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, Dean F. Bajorin, Jeffrey A. Knauf, Jesse D. Riordan, Adam J. Dupuy, James A. Fagin

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)E4951-E4960
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number25
DOIs
StatePublished - Jun 20 2017
Externally publishedYes

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Neoplasm Genes
Beauty
Mutagenesis
Chromatin
Thyroid Gland
Carcinogenesis
Neoplasms
Thyroid Neoplasms
Mutation
Histone Acetyltransferases
Multiprotein Complexes
Chromatin Assembly and Disassembly
Penetrance
Phosphatidylinositol 3-Kinases
Cell Proliferation
Genes

Keywords

  • Pten
  • Ras
  • Sleeping Beauty
  • Swi/Snf
  • Thyroid cancer genomics

ASJC Scopus subject areas

  • General

Cite this

Transposon mutagenesis identifies chromatin modifiers cooperating with Ras in thyroid tumorigenesis and detects ATXN7 as a cancer gene. / Montero-Conde, Cristina; Leandro-Garcia, Luis J.; Chen, Xu; Oler, Gisele; Ruiz-Llorente, Sergio; Ryder, Mabel; Landa, Iñigo; Sanchez-Vega, Francisco; La, Konnor; Ghossein, Ronald A.; Bajorin, Dean F.; Knauf, Jeffrey A.; Riordan, Jesse D.; Dupuy, Adam J.; Fagin, James A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 25, 20.06.2017, p. E4951-E4960.

Research output: Contribution to journalArticle

Montero-Conde, C, Leandro-Garcia, LJ, Chen, X, Oler, G, Ruiz-Llorente, S, Ryder, M, Landa, I, Sanchez-Vega, F, La, K, Ghossein, RA, Bajorin, DF, Knauf, JA, Riordan, JD, Dupuy, AJ & Fagin, JA 2017, 'Transposon mutagenesis identifies chromatin modifiers cooperating with Ras in thyroid tumorigenesis and detects ATXN7 as a cancer gene', Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 25, pp. E4951-E4960. https://doi.org/10.1073/pnas.1702723114
Montero-Conde, Cristina ; Leandro-Garcia, Luis J. ; Chen, Xu ; Oler, Gisele ; Ruiz-Llorente, Sergio ; Ryder, Mabel ; Landa, Iñigo ; Sanchez-Vega, Francisco ; La, Konnor ; Ghossein, Ronald A. ; Bajorin, Dean F. ; Knauf, Jeffrey A. ; Riordan, Jesse D. ; Dupuy, Adam J. ; Fagin, James A. / Transposon mutagenesis identifies chromatin modifiers cooperating with Ras in thyroid tumorigenesis and detects ATXN7 as a cancer gene. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 25. pp. E4951-E4960.
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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.",
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AU - Montero-Conde, Cristina

AU - Leandro-Garcia, Luis J.

AU - Chen, Xu

AU - Oler, Gisele

AU - Ruiz-Llorente, Sergio

AU - Ryder, Mabel

AU - Landa, Iñigo

AU - Sanchez-Vega, Francisco

AU - La, Konnor

AU - Ghossein, Ronald A.

AU - Bajorin, Dean F.

AU - Knauf, Jeffrey A.

AU - Riordan, Jesse D.

AU - Dupuy, Adam J.

AU - Fagin, James A.

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N2 - 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.

AB - 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.

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