Open Access Open Badges Research

Single-cell sequencing analysis characterizes common and cell-lineage-specific mutations in a muscle-invasive bladder cancer

Yingrui Li1, Xun Xu1, Luting Song1234, Yong Hou156, Zesong Li789, Shirley Tsang10, Fuqiang Li1, Kate McGee Im11, Kui Wu1, Hanjie Wu112, Xiaofei Ye1, Guibo Li1, Linlin Wang1, Bo Zhang1, Jie Liang1, Wei Xie156, Renhua Wu1, Hui Jiang1, Xiao Liu1, Chang Yu1, Hancheng Zheng1, Min Jian1, Liping Nie13, Lei Wan14, Min Shi13, Xiaojuan Sun789, Aifa Tang789, Guangwu Guo1, Yaoting Gui13, Zhiming Cai1389, Jingxiang Li1, Wen Wang2, Zuhong Lu56, Xiuqing Zhang1, Lars Bolund115, Karsten Kristiansen116, Jian Wang1, Huanming Yang1*, Michael Dean11* and Jun Wang11617*

Author Affiliations

1 BGI-Shenzhen, Beishan Industrial Zone, Beishan Road, Yantian, Shenzhen, 518083, People’s Republic of China

2 CAS-Max Planck Junior Research Group, State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences (CAS), 32# Jiao-chang Road, Kunming, Yunnan, 650223, People’s Republic of China

3 Graduate University of the Chinese Academy of Sciences, 19A Yuquanlu, Beijing, 100049, People’s Republic of China

4 College of Life Sciences, Wuhan University, Luojia Hill, Wuhan, 430072, People’s Republic of China

5 School of Biological Science and Medical Engineering, Southeast University, Sipailou 2#, Nanjing, 210096, People’s Republic of China

6 State Key Laboratory of Bioelectronics, Southeast University, Sipailou 2#, Nanjing, 210096, People’s Republic of China

7 Shenzhen Key Laboratory of Genitourinary Tumor, Shenzhen Second People’s Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, 518035, People’s Republic of China

8 Department of Urology, Shenzhen Second People’s Hospital, Shenzhen, 518035, People’s Republic of China

9 The Institute of Urogenital Diseases, Shenzhen University, Shenzhen, 518060, People’s Republic of China

10 BioMatrix, LLC, 3029 Windy Knoll Court, Rockville, MD, 20850, USA

11 Cancer and Inflammation Program, National Cancer Institute at Frederick, Building 560, Frederick, MD, 21702, USA

12 School of Bioscience and Biotechnology, Guangzhou Higher Education Mega Centre, South China University of Technology, Panyu District, Guangzhou, 510006, People’s Republic of China

13 Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Shenzhen PKU-HKUST Medical Center, Peking University Shenzhen Hospital, 1120 Lian Hua Road, Futian District, Shenzhen, 518036, People’s Republic of China

14 Department of Urology, Longgang Central Hospital, Shenhui Road, Longgang Town, Shenzhen, 518116, People’s Republic of China

15 Institute of Human Genetics, University of Aarhus, Aarhus, 8100, Denmark

16 The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Ole Maaløes Vej 5, Copenhagen, DK, 2200, Denmark

17 Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, Copenhagen, DK, 2200, Denmark

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GigaScience 2012, 1:12  doi:10.1186/2047-217X-1-12

Published: 14 August 2012



Cancers arise through an evolutionary process in which cell populations are subjected to selection; however, to date, the process of bladder cancer, which is one of the most common cancers in the world, remains unknown at a single-cell level.


We carried out single-cell exome sequencing of 66 individual tumor cells from a muscle-invasive bladder transitional cell carcinoma (TCC). Analyses of the somatic mutant allele frequency spectrum and clonal structure revealed that the tumor cells were derived from a single ancestral cell, but that subsequent evolution occurred, leading to two distinct tumor cell subpopulations. By analyzing recurrently mutant genes in an additional cohort of 99 TCC tumors, we identified genes that might play roles in the maintenance of the ancestral clone and in the muscle-invasive capability of subclones of this bladder cancer, respectively.


This work provides a new approach of investigating the genetic details of bladder tumoral changes at the single-cell level and a new method for assessing bladder cancer evolution at a cell-population level.

Single-cell exome sequencing; Bladder cancer; Tumor evolution; Population genetics