Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity.
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.
Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, California 92093, USA.
Kristen M
KM
Turner
Department of Computer Science and Engineering, University of California at San Diego, La Jolla, California 92093, USA.
Viraj
V
Deshpande
Department of Computer Science and Engineering, University of California at San Diego, La Jolla, California 92093, USA.
Doruk
D
Beyter
Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, California 92093, USA.
Tomoyuki
T
Koga
Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037, USA.
Jessica
J
Rusert
Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037, USA.
Catherine
C
Lee
Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, California 92093, USA.
Bin
B
Li
Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, California 92093, USA.
Karen
K
Arden
Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, California 92093, USA.
Bing
B
Ren
Department of Molecular and Medical Pharmacology, David Geffen UCLA School of Medicine, Los Angeles, California 90095, USA.
David A
DA
Nathanson
Department of Molecular and Medical Pharmacology, David Geffen UCLA School of Medicine, Los Angeles, California 90095, USA.|Neuropsychiatric Institute-Semel Institute for Neuroscience and Human Behavior and Department of Psychiatry and Biobehavioral Sciences, David Geffen UCLA School of Medicine, Los Angeles, California 90095, USA.
Harley I
HI
Kornblum
The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
Michael D
MD
Taylor
Moores Cancer Center, University of California at San Diego, La Jolla, California 92093, USA.
Sharmeela
S
Kaushal
Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, California 92093, USA.
Webster K
WK
Cavenee
Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037, USA.
Robert
R
Wechsler-Reya
Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, California 92093, USA.
Frank B
FB
Furnari
Department of Pathology, University of California San Francisco, San Francisco, California 94143, USA.
Scott R
SR
Vandenberg
Department of Pathology and Laboratory Medicine, David Geffen UCLA School of Medicine, Los Angeles, California 90095, USA.
P Nagesh
PN
Rao
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Geoffrey M
GM
Wahl
Department of Computer Science and Engineering, University of California at San Diego, La Jolla, California 92093, USA.
Vineet
V
Bafna
Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, California 92093, USA.|Moores Cancer Center, University of California at San Diego, La Jolla, California 92093, USA.|Department of Pathology, University of California at San Diego, La Jolla, California 92093, USA.
Paul S
PS
Mischel
D002877:Chromosomes, Human / Q000235:genetics; D020732:Cytogenetic Analysis; D056915:DNA Copy Number Variations / Q000235:genetics*; D004252:DNA Mutational Analysis; D019143:Evolution, Molecular; D005784:Gene Amplification / Q000235:genetics*; D018740:Genetic Heterogeneity; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D008677:Metaphase / Q000235:genetics; D008957:Models, Genetic; D009369:Neoplasms / Q000145:classification / Q000235:genetics*; D009857:Oncogenes / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D012334:RNA, Neoplasm / Q000235:genetics; D015203:Reproducibility of Results; D012984:Software
D012333:RNA, Messenger; D012334:RNA, Neoplasm