Oncogenic Extrachromosomal DNA Functions As Mobile Enhancers to Globally Amplify Chromosomal Transcription

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2021 Apr 9

PMID 33836152

Citations 107

Authors

Yanfen Zhu

Amit D Gujar

Chee-Hong Wong

Harianto Tjong

Chew Yee Ngan

Liang Gong

Yi-An Chen

Hoon Kim

Jihe Liu

Meihong Li

Adam Mil-Homens

Rahul Maurya

Chris Kuhlberg

Fanyue Sun

Eunhee Yi

Ana C deCarvalho

Yijun Ruan

Roel G W Verhaak

Chia-Lin Wei

Affiliations

Soon will be listed here.

Abstract

Extrachromosomal, circular DNA (ecDNA) is emerging as a prevalent yet less characterized oncogenic alteration in cancer genomes. We leverage ChIA-PET and ChIA-Drop chromatin interaction assays to characterize genome-wide ecDNA-mediated chromatin contacts that impact transcriptional programs in cancers. ecDNAs in glioblastoma patient-derived neurosphere and prostate cancer cell cultures are marked by widespread intra-ecDNA and genome-wide chromosomal interactions. ecDNA-chromatin contact foci are characterized by broad and high-level H3K27ac signals converging predominantly on chromosomal genes of increased expression levels. Prostate cancer cells harboring synthetic ecDNA circles composed of characterized enhancers result in the genome-wide activation of chromosomal gene transcription. Deciphering the chromosomal targets of ecDNAs at single-molecule resolution reveals an association with actively expressed oncogenes spatially clustered within ecDNA-directed interaction networks. Our results suggest that ecDNA can function as mobile transcriptional enhancers to promote tumor progression and manifest a potential synthetic aneuploidy mechanism of transcription control in cancer.

Citing Articles

MYC ecDNA promotes intratumour heterogeneity and plasticity in PDAC.

Fiorini E, Malinova A, Schreyer D, Pasini D, Bevere M, Alessio G Nature. 2025; .

PMID: 40074906 DOI: 10.1038/s41586-025-08721-9.

Three-dimensional regulatory hubs support oncogenic programs in glioblastoma.

Breves S, Di Giammartino D, Nicholson J, Cirigliano S, Mahmood S, Lee U bioRxiv. 2025; .

PMID: 40034649 PMC: 11875237. DOI: 10.1101/2024.12.20.629544.

Enhancer reprogramming: critical roles in cancer and promising therapeutic strategies.

Yang J, Zhou F, Luo X, Fang Y, Wang X, Liu X Cell Death Discov. 2025; 11(1):84.

PMID: 40032852 PMC: 11876437. DOI: 10.1038/s41420-025-02366-3.

BRCA1-A and LIG4 complexes mediate ecDNA biogenesis and cancer drug resistance.

Chung O, Yao S, Yang F, Wang L, Cerda-Smith C, Hutchinson H bioRxiv. 2025; .

PMID: 40027615 PMC: 11870461. DOI: 10.1101/2025.02.18.638901.

Epigenetic priming promotes acquisition of tyrosine kinase inhibitor resistance and oncogene amplification in human lung cancer.

Starble R, Sun E, Gbyli R, Radda J, Lu J, Jensen T bioRxiv. 2025; .

PMID: 39974875 PMC: 11838195. DOI: 10.1101/2025.01.26.634826.

References

Ma K, Qiu L, Mrasek K, Zhang J, Liehr T, Quintana L . Common fragile sites: genomic hotspots of DNA damage and carcinogenesis. Int J Mol Sci. 2012; 13(9):11974-11999. PMC: 3472787. DOI: 10.3390/ijms130911974. View

Dixon J, Xu J, Dileep V, Zhan Y, Song F, Le V . Integrative detection and analysis of structural variation in cancer genomes. Nat Genet. 2018; 50(10):1388-1398. PMC: 6301019. DOI: 10.1038/s41588-018-0195-8. View

Kim D, Paggi J, Park C, Bennett C, Salzberg S . Graph-based genome alignment and genotyping with HISAT2 and HISAT-genotype. Nat Biotechnol. 2019; 37(8):907-915. PMC: 7605509. DOI: 10.1038/s41587-019-0201-4. View

Duan Z, Andronescu M, Schutz K, Mcilwain S, Kim Y, Lee C . A three-dimensional model of the yeast genome. Nature. 2010; 465(7296):363-7. PMC: 2874121. DOI: 10.1038/nature08973. View

Spriggs A, Boddington M, Clarke C . Chromosomes of human cancer cells. Br Med J. 1962; 2(5317):1431-5. PMC: 1926782. DOI: 10.1136/bmj.2.5317.1431. View

Paulsen J, Rodland E, Holden L, Holden M, Hovig E . A statistical model of ChIA-PET data for accurate detection of chromatin 3D interactions. Nucleic Acids Res. 2014; 42(18):e143. PMC: 4191384. DOI: 10.1093/nar/gku738. View

Subramanian A, Tamayo P, Mootha V, Mukherjee S, Ebert B, Gillette M . Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005; 102(43):15545-50. PMC: 1239896. DOI: 10.1073/pnas.0506580102. View

Deshpande V, Luebeck J, Nguyen N, Bakhtiari M, Turner K, Schwab R . Exploring the landscape of focal amplifications in cancer using AmpliconArchitect. Nat Commun. 2019; 10(1):392. PMC: 6344493. DOI: 10.1038/s41467-018-08200-y. View

Mi H, Muruganujan A, Ebert D, Huang X, Thomas P . PANTHER version 14: more genomes, a new PANTHER GO-slim and improvements in enrichment analysis tools. Nucleic Acids Res. 2018; 47(D1):D419-D426. PMC: 6323939. DOI: 10.1093/nar/gky1038. View

10.

Repana D, Nulsen J, Dressler L, Bortolomeazzi M, Venkata S, Tourna A . The Network of Cancer Genes (NCG): a comprehensive catalogue of known and candidate cancer genes from cancer sequencing screens. Genome Biol. 2019; 20(1):1. PMC: 6317252. DOI: 10.1186/s13059-018-1612-0. View

11.

Liu T . Use model-based Analysis of ChIP-Seq (MACS) to analyze short reads generated by sequencing protein-DNA interactions in embryonic stem cells. Methods Mol Biol. 2014; 1150:81-95. DOI: 10.1007/978-1-4939-0512-6_4. View

12.

Xue Y, Martelotto L, Baslan T, Vides A, Solomon M, Mai T . An approach to suppress the evolution of resistance in BRAF-mutant cancer. Nat Med. 2017; 23(8):929-937. PMC: 5696266. DOI: 10.1038/nm.4369. View

13.

Kivioja T, Vaharautio A, Karlsson K, Bonke M, Enge M, Linnarsson S . Counting absolute numbers of molecules using unique molecular identifiers. Nat Methods. 2011; 9(1):72-4. DOI: 10.1038/nmeth.1778. View

14.

Li H, Durbin R . Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009; 25(14):1754-60. PMC: 2705234. DOI: 10.1093/bioinformatics/btp324. View

15.

Verhaak R, Bafna V, Mischel P . Extrachromosomal oncogene amplification in tumour pathogenesis and evolution. Nat Rev Cancer. 2019; 19(5):283-288. PMC: 7168519. DOI: 10.1038/s41568-019-0128-6. View

16.

Seaman L, Chen H, Brown M, Wangsa D, Patterson G, Camps J . Nucleome Analysis Reveals Structure-Function Relationships for Colon Cancer. Mol Cancer Res. 2017; 15(7):821-830. PMC: 7934948. DOI: 10.1158/1541-7786.MCR-16-0374. View

17.

Kruse K, Sewitz S, Babu M . A complex network framework for unbiased statistical analyses of DNA-DNA contact maps. Nucleic Acids Res. 2012; 41(2):701-10. PMC: 3553935. DOI: 10.1093/nar/gks1096. View

18.

Forbes S, Beare D, Gunasekaran P, Leung K, Bindal N, Boutselakis H . COSMIC: exploring the world's knowledge of somatic mutations in human cancer. Nucleic Acids Res. 2014; 43(Database issue):D805-11. PMC: 4383913. DOI: 10.1093/nar/gku1075. View

19.

Sanborn J, Salama S, Grifford M, Brennan C, Mikkelsen T, Jhanwar S . Double minute chromosomes in glioblastoma multiforme are revealed by precise reconstruction of oncogenic amplicons. Cancer Res. 2013; 73(19):6036-45. PMC: 3800429. DOI: 10.1158/0008-5472.CAN-13-0186. View

20.

Trapnell C, Hendrickson D, Sauvageau M, Goff L, Rinn J, Pachter L . Differential analysis of gene regulation at transcript resolution with RNA-seq. Nat Biotechnol. 2012; 31(1):46-53. PMC: 3869392. DOI: 10.1038/nbt.2450. View