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  1. Article ; Online: PPM1D mutations are oncogenic drivers of de novo diffuse midline glioma formation.

    Khadka, Prasidda / Reitman, Zachary J / Lu, Sophie / Buchan, Graham / Gionet, Gabrielle / Dubois, Frank / Carvalho, Diana M / Shih, Juliann / Zhang, Shu / Greenwald, Noah F / Zack, Travis / Shapira, Ofer / Pelton, Kristine / Hartley, Rachel / Bear, Heather / Georgis, Yohanna / Jarmale, Spandana / Melanson, Randy / Bonanno, Kevin /
    Schoolcraft, Kathleen / Miller, Peter G / Condurat, Alexandra L / Gonzalez, Elizabeth M / Qian, Kenin / Morin, Eric / Langhnoja, Jaldeep / Lupien, Leslie E / Rendo, Veronica / Digiacomo, Jeromy / Wang, Dayle / Zhou, Kevin / Kumbhani, Rushil / Guerra Garcia, Maria E / Sinai, Claire E / Becker, Sarah / Schneider, Rachel / Vogelzang, Jayne / Krug, Karsten / Goodale, Amy / Abid, Tanaz / Kalani, Zohra / Piccioni, Federica / Beroukhim, Rameen / Persky, Nicole S / Root, David E / Carcaboso, Angel M / Ebert, Benjamin L / Fuller, Christine / Babur, Ozgun / Kieran, Mark W / Jones, Chris / Keshishian, Hasmik / Ligon, Keith L / Carr, Steven A / Phoenix, Timothy N / Bandopadhayay, Pratiti

    Nature communications

    2022  Volume 13, Issue 1, Page(s) 604

    Abstract: The role of PPM1D mutations in de novo gliomagenesis has not been systematically explored. Here we analyze whole genome sequences of 170 pediatric high-grade gliomas and find that truncating mutations in PPM1D that increase the stability of its ... ...

    Abstract The role of PPM1D mutations in de novo gliomagenesis has not been systematically explored. Here we analyze whole genome sequences of 170 pediatric high-grade gliomas and find that truncating mutations in PPM1D that increase the stability of its phosphatase are clonal driver events in 11% of Diffuse Midline Gliomas (DMGs) and are enriched in primary pontine tumors. Through the development of DMG mouse models, we show that PPM1D mutations potentiate gliomagenesis and that PPM1D phosphatase activity is required for in vivo oncogenesis. Finally, we apply integrative phosphoproteomic and functional genomics assays and find that oncogenic effects of PPM1D truncation converge on regulators of cell cycle, DNA damage response, and p53 pathways, revealing therapeutic vulnerabilities including MDM2 inhibition.
    MeSH term(s) Adolescent ; Adult ; Animals ; Brain Stem Neoplasms/genetics ; Carcinogenesis/genetics ; Cell Cycle ; Child ; Child, Preschool ; DNA Damage ; Disease Models, Animal ; Female ; Glioma/genetics ; HEK293 Cells ; Humans ; Infant ; Male ; Mice ; Mutation ; Oncogenes/genetics ; Protein Phosphatase 2C/genetics ; Proto-Oncogene Proteins c-mdm2 ; Transcriptome ; Tumor Suppressor Protein p53/genetics ; Young Adult
    Chemical Substances Tumor Suppressor Protein p53 ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27) ; PPM1D protein, human (EC 3.1.3.16) ; Protein Phosphatase 2C (EC 3.1.3.16)
    Language English
    Publishing date 2022-02-01
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-022-28198-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: FOXR2 Is an Epigenetically Regulated Pan-Cancer Oncogene That Activates ETS Transcriptional Circuits.

    Tsai, Jessica W / Cejas, Paloma / Wang, Dayle K / Patel, Smruti / Wu, David W / Arounleut, Phonepasong / Wei, Xin / Zhou, Ningxuan / Syamala, Sudeepa / Dubois, Frank P B / Crane, Alexander / Pelton, Kristine / Vogelzang, Jayne / Sousa, Cecilia / Baguette, Audrey / Chen, Xiaolong / Condurat, Alexandra L / Dixon-Clarke, Sarah E / Zhou, Kevin N /
    Lu, Sophie D / Gonzalez, Elizabeth M / Chacon, Madison S / Digiacomo, Jeromy J / Kumbhani, Rushil / Novikov, Dana / Hunter, J'Ya / Tsoli, Maria / Ziegler, David S / Dirksen, Uta / Jager, Natalie / Balasubramanian, Gnana Prakash / Kramm, Christof M / Nathrath, Michaela / Bielack, Stefan / Baker, Suzanne J / Zhang, Jinghui / McFarland, James M / Getz, Gad / Aguet, François / Jabado, Nada / Witt, Olaf / Pfister, Stefan M / Ligon, Keith L / Hovestadt, Volker / Kleinman, Claudia L / Long, Henry / Jones, David T W / Bandopadhayay, Pratiti / Phoenix, Timothy N

    Cancer research

    2022  Volume 82, Issue 17, Page(s) 2980–3001

    Abstract: Forkhead box R2 (FOXR2) is a forkhead transcription factor located on the X chromosome whose expression is normally restricted to the testis. In this study, we performed a pan-cancer analysis of FOXR2 activation across more than 10,000 adult and ... ...

    Abstract Forkhead box R2 (FOXR2) is a forkhead transcription factor located on the X chromosome whose expression is normally restricted to the testis. In this study, we performed a pan-cancer analysis of FOXR2 activation across more than 10,000 adult and pediatric cancer samples and found FOXR2 to be aberrantly upregulated in 70% of all cancer types and 8% of all individual tumors. The majority of tumors (78%) aberrantly expressed FOXR2 through a previously undescribed epigenetic mechanism that involves hypomethylation of a novel promoter, which was functionally validated as necessary for FOXR2 expression and proliferation in FOXR2-expressing cancer cells. FOXR2 promoted tumor growth across multiple cancer lineages and co-opted ETS family transcription circuits across cancers. Taken together, this study identifies FOXR2 as a potent and ubiquitous oncogene that is epigenetically activated across the majority of human cancers. The identification of hijacking of ETS transcription circuits by FOXR2 extends the mechanisms known to active ETS transcription factors and highlights how transcription factor families cooperate to enhance tumorigenesis.
    Significance: This work identifies a novel promoter that drives aberrant FOXR2 expression and delineates FOXR2 as a pan-cancer oncogene that specifically activates ETS transcriptional circuits across human cancers. See related commentary by Liu and Northcott, p. 2977.
    MeSH term(s) Adult ; Carcinogenesis/genetics ; Cell Proliferation ; Child ; Epigenesis, Genetic ; Forkhead Transcription Factors/genetics ; Humans ; Male ; Neoplasms/genetics ; Oncogenes/genetics ; Proto-Oncogene Proteins c-ets/genetics ; Proto-Oncogene Proteins c-ets/metabolism ; Transcriptional Activation
    Chemical Substances FOXR2 protein, human ; Forkhead Transcription Factors ; Proto-Oncogene Proteins c-ets
    Language English
    Publishing date 2022-07-08
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-22-0671
    Database MEDical Literature Analysis and Retrieval System OnLINE

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