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Genomic Landscape ofEwing Sarcoma Definesan Aggressive Subtypewith Co-Associationof STAG2 and TP53Mutations Franck TirodeDidier SurdezXiaotu Ma2014 год

Genomic Landscape of Ewing Sarcoma Defines an Aggressive Subtype with Co-Association of STAG2 and TP53 Mutations
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Аннотация: Ewing sarcoma is a primary bone tumor initiated by EWSR1-ETS gene fusions. To identify secondary genetic lesions that contribute to tumor progression, we performed whole-genome sequencing of 112 Ewing sarcoma samples and matched germline DNA. Overall, Ewing sarcoma tumors had relatively few single-nucleotide variants, indels, structural variants, and copy-number alterations. Apart from whole chromosome arm copy-number changes, the most common somatic mutations were detected in STAG2 (17%), CDKN2A (12%), TP53 (7%), EZH2, BCOR, and ZMYM3 (2.7% each). Strikingly, STAG2 mutations and CDKN2A deletions were mutually exclusive, as confirmed in Ewing sarcoma cell lines. In an expanded cohort of 299 patients with clinical data, we discovered that STAG2 and TP53 mutations are often concurrent and are associated with poor outcome. Finally, we detected subclonal STAG2 mutations in diagnostic tumors and expansion of STAG2-immunonegative cells in relapsed tumors as compared with matched diagnostic samples.Whole-genome sequencing reveals that the somatic mutation rate in Ewing sarcoma is low. Tumors that harbor STAG2 and TP53 mutations have a particularly dismal prognosis with current treatments and require alternative therapies. Novel drugs that target epigenetic regulators may constitute viable therapeutic strategies in a subset of patients with mutations in chromatin modifiers.
Год издания: 2014
Авторы: 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 Zaïdi, Gordon Lemmon, Pankaj Gupta, Bhavin Vadodaria, John Easton, Marta Gut, Li Ding, Elaine R. Mardis, Richard K. Wilson, Sheila Shurtleff, Valérie Laurence, Jean Michon, Perrine Marec‐Bérard, Marta Gut, James R. Downing, Michael A. Dyer, Jinghui Zhang, Olivier Delattre
Издательство: American Association for Cancer Research
Источник: Cancer Discovery
Ключевые слова: Sarcoma Diagnosis and Treatment, Cancer Genomics and Diagnostics, Lymphoma Diagnosis and Treatment
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