An epigenetic program dictates MYC amplification dynamics that promote transient, extrachromosomal, and inherited genomic events

MYC amplification is common and often extrachromosomal (ecDNA) in cancer. To define how MYC DNA copy gains arise from diploid genomes, we assessed whether epigenetic enzymes directly control focal MYC over-replication and amplification. We demonstrate that H3K4 methylation primes MYC for amplification by the H3K9/K36 tri-demethylase KDM4C, while the H3K36 tri-methyltransferase SETD2 restrains copy gains. These relationships are also observed in tumor datasets. SETD2 loss or inhibition promotes recruitment of catalytically active KDM4C, which initiates and drives stepwise MYC copy gains. Suppressing apoptosis or losing TP53 accelerates the emergence of higher-level MYC amplification events, including extrachromosomal circular ecDNAs (eccDNAs) and inherited copy gains. Non-transformed cells with these alterations are tumorigenic. Furthermore, KDM4C inhibition suppresses MYC amplification. These data define a chromatin-apoptotic axis directly controlling the initiation and progression of MYC amplification from diploid to hyper-amplification while also identifying potential biomarkers and therapeutic targets to constrain MYC-amplified tumors.