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

Cristina Balbás-Martínez; Ana Sagrera; Enrique Carrillo-De-Santa-Pau; Julie Earl; Mirari Márquez; Miguel Vazquez; Eleonora Lapi; Francesc Castro-Giner; Sergi Beltran; Mònica Bayés; Alfredo Carrato; Juan C. Cigudosa; Orlando Domínguez; Marta Gut; Jesús Herranz; Núria Juanpere; Manolis Kogevinas; Xavier Langa; Elena López-Knowles; José A. Lorente; Josep Lloreta; David G. Pisano; Laia Richart; Daniel Rico; Rocío N. Salgado; Adonina Tardón; Stephen Chanock; Simon Heath; Alfonso Valencia; Ana Losada; Ivo Gut; Núria Malats; Francisco X. Real

doi:10.1038/ng.2799

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

Cristina Balbás-Martínez, Ana Sagrera, Enrique Carrillo-De-Santa-Pau, Julie Earl, Mirari Márquez, Miguel Vazquez, Eleonora Lapi, Francesc Castro-Giner, Sergi Beltran, Mònica Bayés, Alfredo Carrato, Juan C. Cigudosa, Orlando Domínguez, Marta Gut, Jesús Herranz, Núria Juanpere, Manolis Kogevinas, Xavier Langa, Elena López-Knowles, José A. LorenteJosep Lloreta, David G. Pisano, Laia Richart, Daniel Rico, Rocío N. Salgado, Adonina Tardón, Stephen Chanock, Simon Heath, Alfonso Valencia, Ana Losada, Ivo Gut, Núria Malats, Francisco X. Real

Research output: Contribution to journal › Article › peer-review

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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 management. 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.

Original language	English (US)
Pages (from-to)	1464-1469
Number of pages	6
Journal	Nature genetics
Volume	45
Issue number	12
DOIs	https://doi.org/10.1038/ng.2799
State	Published - Dec 2013
Externally published	Yes

ASJC Scopus subject areas

Genetics

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Balbás-Martínez, C., Sagrera, A., Carrillo-De-Santa-Pau, E., Earl, J., Márquez, M., Vazquez, M., Lapi, E., Castro-Giner, F., Beltran, S., Bayés, M., Carrato, A., Cigudosa, J. C., Domínguez, O., Gut, M., Herranz, J., Juanpere, N., Kogevinas, M., Langa, X., López-Knowles, E., ... Real, F. X. (2013). Recurrent inactivation of STAG2 in bladder cancer is not associated with aneuploidy. Nature genetics, 45(12), 1464-1469. https://doi.org/10.1038/ng.2799

Balbás-Martínez, C, Sagrera, A, Carrillo-De-Santa-Pau, E, Earl, J, Márquez, M, Vazquez, M, Lapi, E, Castro-Giner, F, Beltran, S, Bayés, M, Carrato, A, Cigudosa, JC, Domínguez, O, Gut, M, Herranz, J, Juanpere, N, Kogevinas, M, Langa, X, López-Knowles, E, Lorente, JA, Lloreta, J, Pisano, DG, Richart, L, Rico, D, Salgado, RN, Tardón, A, Chanock, S, Heath, S, Valencia, A, Losada, A, Gut, I, Malats, N & Real, FX 2013, 'Recurrent inactivation of STAG2 in bladder cancer is not associated with aneuploidy', Nature genetics, vol. 45, no. 12, pp. 1464-1469. https://doi.org/10.1038/ng.2799

@article{c524c2e81b934ae780271d628845a958,

title = "Recurrent inactivation of STAG2 in bladder cancer is not associated with aneuploidy",

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 management. 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.",

author = "Cristina Balb{\'a}s-Mart{\'i}nez and Ana Sagrera and Enrique Carrillo-De-Santa-Pau and Julie Earl and Mirari M{\'a}rquez and Miguel Vazquez and Eleonora Lapi and Francesc Castro-Giner and Sergi Beltran and M{\`o}nica Bay{\'e}s and Alfredo Carrato and Cigudosa, {Juan C.} and Orlando Dom{\'i}nguez and Marta Gut and Jes{\'u}s Herranz and N{\'u}ria Juanpere and Manolis Kogevinas and Xavier Langa and Elena L{\'o}pez-Knowles and Lorente, {Jos{\'e} A.} and Josep Lloreta and Pisano, {David G.} and Laia Richart and Daniel Rico and Salgado, {Roc{\'i}o N.} and Adonina Tard{\'o}n and Stephen Chanock and Simon Heath and Alfonso Valencia and Ana Losada and Ivo Gut and N{\'u}ria Malats and Real, {Francisco X.}",

note = "Funding Information: We thank F. Algaba, Y. Allory, A. Cuadrado, C. Gonz{\'a}lez, E. L{\'o}pez, P. Lapunzina, T. Lobato, M. Malumbres, S. Remeseiro, V.J. S{\'a}nchez-Ar{\'e}valo, 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 Consol{\'i}der 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 Tem{\'a}tica de Investigaci{\'o}n Cooperativa en C{\'a}ncer (RTICC)), Asociaci{\'o}n Espa{\~n}ola Contra el C{\'a}ncer, 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 Fundaci{\'o}n Banco Santander Postdoctoral Programme.",

year = "2013",

month = dec,

doi = "10.1038/ng.2799",

language = "English (US)",

volume = "45",

pages = "1464--1469",

journal = "Nature genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "12",

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TY - JOUR

T1 - Recurrent inactivation of STAG2 in bladder cancer is not associated with aneuploidy

AU - Balbás-Martínez, Cristina

AU - Sagrera, Ana

AU - Carrillo-De-Santa-Pau, Enrique

AU - Earl, Julie

AU - Márquez, Mirari

AU - Vazquez, Miguel

AU - Lapi, Eleonora

AU - Castro-Giner, Francesc

AU - Beltran, Sergi

AU - Bayés, Mònica

AU - Carrato, Alfredo

AU - Cigudosa, Juan C.

AU - Domínguez, Orlando

AU - Gut, Marta

AU - Herranz, Jesús

AU - Juanpere, Núria

AU - Kogevinas, Manolis

AU - Langa, Xavier

AU - López-Knowles, Elena

AU - Lorente, José A.

AU - Lloreta, Josep

AU - Pisano, David G.

AU - Richart, Laia

AU - Rico, Daniel

AU - Salgado, Rocío N.

AU - Tardón, Adonina

AU - Chanock, Stephen

AU - Heath, Simon

AU - Valencia, Alfonso

AU - Losada, Ana

AU - Gut, Ivo

AU - Malats, Núria

AU - Real, Francisco X.

N1 - Funding Information: 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.

PY - 2013/12

Y1 - 2013/12

N2 - 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 management. 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.

AB - 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 management. 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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U2 - 10.1038/ng.2799

DO - 10.1038/ng.2799

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AN - SCOPUS:84888354078

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EP - 1469

JO - Nature genetics

JF - Nature genetics

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ER -

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

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