eccDNAdb – open the Pandora's box of eccDNAs in human cancers

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As known to all, nuclear DNA in human is packaged into 23 pairs of linear chromosomes. Researchers have long observed the existence of extrachromosomal circular DNA (eccDNA) elements 1, 2. EccDNAs are derived from chromosomes but are independent of chromosomal DNA 6, 8. eccDNA is a driver of eukaryotic genome plasticity and is involved in numerous biological processes 7. Amplification of eccDNA genes plays a crucial role in intratumoral heterogeneity, drug resistance and cancer progression. Revealing the underlying mechanism may broaden the horizon for targeted disruption of key oncogenes currently considered undruggable. Thus, eccDNA and eccDNA genes have great potential as treatment targets to prevent the progression and even the occurrence of cancers and as biomarkers for cancer diagnosis or prognostic prediction.

 

Computational analysis of high-throughput sequencing datasets offers a new perspective on eccDNAs of tumors on a genome-wide scale. Recently, thanks to advances in high-throughput sequencing, eccDNAs were found to exist more ubiquitously in human cancers, including glioblastoma, neuroblastoma, and breast cancer, than previously anticipated 3-6. They drive massive amplification of genes, leading to abnormally high expression of cancerous genes.

Benefiting from this renewed understanding, there is an urgent need for a database to boost the exploration of biological properties of eccDNAs and, more importantly, to exploit eccDNA-based techniques for cancer treatment and prognosis prediction. Here, we developed an integrated database of eccDNAs, eccDNAdb (freely accessible at http://www.eccdnadb.org). To our knowledge, eccDNAdb is the first database for eccDNAs in human cancers. The database aims to identify and annotate known and novel eccDNAs in human cancers using whole-genome sequencing (WGS) data, and further to help researchers to open the Pandora's box of eccDNAs in cancers.

EccDNAdb will aid eccDNA research in multiple ways. (i) A landscape of eccDNAs in human cancers is presented. The analyzed data were derived from 3395 samples across 57 tumor types. (ii) The eccDNAs in eccDNAdb were carefully annotated. Database users can easily retrieve eccDNA structure, eccDNA gene, eccDNA gene expression profile, differentially expressed eccDNA gene, and cancer prognosis. This knowledge facilitates the understanding of why an eccDNA or an eccDNA gene is important in cancer biology, thus providing insight for the development of novel anti-cancer therapies. (iii) Database users can conveniently search eccDNAdb in several modes. Currently, searches by eccDNA, gene, cancer, tissue, and sample type are available. (iv) In addition, chromatin accessibility data of eccDNA-containing genomic regions in primary human cancers are provided in eccDNAdb. These features are very useful for finding the information that database users are interested in. Through large-scale WGS data analysis, eccDNAdb will allow a more comprehensive understanding of cancer etiologies from a new perspective and lay the foundation for new therapeutics and clinical trials.

 

Construction flow

In conclusion, eccDNAdb, the first integrated database of eccDNAs in human cancers, is freely accessible at http://www.eccdnadb.org. The database currently contains 1270 eccDNAs and 54901 eccDNA genes identified from 3395 tumor samples of 57 cancers. eccDNAdb enables users to easily determine the biological function and clinical relevance of eccDNAs in cancer.

 

 

References

1 Cox D, Yuncken C, Spriggs AI. Minute chromatin bodies in malignant tumours of childhood. Lancet 1965; 1: 55-58.

2 Hotta Y, Bassel A. MOLECULAR SIZE AND CIRCULARITY OF DNA IN CELLS OF MAMMALS AND HIGHER PLANTS. Proceedings of the National Academy of Sciences of the United States of America 1965; 53: 356-362.

3 Kim H, Nguyen NP, Turner K, Wu S, Gujar AD, Luebeck J et al. Extrachromosomal DNA is associated with oncogene amplification and poor outcome across multiple cancers. Nat Genet 2020; 52: 891-897.

4 Morton AR, Dogan-Artun N, Faber ZJ, MacLeod G, Bartels CF, Piazza MS et al. Functional Enhancers Shape Extrachromosomal Oncogene Amplifications. Cell 2019; 179: 1330-1341.e1313.

5 Turner KM, Deshpande V, Beyter D, Koga T, Rusert J, Lee C et al. Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity. Nature 2017; 543: 122-125.

6 Wu S, Turner KM, Nguyen N, Raviram R, Erb M, Santini J et al. Circular ecDNA promotes accessible chromatin and high oncogene expression. Nature 2019; 575: 699-703.

7 Yerlici VT, Lu MW, Hoge CR, Miller RV, Neme R, Khurana JS et al. Programmed genome rearrangements in Oxytricha produce transcriptionally active extrachromosomal circular DNA. Nucleic Acids Res 2019; 47: 9741-9760.

8 Zhu J, Chen S, Zhang F, Wang L. Cell-Free eccDNAs: A New Type of Nucleic Acid Component for Liquid Biopsy? Molecular diagnosis & therapy 2018; 22: 515-522.

 

 

Li Peng

Distinguished Associate Professor (Researcher) , Sun Yat-Sen University