KMT2C-deficient tumors have elevated APOBEC mutagenesis and genomic instability in multiple cancers

Area of Science:

• Genetics
• Cancer Biology
• Genomic Instability

Background:

• The histone methyltransferase KMT2C is frequently mutated in cancer.
• KMT2C is crucial for DNA replication fork restart.
• The impact of KMT2C deficiency on cancer genomic instability is not well understood.

Purpose of the Study:

• To investigate the role of KMT2C deficiency in promoting genomic instability during tumorigenesis.
• To determine the relationship between KMT2C mutations and APOBEC mutational signatures.
• To elucidate the mechanisms by which KMT2C deficiency affects DNA replication and mutagenesis.

Main Methods:

• Analysis of 9,663 tumors across 30 cancer cohorts.
• Assessment of APOBEC mutational signatures and expression.
• Evaluation of DNA replication speed and fork restart dynamics.
• Correlation analysis with genome maintenance defects and homologous recombination deficiency.

Main Results:

• KMT2C mutant tumors exhibit a significant excess of APOBEC mutational signatures.
• KMT2C deficiency enhances APOBEC expression and deaminase activity.
• KMT2C deficiency slows DNA replication and delays fork restart, promoting APOBEC mutagenesis.
• APOBEC mutations cluster in specific genomic regions and 3D nuclear domains.
• Excess APOBEC signatures correlate with genome maintenance defects and HR deficiency.

Conclusions:

• KMT2C deficiency promotes APOBEC mutagenesis, contributing to genomic instability in multiple cancer types.
• This mechanism may drive tumor progression by increasing mutation rates and DNA repair defects.