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

The histone methyltransferase 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 deficiency on genomic instability during tumorigenesis are unclear. Analyzing 9,663 tumors from 30 cancer cohorts, we report that mutant tumors have a significant excess of APOBEC mutational signatures in several cancer types. We show that 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 mutant tumors correlate with elevated genome maintenance defects and signatures of homologous recombination deficiency. We propose that deficiency is a likely promoter of APOBEC mutagenesis, which fosters further genomic instability during tumor progression in multiple cancer types.