Synapse - Transposon mutagenesis identifies chromatin modifiers cooperating with Ras in thyroid tumorigenesis and detects ATXN7 as a cancer gene

Transposon mutagenesis identifies chromatin modifiers cooperating with Ras in thyroid tumorigenesis and detects ATXN7 as a cancer gene Journal Article

Authors:	Montero-Conde, C.; Leandro-Garcia, L. J.; Chen, X.; Oler, G.; Ruiz-Llorente, S.; Ryder, M.; Landa, I.; Sanchez-Vega, F.; La, K.; Ghossein, R. A.; Bajorin, D. F.; Knauf, J. A.; Riordan, J. D.; Dupuy, A. J.; Fagin, J. A.
Article Title:	Transposon mutagenesis identifies chromatin modifiers cooperating with Ras in thyroid tumorigenesis and detects ATXN7 as a cancer gene
Abstract:	Oncogenic RAS 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 HrasG12V in thyroid tumor development. Random genomic integration of SB transposons primarily generated loss-of-function events that significantly increased thyroid tumor penetrance in Tpo-Cre/homozygous FR-HrasG12V mice. The thyroid tumors closely phenocopied the histological features of human RAS-driven, poorly differentiated thyroid cancers. Characterization of transposon insertion sites in the SBinduced 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 nextgeneration 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. ATXN7, 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 cooccurred with RAS or NF1 mutations. Expression of ATXN7 mutants cooperated with oncogenic RAS to induce thyroid cell proliferation, pointing to ATXN7 as a previously unrecognized cancer gene.
Keywords:	pten; ras; swi/snf; sleeping beauty; thyroid cancer genomics
Journal Title:	Proceedings of the National Academy of Sciences of the United States of America
Volume:	114
Issue:	25
ISSN:	0027-8424
Publisher:	National Academy of Sciences
Date Published:	2017-06-20
Start Page:	E4951
End Page:	E4960
Language:	English
DOI:	10.1073/pnas.1702723114
PROVIDER:	scopus
PMCID:	PMC5488945
PUBMED:	28584132
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85021145343&doi=10.1073%2fpnas.1702723114&partnerID=40&md5=2cbc55f28f11d4d02fdb9372fb80e94b
Notes:	Article -- Export Date: 2 August 2017 -- Source: Scopus