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

Area of Science:

• Biochemistry
• Genetics
• Oncology

Background:

• Knudson's "two-hit" paradigm describes cancer as requiring inactivation of both tumor suppressor gene copies.
• BRCA2 is a critical breast cancer suppressor protein involved in DNA repair.

Purpose of the Study:

• To investigate the role of methylglyoxal (MGO) in cancer development beyond the "two-hit" paradigm.
• To explore the transient inactivation of BRCA2 by MGO and its link to mutational signatures.

Main Methods:

• Analysis of nonmalignant mammary cells and patient-derived organoids.
• Investigation of MGO accumulation and DNA damage in Kras-driven murine pancreatic cancers and human breast cancers.
• Assessment of BRCA2 proteolysis and functional haploinsufficiency.

Main Results:

• MGO transiently inactivates BRCA2, causing a single-base substitution (SBS) signature without biallelic inactivation.
• Germline monoallelic BRCA2 mutations predispose to MGO-induced SBS signatures.
• Intermittent MGO exposure leads to episodic mutations without permanent BRCA2 loss.

Conclusions:

• MGO-induced BRCA2 haploinsufficiency offers a metabolic mechanism bypassing Knudson's two-hit requirement.
• This pathway links metabolic dysregulation (e.g., glycolysis activation) to cancer-associated mutational signatures.
• Findings suggest a novel connection between metabolism and cancer evolution through transient tumor suppressor inactivation.