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Recurrent inactivation of STAG2 in bladder cancer is not associated with aneuploidy

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Abstract

Urothelial bladder cancer (UBC) is heterogeneous at the clinical, pathological and genetic levels. Tumor invasiveness (T) and grade (G) are the main factors associated with outcome and determine patient management1. A discovery exome sequencing screen (n = 17), followed by a prevalence screen (n = 60), identified new genes mutated in this tumor coding for proteins involved in chromatin modification (MLL2, ASXL2 and BPTF), cell division (STAG2, SMC1A and SMC1B) and DNA repair (ATM, ERCC2 and FANCA). STAG2, a subunit of cohesin, was significantly and commonly mutated or lost in UBC, mainly in tumors of low stage or grade, and its loss was associated with improved outcome. Loss of expression was often observed in chromosomally stable tumors, and STAG2 knockdown in bladder cancer cells did not increase aneuploidy. STAG2 reintroduction in non-expressing cells led to reduced colony formation. Our findings indicate that STAG2 is a new UBC tumor suppressor acting through mechanisms that are different from its role in preventing aneuploidy.

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Figure 1: Distribution of SNVs identified in the discovery screen through exome sequencing.
Figure 2: Distribution of mutations in genes recurrently mutated in UBC that are expressed in >30% of tumors: joint analysis of the discovery and prevalence screens.
Figure 3: Immunohistochemical analysis of STAG2 expression in bladder tumors of different stage and grade.
Figure 4: Loss of STAG2 expression is not associated with aneuploidy in primary tumors and in 639V bladder cancer cells.
Figure 5: Kaplan-Meier plots of the association of STAG2 expression with outcome in individuals with UBC.

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Acknowledgements

We thank F. Algaba, Y. Allory, A. Cuadrado, C. González, E. López, P. Lapunzina, T. Lobato, M. Malumbres, S. Remeseiro, V.J. Sánchez-Arévalo, F. Waldman and the CNIO core facilities for valuable contributions. We also thank TCGA investigators for providing unpublished information for analysis. This work was supported, in part, by grants from Ministerio de Economia y Competitividad, Madrid (grants Consolíder ONCOBIO, Consolider INESGEN, SAF-2010-21517 and SAF2011-15934-E), Instituto de Salud Carlos III (grants G03/174, 00/0745, PI051436, PI061614, G03/174, PI080440, PI120425 and Red Temática de Investigación Cooperativa en Cáncer (RTICC)), Asociación Española Contra el Cáncer, EU-FP7-201663 and US National Institutes of Health grant RO1 CA089715. C.B.-M. is the recipient of a La Caixa International PhD Fellowship. E.L. is supported by a grant from the Fundación Banco Santander Postdoctoral Programme.

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Authors and Affiliations

Authors

Contributions

C.B.-M., E.L. and L.R. designed and performed in vitro functional studies. C.B.-M. performed immunohistochemical analysis of tumor samples. A.S. and C.B.-M. designed and performed mutation validation analyses. A.S. designed and prepared HaloPlex libraries for sequencing. E.C.-d.-S.-P., M.V., F.C.-G., S.B. and D.G.P. processed and analyzed exome sequencing and targeted resequencing data. J.E., E.L.-K., D.R. and S.C. performed gene copy number analyses of tumors. M.M. coordinated subject and sample data management. A.C., M.K., J.A.L. and A.T. contributed to subject recruitment and data collection. J.H. performed statistical analyses. X.L. provided technical support with subject samples. M.B. and M.G. coordinated library preparation and sequencing. O.D. contributed to library preparation and sequencing. J.C.C. and R.N.S. contributed to the in vitro analysis of the effects of STAG2 knockdown on aneuploidy. N.J. and J.L. performed pathological review of samples. I.G. coordinated exome sequencing and targeted resequencing. I.G., S.H. and A.V. supervised bioinformatics analyses. A.L. provided scientific insight and contributed with reagents. N.M. coordinated subject recruitment and the collection of clinical and pathological data and supervised clinical-pathological-molecular association and outcome analyses. F.X.R. and N.M. conceived the study. F.X.R. supervised the overall way in which the study was conducted. F.X.R. wrote the manuscript with N.M., C.B.-M., A.S., E.C.-d.-S.-P., A.V., A.L. and I.G. contributed to manuscript writing.

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Correspondence to Francisco X Real.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–13 and Supplementary Tables 1, 2, 5 and 7–20 (PDF 14705 kb)

Supplementary Table 3

Relevant mutations identified in the discovery screen (exome sequencing) (n = 17) (XLS 565 kb)

Supplementary Table 4

Pathway analyses of genes mutated in UBC (XLSX 38 kb)

Supplementary Table 6

Design of the prevalence screen and genes included therein, depth of coverage and relevant mutations detected (total and in each individual tumor) (XLSX 119 kb)

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Balbás-Martínez, C., Sagrera, A., Carrillo-de-Santa-Pau, E. et al. Recurrent inactivation of STAG2 in bladder cancer is not associated with aneuploidy. Nat Genet 45, 1464–1469 (2013). https://doi.org/10.1038/ng.2799

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