Year: 2019
Type: preprint
Study design: Observational Study
Abstract: Extrachromosomal DNA (ecDNA) amplification promotes high oncogene copy number, intratumoral genetic heterogeneity, and accelerated tumor evolution 1–3 , 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.
DOI: 10.1101/859306
Authors: Hoon Kim, Nam Nguyen, Kristen Turner, Sihan Wu, Jihe Liu, Viraj Deshpande, Sandeep Namburi, Howard Y. Chang, Christine Beck, Paul Mischel, Vineet Bafna, Roel Verhaak
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funders: National Science Foundation, Howard Hughes Medical Institute, National Brain Tumor Society, Musella Foundation For Brain Tumor Research and Information, Nvidia, Ben and Catherine Ivy Foundation, Ziering Family Foundation, Ludwig Institute for Cancer Research, National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke
Awards: (PQ #4) Single cell barcoding for studies of study clonal evolution in glioblastoma, G3171796397, The role of mTORC2 in reprogramming cancer cell metabolism, Collaborative Research: ABI Innovation: Computational population-genetic analysis for detection of soft selective sweeps, III: Small: Algorithms for decoding complex patterns of genomic variation, G9000006652, G9000110418, G9000113943, G9000331997, G9000337004, Computational methods for detecting patterns of complex genomic variation
OpenAlex ID: W2991270386