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Proc Natl Acad Sci U S A. 2017 Jun 20;114(25):E4951-E4960. doi: 10.1073/pnas.1702723114. Epub 2017 Jun 5.

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

Author information

1
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
2
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Center, Madrid, Spain 28029.
3
Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
4
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
5
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
6
Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242.
7
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065; faginj@mskcc.org.

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 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.

KEYWORDS:

Pten; Ras; Sleeping Beauty; Swi/Snf; thyroid cancer genomics

PMID:
28584132
PMCID:
PMC5488945
DOI:
10.1073/pnas.1702723114
[Indexed for MEDLINE]
Free PMC Article

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