The study began with a simple question about families. Why do some people who carry a faulty BRCA2 gene develop cancer, and others don’t? Researchers at the National University of Singapore set out to answer it. They came away with something bigger: a link between the way the body burns sugar and the way tumours start.
The work, led by Professor Ashok Venkitaraman, was carried out at the Cancer Science Institute of Singapore and the NUS Centre for Cancer Research, with colleagues from the Agency for Science, Technology and Research (A*STAR). It appeared in the journal Cell in 2024 under the title “A glycolytic metabolite bypasses ‘two-hit’ tumor suppression by BRCA2.” The details here come from the university’s own account of the findings.
A chemical made from sugar
The team first looked at patients at high risk of breast or ovarian cancer because they inherited one faulty copy of BRCA2 from a parent. Cells from these patients proved unusually sensitive to methylglyoxal. This chemical forms when cells break down glucose for energy. According to the university, it can cause DNA faults that serve as early warning signs of cancer.
The finding did not stop with inherited risk. People who carry no faulty BRCA2 but run higher-than-normal methylglyoxal levels, such as patients with diabetes or pre-diabetes, can build up similar warning signs, the researchers reported. Both conditions are tied to obesity and poor diet.
“Cancer is caused by the interaction between our genes and factors in our environment, such as diet, exercise, and pollution,” Venkitaraman said. Exactly how those factors raise risk, he added, is still unclear, and understanding it matters for prevention.
An old theory revised
The results also push against a theory dating to 1971. Knudson’s “two-hit” idea held that cancer-preventing genes must be permanently switched off before a tumour can form. The NUS team found that methylglyoxal can switch such genes off only temporarily. Repeated episodes of poor diet or uncontrolled diabetes could therefore “add up” over time and raise the risk, according to the researchers.
First author Dr Li Ren Kong, a Lee Kuan Yew Fellow at the NUS Centre for Cancer Research, described the surprise. “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,” he said.
What could come next
Venkitaraman suggested that patients with high methylglyoxal may face greater cancer risk, and that a blood test for HbA1C could potentially serve as a marker. High levels can usually be controlled with medicines and a good diet, he said, which opens the door to steps taken before a cancer begins.
The team plans further studies on whether metabolic disorders and poor diets affect cancer risk in Singapore and other Asian countries. It also hopes to identify more links between metabolism, diet and cancer.
Anyone worried about their own risk should consult a doctor.
