Spatial–Temporal Diversity of Extrachromosomal DNA Shapes Urothelial Carcinoma Evolution and the Tumor Immune Microenvironment

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.

Authors

Institutions

Publication Details

Journal
Cancer Discovery
Published
2025-03-07
DOI
https://doi.org/10.1158/2159-8290.cd-24-1532
Citations
16
Primary Topic
Bladder and Urothelial Cancer Treatments
Type
article
Field-Weighted Citation Impact
32.10
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Spatial–Temporal Diversity of Extrachromosomal DNA Shapes Urothelial Carcinoma Evolution and the Tumor Immune Microenvironment

Yuchen Zeng, Anton George Henssen, Sihan Wu, Huanming Yang et al.
16 citations
Cancer Discovery
Bladder and Urothelial Cancer Treatments
32.10
article

Spatial–Temporal Diversity of Extrachromosomal DNA Shapes Urothelial Carcinoma Evolution and the Tumor Immune Microenvironment

Yuchen Zeng, Anton George Henssen, Sihan Wu, Huanming Yang, Zhe Xu, Peng Han, Tianyu Qin, Jacob B. Hansen, Xi Xiang, Xun Lan, Gino Prasad, Vineet Bafna, Yonglun Luo, Huiying Tao, Bishoy M. Faltas, Roel G.W. Verhaak, Paul S. Mischel, Conghui Li, Yuan Liang, Xiaolong Sui, Yanfen Zhu, Xiaoguang Pan, Jens Luebeck, Qingqing Gao, Elias Rodríguez-Fos, Huajing Teng, Birgitte Regenberg, Y Wang, Chunhua Lin, Chaoyang Sun, Shichun Jiang, Linlin Chen, Lin Lin, Xuesong Li, Wei Dong, Run Zhou, Yongwei Li, Wei Lv, Yue Li, Lars Bolund
article en
16 citations

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.

Cancer DiscoveryVol. 15(6)
BGI Group (China) (CN), Zhejiang International Studies University (CN), Qingdao University (CN), Tongji University (CN), University of Copenhagen (DK), Binzhou Medical University (CN), Shandong University of Aeronautics (CN), Sun Yat-sen University (CN), University of San Diego (US), German Cancer Research Center (DE), Chinese Academy of Sciences (CN), Peking University (CN), Aarhus University (DK), Max Delbrück Center (DE), Cornell University (US), Heidelberg University (DE), Beijing Institute of Genomics (CN), Sir Run Run Shaw Hospital (CN), Yuhuangding Hospital (CN), Lander Institute (IL), Yale University (US), University of California San Diego (US), Humboldt-Universität zu Berlin (DE), Peking University Cancer Hospital (CN), The Seventh Affiliated Hospital of Sun Yat-sen University (CN), Stanford Health Care (US), Hangzhou Academy of Agricultural Sciences (CN), Peking University First Hospital (CN), Stanford Medicine (US), China Academy of Chinese Medical Sciences (CN), Marine Biomedical Research Institute of Qingdao (CN), Ministry of Education (ET), Tongji Hospital (CN), Weill Cornell Medicine (US), Huazhong University of Science and Technology (CN), Zhejiang University (CN), Charité - Universitätsmedizin Berlin (DE), The University of Texas Southwestern Medical Center (US), Stanford University (US), Tsinghua University (CN)
No poverty
Openalex Percentile: Top 0%
Bladder and Urothelial Cancer Treatments
32.10
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.