Scientists believe they have uncovered a missing link between how eating junk food increases the risk of cancer, after a study looked at the effect of methylglyoxal – a compound released when the body breaks down sugary and fatty foods – on a gene that helps fight off tumours.
In a first, the academics from Singapore found that methylglyoxal was able to temporarily shut off the BRCA2 gene’s ability to protect against cancer forming and growing, reports Daily Mail.
Doctors have known for decades that eating junk food is linked to a much higher risk of cancer, even if the person is not obese, but the exact mechanism is still being understood.
This latest finding could, at least in part, explain why cancers among young, ostensibly healthy Americans are becoming so prevalent, particularly tumours in the colon.
The team also noted that the study contradicts a long-standing theory called Knudson’s hypothesis – the ‘two-hit’ paradigm – which said that genes like BRCA2 must be completely inactive in the body to raise cancer risk.
These genes are meant to help protect the body against cancer, though patients who inherit faulty copies from their parents have been shown to have an increased risk of certain cancers, such as breast and pancreatic.
Dr Ashok Venkitaraman, study author and director of the National University of Singapore’s Centre for Cancer Research, said: “(M)ethylglyoxal triggers the destruction of BRCA2 protein, reducing its levels in cells. This effect is temporary, but can last long enough to inhibit the tumour-preventing function of BRCA2.”
Repeated exposure, like through eating processed foods and red meat, among others, would increase the amount of damage to genes like BRCA2, he added.
The team looked at the effect of methylglyoxal on cells from people who had inherited a faulty copy of BRCA2 and were therefore more likely to develop cancer.
They found that methylglyoxal exposure disabled tumour suppression.
“It is well documented that some individuals are at a high risk of developing breast, ovarian, pancreatic or other cancers because they inherit a faulty copy of the cancer-preventing gene – BRCA2 – from their parents,” Venkitaraman said.
“Our recent findings show that cells from such individuals are particularly sensitive to the effects of methylglyoxal, the chemical produced when our cells break down glucose to create energy.
“We find that methylglyoxal inhibits the tumour-preventing function of BRCA2, eventually causing faults in our DNA that are early warning signs of cancer development.”
Additionally, he noted that high levels of methylglyoxal are common in people with diabetes and prediabetes.
“Methylglyoxal can temporarily inactivate such cancer-preventing genes, suggesting that repeated episodes of poor diet or uncontrolled diabetes can ‘add up’ over time to increase cancer risk.”
However, the team cautioned that since the study was carried out in cells rather than people, more research is needed on the topic.
The research adds to a long list of studies suggesting that diet could have an impact on cancer risk, particularly colorectal cancer.
Research from the Cleveland Clinic, for example, found that people under 50 who ate diets rich in red meat and sugar had lower levels of the compound citrate, which is created when the body converts food into energy and has been shown to inhibit tumour growth.
The study was published in the journal Cell.
Study details
A glycolytic metabolite bypasses “two-hit” tumor suppression by BRCA2
Li Ren Kong, Komal Gupta, Andy Jialun Wu et al.
Published in Cell on 11 April 2024
Summary
Knudson’s “two-hit” paradigm posits that carcinogenesis requires inactivation of both copies of an autosomal tumour-suppressor gene. Here, we report that the glycolytic metabolite methylglyoxal (MGO) transiently bypasses Knudson’s paradigm by inactivating the breast cancer suppressor protein BRCA2 to elicit a cancer-associated, mutational single-base substitution (SBS) signature in non-malignant mammary cells or patient-derived organoids. Germline monoallelic BRCA2 mutations predispose to these changes. An analogous SBS signature, again without biallelic BRCA2 inactivation, accompanies MGO accumulation and DNA damage in Kras-driven, Brca2-mutant murine pancreatic cancers and human breast cancers. MGO triggers BRCA2 proteolysis, temporarily disabling BRCA2’s tumour suppressive functions in DNA repair and replication, causing functional haploinsufficiency. Intermittent MGO exposure incites episodic SBS mutations without permanent BRCA2 inactivation. Thus, a metabolic mechanism wherein MGO-induced BRCA2 haploin-sufficiency transiently bypasses Knudson’s two-hit requirement could link glycolysis activation by oncogenes, metabolic disorders, or dietary challenges to mutational signatures implicated in cancer evolution.
Cell article – A glycolytic metabolite bypasses “two-hit” tumor suppression by BRCA2 (Open access)
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