Journal Article

Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity

Rao, P. Nagesh, Furnari, Frank B., Lee, Catherine, Nathanson, David A., Ren, Bing, Wahl, Geoffrey M., Arden, Karen, Deshpande, Viraj, Kaushal, Sharmeela, Cavenee, Webster K., Mischel, Paul S., Koga, Tomoyuki, Bafna, Vineet, Rusert, Jessica, Vandenberg, Scott R., Wechsler-Reya, Robert, Kornblum, Harley I., Li, Bin, Taylor, Michael D., Turner, Kristen M., Beyter, Doruk

2017

Overview

Circular extrachromosomal DNA is found in nearly half of human cancers of a wide variety of histologic types, increasing the copy number of driver oncogenes and intratumoral heterogeneity more effectively than chromosomal amplification and contributing to tumor evolution. Extrachromosomal DNA in cancer evolution Extrachromosomal DNA has been shown to play a role in oncogenesis, but its frequency and importance have not been clear. Here, the authors perform whole-genome sequencing, structural modelling and cytogenetic analysis of 17 different types of cancer to explore how extrachromosomal elements contribute to the heterogeneity and plasticity of tumours. They find extrachromosomal DNA in nearly half of the cancers, but in almost no healthy cells, with driver oncogenes being the most commonly amplified, resulting in increased transcript levels. Mathematical modelling predicts that amplification of extrachromosomal DNA could increase oncogene copy number more than chromosomal amplification. The results suggest that extrachromosomal DNA has a broad role in the adaptation and evolution of cancer cells. Human cells have twenty-three pairs of chromosomes. In cancer, however, genes can be amplified in chromosomes or in circular extrachromosomal DNA (ecDNA), although the frequency and functional importance of ecDNA are not understood 1 , 2 , 3 , 4 . We performed whole-genome sequencing, structural modelling and cytogenetic analyses of 17 different cancer types, including analysis of the structure and function of chromosomes during metaphase of 2,572 dividing cells, and developed a software package called ECdetect to conduct unbiased, integrated ecDNA detection and analysis. Here we show that ecDNA was found in nearly half of human cancers; its frequency varied by tumour type, but it was almost never found in normal cells. Driver oncogenes were amplified most commonly in ecDNA, thereby increasing transcript level. Mathematical modelling predicted that ecDNA amplification would increase oncogene copy number and intratumoural heterogeneity more effectively than chromosomal amplification. We validated these predictions by quantitative analyses of cancer samples. The results presented here suggest that ecDNA contributes to accelerated evolution in cancer.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/67 / 631/67/68 / Cancer / Cancer genetics / Cancer research / Cancer therapies / Cell culture / Chromosomes / Chromosomes, Human - genetics / Cytogenetic Analysis / Deoxyribonucleic acid / DNA / DNA Copy Number Variations - genetics / DNA Mutational Analysis / Evolution, Molecular / Gene amplification / Gene Amplification - genetics / Genetic Heterogeneity / Genome, Human - genetics / Genomes / Heterogeneity / Humanities and Social Sciences / Humans / Kinases / letter / Medical research / Metaphase - genetics / Methods / Models, Genetic / multidisciplinary / Mutation / Neoplasms - classification / Neoplasms - genetics / Oncogenes / Oncogenes - genetics / Physiological aspects / Reproducibility of Results / RNA, Messenger - analysis / RNA, Neoplasm - genetics / Science / Software / Tumors