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oai:repisalud.isciii.es:20.500.12105/272082026-02-07T01:19:27Zcom_20.500.12105_2327com_20.500.12105_2290col_20.500.12105_16991

00925njm 22002777a 4500 dc Montero-Conde, Cristina author Leandro-Garcia, Luis J author Chen, Xu author Oler, Gisele author Ruiz-Llorente, Sergio author Ryder, Mabel author Landa, Iñigo author Sanchez-Vega, Francisco author La, Konnor author Ghossein, Ronald A author Bajorin, Dean F author Knauf, Jeffrey A author Riordan, Jesse D author Dupuy, Adam J author Fagin, James A author 2017-06-20 Oncogenic mutations are present in 15-30% of thyroid carcinomas. Endogenous expression of mutant Ras is insufficient to initiate thyroid tumorigenesis in murine models, indicating that additional genetic alterations are required. We used Sleeping Beauty (SB) transposon mutagenesis to identify events that cooperate with Hras in thyroid tumor development. Random genomic integration of SB transposons primarily generated loss-of-function events that significantly increased thyroid tumor penetrance in mice. The thyroid tumors closely phenocopied the histological features of human RAS-driven, poorly differentiated thyroid cancers. Characterization of transposon insertion sites in the SB-induced tumors identified 45 recurrently mutated candidate cancer genes. These mutation profiles were remarkably concordant with mutated cancer genes identified in a large series of human poorly differentiated and anaplastic thyroid cancers screened by next-generation sequencing using the MSK-IMPACT panel of cancer genes, which we modified to include all SB candidates. The disrupted genes primarily clustered in chromatin remodeling functional nodes and in the PI3K pathway. , a component of a multiprotein complex with histone acetylase activity, scored as a significant SB hit. It was recurrently mutated in advanced human cancers and significantly co-occurred with or mutations. Expression of mutants cooperated with oncogenic RAS to induce thyroid cell proliferation, pointing to as a previously unrecognized cancer gene. Proc Natl Acad Sci U S A . 2017 Jun 20;114(25):E4951-E4960. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 28584132 https://hdl.handle.net/20.500.12105/27208 Pten Ras Sleeping Beauty Swi/Snf thyroid cancer genomics Transposon mutagenesis identifies chromatin modifiers cooperating with in thyroid tumorigenesis and detects as a cancer gene.