in line with most previous studies, and could be used as a guide for future preventive strategies.”

Obesity is a recognized risk factor for several major cancer types, such as colorectal, breast, endometrial, kidney, and esophageal, the authors noted, and globally, the fraction of all cancer cases that can be attributed to obesity—the population attributable fraction, or PAF—is estimated to be 5–10%, but even higher, at more than 30% for esophageal and uterine corpus cancer in developed parts of the world. “In some cases, obesity has surpassed smoking as the leading modifiable risk factor for cancer,” the team continued. “This is particularly alarming in light of the ongoing global increase in the prevalence of obesity in both men and women over the last fifty years.”

Studies have in addition indicated that while body fat accumulation, as assessed by body mass index (BMI), represents a cancer risk, body fat distribution, measured, for example, as waist-to-hip ratio (WHR) or waist circumference (WC), may also be independently associated with cancer risk. And while this fat distribution differs “dramatically” between the sexes, the team continued, “… due to the intercorrelations between different adiposity traits and measurements, it is still unclear how different aspects of adiposity affect cancer risk. A systematic investigation of how different adiposity-related traits influence the risk of different types of cancer has not previously been presented.”

“An important aspect of obesity-associated disease risk is the distribution of fat in different compartments of the body,” Johansson further commented. “Fat stored in the abdomen is considered more pathogenic compared to subcutaneous fat. In addition, the amount of fat stored in different compartments, as well as the rates of most cancers, is known to differ between females and males. These facts motivated a careful sex-stratified analysis of adiposity-related cancer risk.”

For their study the investigators turned to data from 442,519 participants in the UK Biobank, a cross-sectional cohort of 500,000 U.K. residents aged between 37 and 73, who were recruited between 2006 and 2010 and then followed for a mean time of 13.4 years. Among the data collected from participants in the database were details about the distribution of fat in their bodies and whether they developed cancer. “… we determined and contrasted the sex-specific effects of 14 different adiposity traits that represent fat accumulation or fat distribution on 19 types of cancer, as well as eight histological subtypes of lung, esophageal, kidney, and liver cancer …” they wrote.

The researchers used Cox proportional hazards modeling to identify the associations between the levels and distribution of fat in the participants’ bodies at the time of the initial assessment, and their later rates of cancer. They found that all cancer types, except brain, cervical, and testicular cancers are associated with at least one obesity-related trait. “While previous studies were more limited regarding the number of cancers and adiposity traits, our study provides a comprehensive and systematic overview of the effects of fat distribution and accumulation traits on the risks for several cancer types and subtypes using a highly powered prospective study design,” the team noted.

In female patients, the strongest links between overall fat accumulation and cancer were in gallbladder cancer, endometrial cancer, and esophageal adenocarcinoma. In males, the strongest links between overall fat accumulation and cancer were in breast cancer, hepatocellular carcinoma, and renal cell carcinoma. In terms of fat accumulation and distribution, there were differential effects between sexes on colorectal, esophageal, and liver cancer. For instance, a larger proportion of fat stored in the abdomen was associated with esophageal squamous cell carcinoma in females, but not in males. Additionally, body fat accumulation was associated with a high risk for hepatocellular carcinoma in males, an effect that was not present in females.

“We were surprised to see that there appeared to be a difference in the effect of obesity on cancer risk, not only between males and females, but also between post- and pre-menopausal females,” said Johansson. “Most remarkable, obesity is only a risk factor for breast cancer after menopause, probably due to the change in estrogen production in association with menopause.”

The investigators did note limitations to their study, especially that it was limited largely to British White participants, which make up almost 95% of the UK Biobank. They explained that their findings may differ from or may not be applicable to other ethnicities. They also acknowledged that because participants were older, the results are likely not directly transferable to younger populations.

Nevertheless, they noted, “We show that many adiposity effects are heterogeneous between sexes, in particular for fat accumulation traits. In combination with the sex-specific genetic architecture of these traits that have been identified in previous studies this strongly supports that risk assessment in the clinic should be performed differently for men and women.”

The researchers plan to do additional studies to help develop a complete understanding of the molecular mechanisms underlying these findings. Future work will also focus on genetic and environmental risk factors for cancer, which are not static but differ across a person’s lifespan. This includes taking a closer look at the variation in the effects of obesity before and after menopause.

“Given the rapidly increasing rates of obesity globally, obesity is now the fastest-growing risk factor for overall cancer risk,” Rask-Andersen further pointed out. “Measures to prevent and reduce the occurrence of obesity and being overweight are therefore highly motivated. However, it is important to consider that reducing weight does not eliminate the risk of cancer. There are still many individual risk factors that play a much larger impact on specific types of cancer, such as smoking for lung cancer and exposure to sun for skin cancer.”

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