Cancer genetics has long leaned on a tidy rule known as Knudson’s two-hit paradigm. A tumor suppressor gene has two copies, and both have to fail before a tumor can take hold. A paper that appeared in the journal Cell on 11 April 2024 says that rule has a gap. The authors, working at the Cancer Science Institute of Singapore, report that a chemical made when cells burn sugar can briefly knock out a second BRCA2 copy that is perfectly healthy.
The chemical is methylglyoxal, abbreviated MGO. Cells produce it as a by-product of glycolysis, the breakdown of glucose for energy. According to the paper, MGO sets off the breakdown of BRCA2 protein. A cell is left with less of it, and its ability to repair and copy DNA suffers. The authors call the result functional haploinsufficiency. The effect is temporary. Ashok Venkitaraman, a study author who runs cancer research at the National University of Singapore, said the effect “is temporary, but can last long enough to inhibit the tumour-preventing function of BRCA2.”
Who is most exposed
People who inherit one faulty BRCA2 copy already face higher odds of breast, ovarian and pancreatic cancers. In the team’s experiments, cells from such carriers proved especially sensitive to MGO. “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,” Venkitaraman said.
The researchers saw a distinctive pattern of single-base mutations in non-malignant mammary cells and in patient-derived organoids exposed to MGO. A similar pattern appeared in mouse pancreatic cancers and in human breast cancers where MGO had built up. Exposure that came and went produced mutations in episodes, without BRCA2 ever being lost for good. That is why the authors think repeated hits could add up. Li Ren Kong, the first author, wrote that bouts of bad eating or poorly controlled diabetes can “add up” over time and push cancer risk higher.
What it does not show
The limits matter. The work was done in cell and animal models and in patient-derived organoids, not in a trial of patients, and Kong was direct about it: “It is important to take note that our work was carried out in cellular models, not in patients, so it would be premature to give specific advice to reduce risk on this basis.”
MGO is hard to measure on its own. Kong pointed out that a routine HbA1C blood test, which tracks average blood sugar over the previous two to three months, could offer an early hint of elevated levels. His group is turning to larger groups of cancer patients, and he said the goal is to find out whether high MGO in families with a BRCA2 mutation can be controlled the way it usually is in prediabetes and diabetes, with diet, exercise or medicine.
For now the paper amounts to a mechanism, not a prescription. It does offer a biological route by which metabolic trouble and inherited cancer risk might meet.
Sources
- A Glycolytic Metabolite Bypasses two-hit Tumor Suppression by BRCA2 (Cell, Apr 2024) – NUS Cancer Science Institute
- The missing link between junk food diets and cancer (Juta MedicalBrief, citing Daily Mail)
- Researchers Discover New Mechanism Linking Diet and Cancer Risk (The Silo, via Epoch Times)
