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

Xiaoju Hu, Antara Biswas, Subhajyoti De

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


The histone methyltransferase KMT2C is among the most frequently mutated epigenetic modifier genes in cancer and plays an essential role in MRE11-dependent DNA replication fork restart. However, the effects of KMT2C deficiency on genomic instability during tumorigenesis are unclear. Analyzing 9,663 tumors from 30 cancer cohorts, we report that KMT2C mutant tumors have a significant excess of APOBEC mutational signatures in several cancer types. We show that KMT2C deficiency promotes APOBEC expression and deaminase activity, and compromises DNA replication speed and delays fork restart, facilitating APOBEC mutagenesis targeting single stranded DNA near stalled forks. APOBEC-mediated mutations primarily accumulate during early replication and tend to cluster along the genome and also in 3D nuclear domains. Excessive APOBEC mutational signatures in KMT2C mutant tumors correlate with elevated genome maintenance defects and signatures of homologous recombination deficiency. We propose that KMT2C deficiency is a likely promoter of APOBEC mutagenesis, which fosters further genomic instability during tumor progression in multiple cancer types.

Original languageEnglish (US)
Article numberzcac023
JournalNAR Cancer
Issue number3
StatePublished - Sep 1 2022

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research


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