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  3. A glycolytic metabolite bypasses "two-hit" tumor suppression by BRCA2

A glycolytic metabolite bypasses "two-hit" tumor suppression by BRCA2

  • Cell. 2024 Apr 25;187(9):2269-2287.e16. doi: 10.1016/j.cell.2024.03.006.
Li Ren Kong 1,  Komal Gupta 2,  Andy Jialun Wu 3,  David Perera 4,  Roland Ivanyi-Nagy 3,  Syed Moiz Ahmed 3,  Tuan Zea Tan 3,  Shawn Lu-Wen Tan 5,  Alessandra Fuddin 3,  Elayanambi Sundaramoorthy 3,  Grace Shiqing Goh 3,  Regina Tong Xin Wong 3,  Ana S H Costa 4,  Callum Oddy 6,  Hannan Wong 3,  C Pawan K Patro 3,  Yun Suen Kho 7,  Xiao Zi Huang 7,  Joan Choo 8,  Mona Shehata 9,  Soo Chin Lee 10,  Boon Cher Goh 10,  Christian Frezza 11,  Jason J Pitt 12,  Ashok R Venkitaraman 13
Affiliations

Affiliations

  • 1 Cancer 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.
  • 2 Cancer Science Institute of Singapore, Singapore 117599, Singapore; MRC Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK.
  • 3 Cancer Science Institute of Singapore, Singapore 117599, Singapore.
  • 4 MRC Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK.
  • 5 MRC Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK; Institute of Molecular and Cell Biology (IMCB), A(∗)STAR, Singapore 138673, Singapore.
  • 6 Department of Oncology, University of Cambridge, Cambridge CB2 0XZ, UK.
  • 7 Cancer Science Institute of Singapore, Singapore 117599, Singapore; NUS Centre for Cancer Research (N2CR), National University of Singapore, Singapore 117599, Singapore.
  • 8 Department of Medicine, National University of Singapore, Singapore 119228, Singapore.
  • 9 MRC Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK; Department of Oncology, University of Cambridge, Cambridge CB2 0XZ, UK.
  • 10 Cancer 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.
  • 11 MRC Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK; University of Cologne, 50923 Köln, Germany.
  • 12 Cancer 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.
  • 13 Cancer 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.
PMID: 38608703 DOI: 10.1016/j.cell.2024.03.006
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.

Keywords

DNA repair and replication; breast cancer gene BRCA2; cancer genome; cancer metabolism; environmental carcinogenesis; gene-environment interaction; glycolysis; methylglyoxal; mutational signature; tumor suppression.

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