Extrachromosomal DNA is associated with oncogene amplification and poor outcome across multiple cancers

Hoon Kim; Nam Phuong Nguyen; Kristen Turner; Sihan Wu; Amit D. Gujar; Jens Luebeck; Jihe Liu; Viraj Deshpande; Utkrisht Rajkumar; Sandeep Namburi; Samirkumar B. Amin; Eunhee Yi; Francesca Menghi; Johannes H. Schulte; Anton G. Henssen; Howard Y. Chang; Christine R. Beck; Paul S. Mischel; Vineet Bafna; Roel G.W. Verhaak

doi:10.1038/s41588-020-0678-2

Extrachromosomal DNA is associated with oncogene amplification and poor outcome across multiple cancers

Hoon Kim, Nam Phuong Nguyen, Kristen Turner, Sihan Wu, Amit D. Gujar, Jens Luebeck, Jihe Liu, Viraj Deshpande, Utkrisht Rajkumar, Sandeep Namburi, Samirkumar B. Amin, Eunhee Yi, Francesca Menghi, Johannes H. Schulte, Anton G. Henssen, Howard Y. Chang, Christine R. Beck, Paul S. Mischel, Vineet Bafna, Roel G.W. Verhaak

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195 Scopus citations

Abstract

Extrachromosomal DNA (ecDNA) amplification promotes intratumoral genetic heterogeneity and accelerated tumor evolution^1–3; however, its frequency and clinical impact are unclear. Using computational analysis of whole-genome sequencing data from 3,212 cancer patients, we show that ecDNA amplification frequently occurs in most cancer types but not in blood or normal tissue. Oncogenes were highly enriched on amplified ecDNA, and the most common recurrent oncogene amplifications arose on ecDNA. EcDNA amplifications resulted in higher levels of oncogene transcription compared to copy number-matched linear DNA, coupled with enhanced chromatin accessibility, and more frequently resulted in transcript fusions. Patients whose cancers carried ecDNA had significantly shorter survival, even when controlled for tissue type, than patients whose cancers were not driven by ecDNA-based oncogene amplification. The results presented here demonstrate that ecDNA-based oncogene amplification is common in cancer, is different from chromosomal amplification and drives poor outcome for patients across many cancer types.

Original language	English (US)
Pages (from-to)	891-897
Number of pages	7
Journal	Nature genetics
Volume	52
Issue number	9
DOIs	https://doi.org/10.1038/s41588-020-0678-2
State	Published - Sep 1 2020
Externally published	Yes

ASJC Scopus subject areas

Genetics

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Kim, H., Nguyen, N. P., Turner, K., Wu, S., Gujar, A. D., Luebeck, J., Liu, J., Deshpande, V., Rajkumar, U., Namburi, S., Amin, S. B., Yi, E., Menghi, F., Schulte, J. H., Henssen, A. G., Chang, H. Y., Beck, C. R., Mischel, P. S., Bafna, V., & Verhaak, R. G. W. (2020). Extrachromosomal DNA is associated with oncogene amplification and poor outcome across multiple cancers. Nature genetics, 52(9), 891-897. https://doi.org/10.1038/s41588-020-0678-2

Kim, H, Nguyen, NP, Turner, K, Wu, S, Gujar, AD, Luebeck, J, Liu, J, Deshpande, V, Rajkumar, U, Namburi, S, Amin, SB, Yi, E, Menghi, F, Schulte, JH, Henssen, AG, Chang, HY, Beck, CR, Mischel, PS, Bafna, V & Verhaak, RGW 2020, 'Extrachromosomal DNA is associated with oncogene amplification and poor outcome across multiple cancers', Nature genetics, vol. 52, no. 9, pp. 891-897. https://doi.org/10.1038/s41588-020-0678-2

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title = "Extrachromosomal DNA is associated with oncogene amplification and poor outcome across multiple cancers",

abstract = "Extrachromosomal DNA (ecDNA) amplification promotes intratumoral genetic heterogeneity and accelerated tumor evolution1–3; however, its frequency and clinical impact are unclear. Using computational analysis of whole-genome sequencing data from 3,212 cancer patients, we show that ecDNA amplification frequently occurs in most cancer types but not in blood or normal tissue. Oncogenes were highly enriched on amplified ecDNA, and the most common recurrent oncogene amplifications arose on ecDNA. EcDNA amplifications resulted in higher levels of oncogene transcription compared to copy number-matched linear DNA, coupled with enhanced chromatin accessibility, and more frequently resulted in transcript fusions. Patients whose cancers carried ecDNA had significantly shorter survival, even when controlled for tissue type, than patients whose cancers were not driven by ecDNA-based oncogene amplification. The results presented here demonstrate that ecDNA-based oncogene amplification is common in cancer, is different from chromosomal amplification and drives poor outcome for patients across many cancer types.",

author = "Hoon Kim and Nguyen, {Nam Phuong} and Kristen Turner and Sihan Wu and Gujar, {Amit D.} and Jens Luebeck and Jihe Liu and Viraj Deshpande and Utkrisht Rajkumar and Sandeep Namburi and Amin, {Samirkumar B.} and Eunhee Yi and Francesca Menghi and Schulte, {Johannes H.} and Henssen, {Anton G.} and Chang, {Howard Y.} and Beck, {Christine R.} and Mischel, {Paul S.} and Vineet Bafna and Verhaak, {Roel G.W.}",

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doi = "10.1038/s41588-020-0678-2",

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AU - Nguyen, Nam Phuong

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AU - Gujar, Amit D.

AU - Luebeck, Jens

AU - Liu, Jihe

AU - Deshpande, Viraj

AU - Rajkumar, Utkrisht

AU - Namburi, Sandeep

AU - Amin, Samirkumar B.

AU - Yi, Eunhee

AU - Menghi, Francesca

AU - Schulte, Johannes H.

AU - Henssen, Anton G.

AU - Chang, Howard Y.

AU - Beck, Christine R.

AU - Mischel, Paul S.

AU - Bafna, Vineet

AU - Verhaak, Roel G.W.

PY - 2020/9/1

Y1 - 2020/9/1

N2 - Extrachromosomal DNA (ecDNA) amplification promotes intratumoral genetic heterogeneity and accelerated tumor evolution1–3; however, its frequency and clinical impact are unclear. Using computational analysis of whole-genome sequencing data from 3,212 cancer patients, we show that ecDNA amplification frequently occurs in most cancer types but not in blood or normal tissue. Oncogenes were highly enriched on amplified ecDNA, and the most common recurrent oncogene amplifications arose on ecDNA. EcDNA amplifications resulted in higher levels of oncogene transcription compared to copy number-matched linear DNA, coupled with enhanced chromatin accessibility, and more frequently resulted in transcript fusions. Patients whose cancers carried ecDNA had significantly shorter survival, even when controlled for tissue type, than patients whose cancers were not driven by ecDNA-based oncogene amplification. The results presented here demonstrate that ecDNA-based oncogene amplification is common in cancer, is different from chromosomal amplification and drives poor outcome for patients across many cancer types.

AB - Extrachromosomal DNA (ecDNA) amplification promotes intratumoral genetic heterogeneity and accelerated tumor evolution1–3; however, its frequency and clinical impact are unclear. Using computational analysis of whole-genome sequencing data from 3,212 cancer patients, we show that ecDNA amplification frequently occurs in most cancer types but not in blood or normal tissue. Oncogenes were highly enriched on amplified ecDNA, and the most common recurrent oncogene amplifications arose on ecDNA. EcDNA amplifications resulted in higher levels of oncogene transcription compared to copy number-matched linear DNA, coupled with enhanced chromatin accessibility, and more frequently resulted in transcript fusions. Patients whose cancers carried ecDNA had significantly shorter survival, even when controlled for tissue type, than patients whose cancers were not driven by ecDNA-based oncogene amplification. The results presented here demonstrate that ecDNA-based oncogene amplification is common in cancer, is different from chromosomal amplification and drives poor outcome for patients across many cancer types.

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Extrachromosomal DNA is associated with oncogene amplification and poor outcome across multiple cancers

Abstract

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