Whole-genome and whole-exome sequencing of bladder cancer identifies frequent alterations in genes involved in sister chromatid cohesion and segregation

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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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Journal ID (nlm-journal-id): 9216904

Journal ID (pubmed-jr-id): 2419

Journal ID (nlm-ta): Nat Genet

Journal ID (iso-abbrev): Nat. Genet.

Title: Nature genetics

ISSN (Print): 1061-4036

ISSN (Electronic): 1546-1718

Publication date Nihms-submitted: 16 September 2020

Publication date (Electronic): 13 October 2013

Publication date (Print): December 2013

Publication date PMC-release: 24 September 2020

Volume: 45

Issue: 12

Pages: 1459-1463

Affiliations

[1 ]Department of Urological Surgery, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China.

[2 ]BGI-Shenzhen, Shenzhen, China.

[3 ]National-Regional Key Technology Engineering Laboratory for Clinical Application of Cancer Genomics, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China.

[4 ]Shenzhen Engineering Laboratory of Tumor Clinical Immune Gene Therapy, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China.

[5 ]Shenzhen Key Laboratory of Genitourinary Tumor, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China.

[6 ]Institute of Immunology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.

[7 ]Department of Urology, Sun Yat-Sen University Cancer Center, Guangzhou, China.

[8 ]Cancer and Inflammation Program, National Cancer Institute, US National Institutes of Health (NIH), Frederick, Maryland, USA.

[9 ]Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, China.

[10 ]Department of Urology, The Second Xiangya Hospital of Central-Southern University, Changsha, China.

[11 ]Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.

[12 ]Department of Urology, Zhujiang Hospital of Southern Medical University, Guangzhou, China.

[13 ]Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China.

[14 ]BioMatrix, Rockville, Maryland, USA.

[15 ]Department of Surgery, University of Colorado Comprehensive Cancer Center, Aurora, Colorado, USA.

[16 ]Department of Biology, U niversity of Copenhagen, Copenhagen, Denmark.

[17 ]The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.

[18 ]These authors contributed equally to this work.

Author notes

Correspondence should be addressed to Z.C. ( caizhiming2000@ 123456163.com ), Jun Wang ( wangj@ 123456genomics.org.cn ) or Y.G. ( guiyaoting@ 123456hotmail.com ).

AUTHOR CONTRIBUTIONS

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.

Article

Accession ID: PMC7512009 Pmcid ID: PMC7512009 Pmc-uid ID: 7512009 Manuscript ID: nihpa1627063

DOI: 10.1038/ng.2798

PMC ID: 7512009

PubMed ID: 24121792

SO-VID: dc0cce29-6f6f-46b2-a86b-3e25062367fb

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Whole-genome and whole-exome sequencing of bladder cancer identifies frequent alterations in genes involved in sister chromatid cohesion and segregation

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