Abstract Cancer patients face an extraordinary challenge when oncogenes unleash themselves from chromosomes. Extrachromosomal DNA (ecDNA) are large, megabase-sized circular episomes containing oncogenes and regulatory DNA elements. EcDNAs have a remarkable transcriptional advantage and rapidly change copy number--a moving target driving accelerated evolution in cancer. EcDNAs are common in many of the most aggressive forms of cancer of women and men, children and adults, and contribute to treatment resistance and shorter survival for patients. Here, we show that ecDNAs are major platforms for generating and amplifying oncogene fusion transcripts across diverse cancer types. Moreover, by exploiting the basic rules for how random ecDNA inheritance drives oncogene copy number and distribution, we develop a strategy to leverage the extensive intratumoural heterogeneity of ecDNA copy number to identify ecDNA containing tumors with single cell resolution. We analyze the subclonal evolution of ecDNA+ subclones and identify the effect of ecDNA amplifications on the chromatin accessibility landscape of cancer cells. These results demonstrate that ecDNA fosters genome instability at the level of cells and genes, enabling major hallmarks of cancer. Citation Format: Howard Y. Chang. Cancer genes beyond chromosomes abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr SY20-02.
H J Chang (Fri,) studied this question.