Abstract
Bladder cancer is one of the most common cancers worldwide, with transitional cell carcinoma (TCC) being the predominant form. Here we report a genomic analysis of TCC by both whole-genome and whole-exome sequencing of 99 individuals with TCC. Beyond confirming recurrent mutations in genes previously identified as being mutated in TCC, we identified additional altered genes and pathways that were implicated in TCC. Notably, we discovered frequent alterations in STAG2 and ESPL1, two genes involved in the sister chromatid cohesion and segregation (SCCS) process. Furthermore, we also detected a recurrent fusion involving FGFR3 and TACC3, another component of SCCS, by transcriptome sequencing of 42 DNA-sequenced tumors. Overall, 32 of the 99 tumors (32%) harbored genetic alterations in the SCCS process. Our analysis provides evidence that genetic alterations affecting the SCCS process may be involved in bladder tumorigenesis and identifies a new therapeutic possibility for bladder cancer.
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Acknowledgements
This work was supported by grants from the Chinese High-Tech (863) Program (2012AA02A201 and 2012AA02A208), the Guangdong Innovative Research Team Program (2009010016), the State Key Development Program for Basic Research of China–973 Program (2011CB809203 and 2014CB745200) and the Shenzhen Municipal Government of China (JC201005260191A, CXB201108250096A, ZDSY20120615154448514 and BGI20100001).
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Jun Wang, Z.C., Jian Wang, H.Y., Y. Li, X. Zhang and Y.G. managed the project. X.S., S. Wu, Z. Li, A.T., X.L., Xiaokun Zhao, S.Z., M.Q., L. Xie, X. Zou, L. Xing, Z. Lv, H.M., C. Liang, J.L., C. Liu, C. Li, J.C., Y. Lai, Zheguang Lin and F. Zhou prepared the samples. P.H., P.S., F.F., Y.Y. and Xin Zhao performed the sequencing. G.G., C.C., Y.H., W.J., Q.Z., Z.Y., R.Y., Zhao Lin, S. Wan, M.L.N., M.D., S.G., Z.G., L.L., X.F., J.Y., F. Zhang, S.T. and D.T. performed the bioinformatic analysis. X.S., P.H., Z. Li, P.S., F.F., X.H., Z.J., H.C. and H.C.C. performed the validation of somatic mutations, CNAs and gene fusion events. G.G. wrote the manuscript. G.G., X.S., C.C., S. Wu, P.H. and Z. Li revised the manuscript.
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Supplementary Text and Figures
Supplementary Note, Supplementary Figures 1–23 and Supplementary Tables 1, 2 and 5–14 (PDF 32390 kb)
Supplementary Table 3
Predicted somatic mutations in 99 TCC patients (XLSX 857 kb)
Supplementary Table 4
A list of all confirmed somatic mutations detected in 99 TCC patients (XLSX 83 kb)
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Guo, G., Sun, X., Chen, C. et al. Whole-genome and whole-exome sequencing of bladder cancer identifies frequent alterations in genes involved in sister chromatid cohesion and segregation. Nat Genet 45, 1459–1463 (2013). https://doi.org/10.1038/ng.2798
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DOI: https://doi.org/10.1038/ng.2798
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