KMT2C deficiency promotes APOBEC mutagenesis and genomic instability in multiple cancers

Histone methyltransferase KMT2C is among the frequently mutated epigenetic modifier genes in cancer. It has additional roles in DNA replication, but the effects of KMT2C deficiency on genomic instability during tumorigenesis are unclear. Analyzing 9,663 tumors from 30 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 ssDNA near stalled forks. APOBEC-mediated mutations primarily accumulate during early replication, and tend to cluster along the genome and also in 3D nuclear contexts. Excessive APOBEC mutational signatures in KMT2C mutant tumors correlate with elevated genomic instability and signatures of homologous recombination deficiency. We propose that in multiple cancer types KMT2C deficiency is a likely driver of APOBEC mutagenesis, which promotes further genomic instability during cancer progression.