General, central obesities linked to higher risk of colorectal cancer

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Obesity rates are rising worldwide. In India, a 2022 study in The Lancet estimated the percentage of obese women and men to be 9.8% and 5.4% respectively. Along with higher risk of heart disease and diabetes, obesity has been linked to a higher susceptibility to colorectal cancer (CRC), among others.

CRC refers to cancers of the colon or the rectum. The CRC incidence is relatively low in India, but the percentage of people who are alive five years after a CRC diagnosis is reportedly under 40% — one of the lowest in the world. According to a 2017 study in the Indian Journal of Surgical Oncology, CRC patients in India are generally young and present more frequently with advanced stages of the disease.

Not all are equal

While researchers have known that obese individuals have a higher risk of CRC, a Science Advances study published in April 2024 reported evidence that not all obese people are at equal risk.

Instead, the risk seems to be higher for those who are "generally obese" and those who are "tall [and] centrally obese".

The study argued that different genetic pathways may explain how CRC is caused in different obesity subtypes.

"The study highlights the importance of considering body shapes as compared to BMI for risk assessment" of CRC," Dhruvi Shah, a doctoral candidate at the University of Bonn studying the association between obesity and influenza, said. Ms. Shah has studied the relationship between obesity and pancreatic cancer.

Data from the study could also be used to develop new screening tools for CRC in the future, she added.

Types of obesity

Obesity is generally defined with the body mass index (BMI), a number that accounts for the height and the weight of the individual. A BMI of 25 kg/m2 or above indicates being 'overweight' while 30 kg/m2 indicates 'obesity'.

However, this definition doesn't say anything about how fat is distributed in the body. Scientists are interested in this detail because body fat distribution better predicts obesity's adverse effects.

The distribution of fat in the body can be described using measures like waist circumference, hip circumference or the ratio between the two, i.e. waist-to-hip ratio.

But according to Neetu Kalra, a cancer therapeutics researcher at Azim Premji University, Bhopal, these estimates don't indicate whether certain types of body fat distribution put individuals at higher risk of obesity-related diseases. 

Two groups at risk

In the new study, scientists at the International Agency for Research on Cancer, France; Imperial College London; and the Girona Biomedical Research Institute, Spain, considered how these measures related collectively to CRC risk.

They began by analysing the BMI, weight, height, waist circumference, hip circumference, and the waist-to-hip ratio of more than 3 lakh people to group them into four body shapes based on their observable characteristics: PC1, PC2, PC3, and PC4.

PC1 individuals were "generally obese", while PC2 included tall individuals with a low waist-to-hip ratio.

PC3 included tall individuals with central obesity — with excess fat deposited around the abdomen. And PC4 had those who had an "athletic body shape".

The data were derived from the U.K. Biobank, a large database with information about the genetics, lifestyles, and other health parameters of more than half a million people in the country. Of the 3 lakh individuals, 3,728 had been diagnosed with CRC.

PC1 and PC3 individuals were strongly correlated with higher CRC risk while "PC2 and PC4 were not associated with CRC risk," the researchers found. These associations were also linked to the site at which CRC occurred and the sex of the individual.

Different obesities, different genes

Next, using a technique called genome-wide association study (GWAS), the researchers looked for small variations in the DNA of more than 400,000 participants in the Biobank database and found 570 novel variations characterising the four body shapes.

GWAS is used to find correlations between gene variations and traits in large groups of people.

For example, they found that a variation in a gene called AKT was implicated in the higher CRC risk for PC1 individuals. AKT regulates cell survival, insulin signalling, and the formation of blood vessels and tumours in humans.

Similarly, a variation of the RAF1 gene was found to be implicated in PC3 individuals' CRC risk. RAF1 mediates, among other processes, the transformation of normal cells into cancerous cells.

These genetic variations could explain the increased CRC risk in "generally obese" and "tall [and] centrally obese" body types, they wrote in their paper.

The genes at play

But gene expression varies between different body shapes and from tissue to tissue. A tissue is a group of similar cells that perform a specific function. The scientists studied whether the gene variations associated with each body type were expressed distinctly in different tissues.

Based on this analysis, they found that genetic variations associated with risk for PC1 individuals were most highly expressed in the "brain and in the pituitary gland".

The pituitary gland is located as the base of the brain and produces hormones important for regulating growth, blood pressure, and functions of the sex organs, the thyroid glands, and the kidneys. 

In contrast, the variations associated with risk in PC3 individuals were found enriched in "adipose tissue, nerve, cervix uteri, uterus, blood vessel, breast, fallopian tube, and ovary".

Could these genetic variations be directly responsible for the higher risk of CRC in PC1 and PC3 individuals? To answer this question, the researchers conducted a Mendelian randomisation test. Named for the founder of modern genetics, Gregor Mendel, the test uses statistical methods to check whether one variable (measured variation in genes) could be causing changes in the value of another (risk of CRC).

For this, the researchers used data from the Colorectal Transdisciplinary Study (CORECT), the Colon Cancer Family Registry (CCFR), and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) repositories.

They found that the genetic variations found in the GWAS analysis of PC1 and PC3 were "positively associated" with CRC risk. That is, the increased risk of CRC in these body types could be the effect of the corresponding gene variations.

'Large independent datasets'

The authors wrote in their paper that "the observed difference in genetic and tissue expressions suggests that PC1 and PC3 may capture different molecular origins and metabolic consequences of these body shapes and may reflect divergent mechanisms by which body shapes influence the risk of CRC."

That is, CRC arises in different body shapes through different physiological mechanisms.

Dr. Kalra, the cancer therapeutics researcher, said a key strength of the study lies in its use of "large independent datasets" that help the study cement its findings.

But she also said a person's body shape may change over time and that "the study doesn't provide information on whether and how" these changes "affect their CRC risk."

Further, GWAS, the technique the researchers used to identify genes that could be linked to higher CRC risk in PC1 and PC3 individuals, may also identify gene variants that may not be directly relevant to the disease. While flagging this concern, Dr. Kalra also said most variants identified in the study have been reported before and that "quite a few" of the novel ones have known "implications in tumour formation."

Ms. Shah, the University of Bonn obesity researcher, said recent studies point to cases where obese individuals can be free from cardiac problems, diabetes, and high blood pressure and cholesterol — and suggested future studies could examine CRC risk associated with these individuals.

Sayantan Datta is a science journalist and a faculty member at Krea University. They tweet at @queersprings.