Frequent extrachromosomal oncogene amplification drives aggressive tumors

Extrachromosomal DNA (ecDNA) amplification promotes high oncogene copy number, intratumoral genetic heterogeneity, and accelerated tumor evolution1-3, but its frequency and clinical impact are not well understood. Here we show, using computational analysis of whole-genome sequencing data from 1,979 cancer patients, that ecDNA amplification occurs in at least 26% of human cancers, of a wide variety of histological types, but not in whole blood or normal tissue. We demonstrate a highly significant enrichment for oncogenes on amplified ecDNA and that the most common recurrent oncogene amplifications arise on ecDNA. EcDNA amplifications resulted in higher levels of oncogene transcription compared to copy number matched linear DNA, coupled with enhanced chromatin accessibility. Patients whose tumors have ecDNA-based oncogene amplification showed increase of cell proliferation signature activity, greater likelihood of lymph node spread at initial diagnosis, and significantly shorter survival, even when controlled for tissue type, than do patients whose cancers are not driven by ecDNA-based oncogene amplification. The results presented here demonstrate that ecDNA-based oncogene amplification plays a central role in driving the poor outcome for patients with some of the most aggressive forms of cancers.