General, central obesity linked to higher risk of colorectal cancer

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

CRC refers to cancer of the colon or rectum. The incidence of CRC in India is relatively low, but the percentage of people alive five years after CRC diagnosis is reportedly less than 40% – one of the lowest in the world. According to a 2017 study Indian Journal of Surgical OncologyCRC patients in India are generally young and often present with advanced stages of the disease.

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all are not equal

While researchers have known that obese individuals have a higher risk of CRC science advancement The study, published in April 2024, provides evidence that not all obese people are at equal risk.

Instead, the risk appears to be greater 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 occurs in different obesity subtypes.

“The CRC study highlights the importance of considering body size rather than BMI for risk assessment,” said Dhruv Shah, a doctoral candidate at the University of Bonn who studies the link between obesity and influenza. Ms Shah has studied the relationship between obesity and pancreatic cancer.

He said data from the study could also be used to develop new screening tools for CRC in the future.

types of obesity

Obesity is typically defined by body mass index (BMI), a number that takes account of a person's height and weight. BMI of 25 kg/m2 or above indicates being 'overweight' while 30 kg/m2 Refers to 'obesity'.

However, this definition says nothing about how fat is distributed in the body. Scientists are interested in this detail because body fat distribution better predicts the adverse effects of obesity.

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

But according to Neetu Kalra, a cancer clinical researcher at Azim Premji University, Bhopal, these estimates do not reflect whether certain types of fat distribution in the body put individuals at greater risk of obesity-related diseases.

two groups in danger

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

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

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PC1 individuals were “generally obese”, while PC2 included tall individuals with low waist-to-hip ratios.

PC3 included tall individuals with central obesity – those with excess fat accumulation around the abdomen. And PC4 included those who had an “athletic body shape.”

The data was obtained from the UK Biobank, a large database containing information about the genetics, lifestyle and other health parameters of more than half a million people in the country. Of the 3 lakh individuals, 3,728 were diagnosed with CRC.

The researchers found that PC1 and PC3 individuals were strongly associated with higher CRC risk, while “PC2 and PC4 were not associated with CRC risk.” These associations were also related to the site where CRC occurred and the person's gender.

Different obesity, 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 new variations characterizing four body shapes.

GWAS are used to find associations between gene variations and traits in large groups of people.

For example, they found that there is variation in a gene called akt PC1 was implicated in higher CRC risk for individuals. akt Regulates cell survival, insulin signaling, and formation of blood vessels and tumors in humans.

Similarly, a variation of RAF1 Genes found to be involved in CRC risk of PC3 individuals. RAF1 Mediates the transformation of normal cells into cancer cells, among other processes.

These genetic variations may explain increased CRC risk in “typically obese” and “tall” people [and] “centrally obese” body type, they wrote in their paper.

genes are playing

But gene expression varies between different body sizes and tissue to tissue. 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 distinctly expressed in different tissues.

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

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

In contrast, risk-associated variations in PC3 individuals were found to be enriched in “adipose tissue, nerve, cervical uterus, 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, researchers conducted a Mendelian randomization test. Named after Gregor Mendel, the founder of modern genetics, this test uses statistical methods to test whether one variable (a measured variation in a gene) can cause a change in the value of another (risk of CRC). .

To this end, 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) repository.

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 may be an effect of associated gene variations.

'Large independent datasets'

The authors write in their paper that “the observed differences in genetic and tissue expressions suggest that PC1 and PC3 may capture different molecular origins and metabolic consequences of these body shapes and may reflect distinct mechanisms by which body shape changes.” influence the risk of CRC.”

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

Dr. Kalra, a cancer therapeutics researcher, said a major strength of the study lies in its use of a “large independent dataset” that helps the study strengthen its findings.

But he also said that a person's body shape can change over time and “the study does not provide information about whether and how” these changes “affect their CRC risk.”

Additionally, GWAS, the technique that researchers use to identify genes that may be associated with higher CRC risk in PC1 and PC3 individuals, can also identify gene variants that are directly related to the disease. Can't be. Highlighting this concern, Dr. Kalra also said that most of the variants identified in the study have been reported before and “quite a few” of the new variants are known to have “implications in tumor formation.”

Ms Shah, the obesity researcher at the University of Bonn, said recent studies point to cases where obese individuals can be free from cardiovascular problems, diabetes and high blood pressure and cholesterol – and suggested that future studies involving these individuals Can check CRC risk.

Sayantan Dutta is a science journalist and faculty member at Kriya University. They tweet at @queersprings.

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