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| Item Type: | Article |
|---|---|
| Title: | Spatial-temporal diversity of extrachromosomal DNA shapes urothelial carcinoma evolution and tumor-immune microenvironment |
| Creators Name: | Lv, W., Zeng, Y., Li, C., Liang, Y., Tao, H., Zhu, Y., Sui, X., Li, Y., Jiang, S., Gao, Q., Rodriguez-Fos, E., Prasad, G., Wang, Y., Zhou, R., Xu, Z., Pan, X., Chen, L., Xiang, X., Teng, H., Sun, C., Qin, T., Dong, W., Li, Y., Lan, X., Li, X., Lin, L., Bolund, L., Yang, H., Verhaak, R.G.W., Faltas, B.M., Hansen, J.B., Wu, S., Mischel, P.S., Henssen, A.G., Bafna, V., Luebeck, J., Regenberg, B., Luo, Y., Lin, C. and Han, P. |
| Abstract: | Extrachromosomal DNA (ecDNA) presents a promising target for cancer therapy; however, its spatial-temporal diversity and influence on tumor evolution and the immune microenvironment remain largely unclear. We apply computational methods to analyze ecDNA from whole-genome sequencing data of 595 urothelial carcinoma (UC) patients. We demonstrate that ecDNA drives clonal evolution through structural rearrangements during malignant transformation and recurrence of UC. This supports a model wherein tumors evolve via the selective expansion of ecDNA-bearing cells. Through multi-regional sampling of tumors, we demonstrate that ecDNA contributes to the evolution of multifocality and increased intratumoral heterogeneity. EcDNA is present in 36% of UC tumors and correlates with an immunosuppressive phenotype and poor prognosis. Single-cell RNA sequencing analyses reveal that ecDNA+ malignant cells exhibit diminished expression of major histocompatibility complex class I molecules, enabling them to evade T-cell immunity. Finally, we show that sequencing of urinary sediment-derived DNA has excellent specificity in detecting ecDNA. |
| Keywords: | Urothelial Carcinoma, Extrachromosomal DNA, Cancer Genetics, Tumor Heterogeneity, Tumor Evolution, Tumor Microenvironment, Liquid Biopsy |
| Source: | Cancer Discovery |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date: | 11 March 2025 |
| Official Publication: | https://doi.org/10.1158/2159-8290.cd-24-1532 |
| PubMed: | View item in PubMed |
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