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 Marquez,Miguel Vazquez,Eleonora Lapi,Francesc Castro-Giner,Sergi Beltran,Mònica Bayés,Alfredo Carrato,Juan C. Cigudosa,Orlando Domínguez,Marta Gut,Jesús Herranz,Nuria Juanpere,Manolis Kogevinas,Xavier Langa,Elena Lopez-Knowles,José A. Lorente,Josep Lloreta,David G. Pisano,Laia Richart,Daniel Rico,Rocío Salgado,Adonina Tardón,Stephen J. Chanock,Simon Heath,Alfonso Valencia,Ana Losada,Ivo Gut,Núria Malats,Francisco X. Real +32 more
TLDR
It is indicated that STAG2 is a new UBC tumor suppressor acting through mechanisms that are different from its role in preventing aneuploidy, and its loss was associated with improved outcome.Abstract:
Francisco Real and colleagues report exome sequencing in urothelial bladder tumors. They show that STAG2, a subunit of the cohesin complex, is recurrently mutated and provide evidence that STAG2 loss does not lead to increases in aneuploidy. 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.read more
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Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer
A. Gordon Robertson,Jaegil Kim,Hikmat Al-Ahmadie,Joaquim Bellmunt,Guangwu Guo,Andrew D. Cherniack,Toshinori Hinoue,Peter W. Laird,Katherine A. Hoadley,Rehan Akbani,Mauro A. A. Castro,Ewan A. Gibb,Rupa S. Kanchi,Dmitry A. Gordenin,Sachet A. Shukla,Francisco Sanchez-Vega,Donna E. Hansel,Bogdan Czerniak,Victor E. Reuter,Xiaoping Su,Benilton S. Carvalho,Vinicius S Chagas,Karen Mungall,Sara Sadeghi,Chandra Sekhar Pedamallu,Yiling Lu,Leszek J. Klimczak,Jiexin Zhang,Caleb Choo,Akinyemi I. Ojesina,Susan Bullman,Kristen M. Leraas,Tara M. Lichtenberg,Catherine J. Wu,N. Schultz,Gad Getz,Matthew Meyerson,Gordon B. Mills,David J. McConkey,Monique Albert,Iakovina Alexopoulou,Adrian Ally,Tatjana Antic,Manju Aron,Miruna Balasundaram,John M. S. Bartlett,Stephen B. Baylin,Allison Beaver,Inanc Birol,Lori Boice,Moiz S. Bootwalla,Jay Bowen,Reanne Bowlby,Denise Brooks,Bradley M. Broom,Wiam Bshara,Eric J. Burks,Flavio Mavignier Carcano,Rebecca Carlsen,André Lopes Carvalho,Eric P. Castle,Patricia Castro,James W.F. Catto,David Chesla,Eric Chuah,Sudha Chudamani,Victoria K. Cortessis,Sandra Cottingham,Daniel Crain,Erin Curley,Siamak Daneshmand,John A. Demchok,Noreen Dhalla,Hooman Djaladat,John Eckman,Sophie C. Egea,Jay Engel,Ina Felau,Martin L. Ferguson,Johanna Gardner,Julie M. Gastier-Foster,Mark Gerken,Carmen Gomez-Fernandez,Jodi Harr,Arndt Hartmann,Lynn M. Herbert,Thai H. Ho,Robert A. Holt,Carolyn M. Hutter,Steven J.M. Jones,Merce Jorda,Richard J. Kahnoski,Katayoon Kasaian,David J. Kwiatkowski,Phillip H. Lai,Brian R. Lane,Seth P. Lerner,Jia Liu,Laxmi Lolla,Yair Lotan,Fabiano R. Lucchesi,Yussanne Ma,Roberto Dias Machado,Dennis T. Maglinte,David Mallery,Marco A. Marra,Sue E. Martin,Michael Mayo,Anoop Meraney,Alireza Moinzadeh,Richard A. Moore,Edna M. Mora Pinero,Scott Morris,Carl Morrison,Andrew J. Mungall,Jerome Myers,Rashi Naresh,Peter H. O'Donnell,Dipen J. Parekh,Jeremy Parfitt,Joseph Paulauskis,Robert Penny,Todd Pihl,Sima P. Porten,Mario Quintero-Aguilo,Nilsa C. Ramirez,W. Kimryn Rathmell,Kimberly M. Rieger-Christ,Charles Saller,Andrew Salner,George E. Sandusky,Cristovam Scapulatempo-Neto,Jacqueline E. Schein,Anne Schuckman,Candace Shelton,Troy Shelton,Jeff Simko,Parminder Singh,Payal Sipahimalani,Norm D. Smith,Heidi J. Sofia,Andrea Sorcini,Melissa L. Stanton,Gary D. Steinberg,Robert Stoehr,Travis Sullivan,Qiang Sun,Angela Tam,Roy Tarnuzzer,Katherine Tarvin,Helge Taubert,Nina Thiessen,Leigh B. Thorne,Kane Tse,Kelinda Tucker,David Van Den Berg,Kim E.M. van Kessel,Sven Wach,Yunhu Wan,Zhining Wang,John N. Weinstein,Daniel J. Weisenberger,Lisa Wise,Tina Wong,Ye Wu,Liming Yang,Leigh Anne Zach,Jean C. Zenklusen,Jiashan Zhang,Erik Zmuda,Ellen C. Zwarthoff +170 more
TL;DR: An analysis of 412 muscle-invasive bladder cancers characterized by multiple TCGA analytical platforms identified 5 expression subtypes that may stratify response to different treatments and identified a poor-survival "neuronal" subtype in which the majority of tumors lacked small cell or neuroendocrine histology.
Journal ArticleDOI
The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs-Part B: Prostate and Bladder Tumours.
TL;DR: Modifications to the Gleason grading system are incorporated into the 2016 WHO section on grading of prostate cancer, and it is recommended that the percentage of pattern 4 should be reported for Gleason score 7.
Journal ArticleDOI
Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity
TL;DR: Improved understanding of molecular features, disease pathogenesis and heterogeneity provides new opportunities for prognostic application, disease monitoring and personalized therapy in urothelial cancer.
Journal ArticleDOI
Genomic Landscape of Ewing Sarcoma Defines an Aggressive Subtype with Co-Association of STAG2 and TP53 Mutations
Franck Tirode,Didier Surdez,Xiaotu Ma,Matthew Parker,Marie-Cécile Le Deley,Armita Bahrami,Zhaojie Zhang,Eve Lapouble,Sandrine Grossetête-Lalami,Michael Rusch,Stéphanie Reynaud,Thomas Rio-Frio,Erin Hedlund,Gang Wu,Xiang Chen,Gaëlle Pierron,Odile Oberlin,Sakina Zaidi,Gordon Lemmon,Pankaj Gupta,Bhavin Vadodaria,John Easton,Marta Gut,Li Ding,Elaine R. Mardis,Richard K. Wilson,Sheila A. Shurtleff,Valérie Laurence,Jean Michon,Perrine Marec-Berard,Ivo Gut,James R. Downing,Michael A. Dyer,Michael A. Dyer,Jinghui Zhang,Olivier Delattre +35 more
TL;DR: Tumors that harbor STAG2 and TP53 mutations have a particularly dismal prognosis with current treatments and require alternative therapies, and novel drugs that target epigenetic regulators may constitute viable therapeutic strategies in a subset of patients with mutations in chromatin modifiers.
Journal ArticleDOI
The genomic landscape of pediatric Ewing sarcoma
Brian D. Crompton,Chip Stewart,Amaro Taylor-Weiner,Gabriela Alexe,Kyle C. Kurek,Monica L. Calicchio,Adam Kiezun,Scott L. Carter,Sachet A. Shukla,Swapnil Mehta,Aaron R. Thorner,Carmen de Torres,Cinzia Lavarino,Mariona Suñol,Aaron McKenna,Andrey Sivachenko,Kristian Cibulskis,Michael S. Lawrence,Petar Stojanov,Mara Rosenberg,Lauren Ambrogio,Daniel Auclair,Sara Seepo,Brendan Blumenstiel,Matthew Defelice,Ivan Imaz-Rosshandler,Angela Schwarz-Cruz y Celis,Miguel Rivera,Carlos Rodriguez-Galindo,Mark D. Fleming,Todd R. Golub,Gad Getz,Jaume Mora,Kimberly Stegmaier,Kimberly Stegmaier +34 more
TL;DR: Next-generation sequencing of Ewing sarcoma found remarkably few mutations, however, it was discovered that loss of STAG2 expression occurs in 15% of tumors and is associated with metastatic disease, suggesting a potential genetic vulnerability in Ewing Sarcoma.
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