Research published in PLOS Medicine today uses genetic evidence to link obesity to cancer of the digestive system. But while previous research has linked increased body size to various cancer types, findings from this study are more targeted, indicating specifically that fat mass is the main obesity-related risk factor for digestive system cancer, and that obesity influences certain cancer types but not others.

It’s well known that being large is linked with having a greater risk of cancer,” said Dr Stephen Burgess, a statistician based at the MRC Biostatistics Unit. “But what was not known is whether the increased risk is an inevitable result of being a big person, or whether it is caused by a specific component of obesity that people can change.”

Researchers at the University of Cambridge, Imperial College London, Karolinska Institutet in Stockholm, and the University of Bristol took genetic variants that influence an individual’s height and weight, and compared whether having genes that predispose an individual to increased body mass index (BMI) also predisposed them to higher risk of various cancer types. They did the same for genes that predispose an individual to being taller. However, while increased genetic predisposition to being tall was consistently associated with increased risk across the different cancer types investigated, genetic predisposition to increased BMI was associated with increased risk of cancers of the digestive system – including cancer of the liver, stomach, oesophagus, and pancreas – but not associated with increased overall risk of other cancers.

Looking further, there were opposite directions of effect for different cancer types. In particular for sex-linked cancers, genetic predisposition to increased BMI was associated with increased risk of cervical and endometrial cancer, but decreased risk of breast and prostate cancer. The scientists also compared associations of genes that influence an individual’s fat mass versus fat-free mass to differentiate between these components of body size. Fat mass is the portion of an individual’s weight attributable to fat; fat-free mass is an individual’s weight excluding body fat. The increased risk of various digestive cancers was primarily attributable to fat mass.

By comparing individuals based on their genes rather than based on their measured height or weight directly, the researchers were able to avoid some of the pitfalls of judging causation from observational data, such as “reverse causation” – whereby individuals with cancer often lose weight due to either cancer or the cancer treatment, meaning that the association between body size and cancer risk is distorted. In contrast, genes are fixed throughout an individual’s life, so they are not affected by the presence of cancer, or any other risk factor that may lead to a correlation that is unrepresentative of the true causal relationship between body size and cancer risk.

Although the study did not provide any definitive evidence about the mechanisms linking body size to increase cancer risk, it is generally thought that tall people have higher cancer risk because they have more cells in their body, so there are more chances for cancer to develop. A specific link between fat mass and digestive cancers may be driven by increased consumption of cancer-causing substances (carcinogens) in fatty food, or increased levels of fatty tissue leading to increased inflammation in the digestive tract. Links between obesity and sex-specific cancers are likely driven by the production of reproductive hormones in fatty tissue.

“This result has important clinical implications” says lead author Dr Mathew Vithayathil, a clinical researcher in gastroenterology at Imperial College London. “While our research supports a causal role of obesity in driving and protecting against certain cancers, it suggests differential effects of BMI for different malignancies which should be explored further. Rather than presenting obesity as a generic cancer risk factor, a more nuanced public health message with regards to obesity as a risk factor for digestive system cancers may be more appropriate.”

“The key message to the public should focus less on physical size, which people can often do little about, and more on managing the amount of fat that they carry,” says Dr Amy Mason, a statistician at the Department of Public Health and Primary Care in the University of Cambridge.

To read the paper in full, go to: https://journals.plos.org/plosone/article?id=10.1371/journal.pmed.1003706