Scientists from Singapore and the UK have unveiled a previously unknown mechanism for gene inactivation which may reveal the link between diet-related health conditions and cancer risk.
Their research, conducted using mouse models, human tissue samples, and lab-grown human breast organoids, has revealed how alterations in glucose metabolism can temporarily disable the BRCA2 gene, a crucial suppressor of tumour formation.
The finding offers insights into why unhealthy dietary habits and unmanaged metabolic conditions like diabetes are associated with an increased risk of cancer development, reported Science Alert.
"These findings raise awareness of the impact of diet and weight control in the management of cancer risks," says the first author of the new study, cancer pharmacologist Li Ren Kong from the Cancer Science Institute of Singapore (CSI Singapore).
"We started the study aiming to understand what factors elevate risk in families susceptible to cancer, but ended up discovering a deeper mechanism linking an essential energy consumption pathway to cancer development," Kong added.
Professor Ashok Venkitaraman spearheaded the study, which was carried out by researchers from the Cancer Science Institute of Singapore (CSI Singapore) at NUS and NUS Centre for Cancer Research (N2CR) at the Yong Loo Lin School of Medicine, alongside colleagues from the Agency for Science, Technology and Research (A*STAR).
Prof Venkitaraman, Director of CSI Singapore, as quoted by NUS News, said, "Cancer is caused by the interaction between our genes and factors in our environment, such as diet, exercise, and pollution. How such environmental factors increase cancer risk is not yet very clear, but it is vital to understand the connection if we are to take preventive measures that help us stay healthy longer."
According to Knudson's theory from 1971, both copies of a gene called BRCA2 must be damaged for cancer to begin. But recent studies suggest that even if just one copy of BRCA2 is mutated, it can still lead to cancer.
Surprisingly, cells with this single mutation don't show the usual signs of genetic instability seen in cells with both copies of the gene damaged.
In mice, having only one copy of BRCA2 affected doesn't seem to cause big problems in organ growth or fixing DNA in most body parts. But cells with this change seem to be weaker against things like toxins in the environment, such as formaldehyde or acetaldehyde.
The team studied individuals inheriting one faulty BRCA2 copy. They found their cells were more sensitive to MGO, or, methylglyoxal, a byproduct of glucose breakdown in glycolysis. Glycolysis usually controls MGO levels, but high MGO can harm DNA and proteins.
In conditions like diabetes, high blood sugar increases MGO, worsening complications.
Researchers found MGO can temporarily deactivate BRCA2, causing cancer-linked mutations. While BRCA2 can recover, repeated MGO exposure can lead to more mutations, promoting cancer. Thus revealing how glucose metabolism changes can disrupt BRCA2, aiding cancer development.
Since MGO can briefly impair BRCA2's DNA repair function, it's logical that an unhealthy diet or unmanaged diabetes might raise cancer risk, even in those with two healthy BRCA2 copies the study claimed.
"Methylglyoxal can be easily detected by a blood test for HbA1C, which could potentially be used as a marker," Venkitaraman says.
"Furthermore, high methylglyoxal levels can usually be controlled with medicines and a good diet, creating avenues for proactive measures against the initiation of cancer."
The researchers said they intend to delve deeper into whether metabolic disorders like diabetes or unhealthy diets impact cancer risk not only in Singapore but also in other Asian nations.
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