Kong LR, Gupta K, Wu AJ, Perera D, Ivanyi-Nagy R, Ahmed SM, Tan TZ, Tan SL, Fuddin A, Sundaramoorthy E, Goh GS, Wong RTX, Costa ASH, Oddy C, Wong H, Patro CPK, Kho YS, Huang XZ, Choo J, Shehata M, Lee SC, Goh BC, Frezza C, Pitt JJ, Venkitaraman AR.
Affiliations
- 1Cancer Science Institute of Singapore, Singapore 117599, Singapore; NUS Centre for Cancer Research (N2CR), National University of Singapore, Singapore 117599, Singapore; MRC Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK; Department of Pharmacology, National University of Singapore, Singapore 117600, Singapore.
- 2Cancer Science Institute of Singapore, Singapore 117599, Singapore; MRC Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK.
- 3Cancer Science Institute of Singapore, Singapore 117599, Singapore.
- 4MRC Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK.
- 5MRC Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK; Institute of Molecular and Cell Biology (IMCB), A(∗)STAR, Singapore 138673, Singapore.
- 6Department of Oncology, University of Cambridge, Cambridge CB2 0XZ, UK.
- 7Cancer Science Institute of Singapore, Singapore 117599, Singapore; NUS Centre for Cancer Research (N2CR), National University of Singapore, Singapore 117599, Singapore.
- 8Department of Medicine, National University of Singapore, Singapore 119228, Singapore.
- 9MRC Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK; Department of Oncology, University of Cambridge, Cambridge CB2 0XZ, UK.
- 10Cancer Science Institute of Singapore, Singapore 117599, Singapore; NUS Centre for Cancer Research (N2CR), National University of Singapore, Singapore 117599, Singapore; Department of Medicine, National University of Singapore, Singapore 119228, Singapore.
- 11MRC Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK; University of Cologne, 50923 Köln, Germany.
- 12Cancer Science Institute of Singapore, Singapore 117599, Singapore; NUS Centre for Cancer Research (N2CR), National University of Singapore, Singapore 117599, Singapore; Genome Institute of Singapore, A(∗)STAR, Singapore 138673, Singapore.
- 13Cancer Science Institute of Singapore, Singapore 117599, Singapore; NUS Centre for Cancer Research (N2CR), National University of Singapore, Singapore 117599, Singapore; MRC Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK; Institute of Molecular and Cell Biology (IMCB), A(∗)STAR, Singapore 138673, Singapore; Department of Oncology, University of Cambridge, Cambridge CB2 0XZ, UK; Department of Medicine, National University of Singapore, Singapore 119228, Singapore. Electronic address: arv22@nus.edu.sg.
Abstract
Knudson’s “two-hit” paradigm posits that carcinogenesis requires inactivation of both copies of an autosomal tumor 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 nonmalignant 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 tumor 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 haploinsufficiency 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.
PMID: 38608703 DOI: 10.1016/j.cell.2024.03.006