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Transposon mutagenesis identifies chromatin modifiers cooperating with Ras in thyroid tumorigenesis and detects ATXN7 as a cancer gene
Journal article   Open access   Peer reviewed

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

Cristina Montero-Conde, Luis J Leandro-Garcia, Xu Chen, Gisele Oler, Sergio Ruiz-Llorente, Mabel Ryder, Iñigo Landa, Francisco Sanchez-Vega, Konnor La, Ronald A Ghossein, …
Proceedings of the National Academy of Sciences - PNAS, Vol.114(25), pp.E4951-E4960
PNAS Plus
06/20/2017
DOI: 10.1073/pnas.1702723114
PMCID: PMC5488945
PMID: 28584132
url
https://doi.org/10.1073/pnas.1702723114View
Published (Version of record) Open Access

Abstract

Mutations of RAS are believed to be early events in thyroid tumorigenesis but are insufficient to induce transformation. A forward genetic screen with transposons engineered to integrate randomly into the mouse Ras-mutant thyroid cell genome and to disrupt genes at their insertion sites resulted in tumors that phenocopied human RAS-driven, poorly differentiated thyroid cancers. Analysis of the transposon-integration sites revealed recurrent mutations of chromatin modifiers and PI3K pathway genes, consistent with mutations seen in human advanced thyroid cancers. These human cancers have a high mutation burden, which confounds distinctions between driver and passenger mutations. This unbiased screen for genes selected during tumorigenesis provides strong functional support for genetic disruptions in these pathways in RAS-induced thyroid tumor progression. 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 Hras G12V 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-Hras G12V 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. 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 co-occurred 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.
 Biological Sciences thyroid cancer genomics PNAS Plus Swi Ras Snf Pten Sleeping Beauty

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