Extrachromosomal oncogene amplification drives tumor evolution and genetic heterogeneity

By Kristen M. Turner, Viraj Deshpande, Doruk Beyter, Tomoyuki Koga, Jessica M. Rusert, Catherine Lee, Bin Li, K. Arden, Bing Ren, D. Nathanson and 11 more. Nature, 2017

727 citations recorded by the source corpus.

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. 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.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/531b47bddeedb08bd810733ada56a27247952c6c

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

In Molecular Biology

Citations in the corpus

Intratumor heterogeneity: the Rosetta stone of therapy resistance (2020, background): “The instability of copy number variations is most pertinent for extrachromosomal DNA (ecDNA), which has been shown to mediate inheritance of many “driver” genes across multiple cancers (deCarvalho et al., 2018; Turner et al., 2017; Verhaak et al., 2019).”
Genomic Evolution of Breast Cancer Metastasis and Relapse (2017, background): “Gain-of-function mutations in TP53 have been associated with metastasis and drug resistance in cellline and xenograft models (Petitjean et al., 2007; Turner et al., 2017), but in our cohort loss-of-function and gain-of-function mutations were equally enriched in patients with progressive disease…”