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Drier, Yotam

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Drier

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Yotam

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Drier, Yotam
Author's Publications: search.filters.isAuthorOfPublication.2a2e4726-c16d-498e-8899-19913d9f7e7c

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Now showing 1 - 7 of 7
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    Regulation of the glucocorticoid receptor via a BET-dependent enhancer drives antiandrogen resistance in prostate cancer
    (eLife Sciences Publications, Ltd, 2017) Shah, Neel; Wang, Ping; Wongvipat, John; Karthaus, Wouter R; Abida, Wassim; Armenia, Joshua; Rockowitz, Shira; Drier, Yotam; Bernstein, Bradley; Long, Henry; Freedman, Matthew; Arora, Vivek K; Zheng, Deyou; Sawyers, Charles L
    In prostate cancer, resistance to the antiandrogen enzalutamide (Enz) can occur through bypass of androgen receptor (AR) blockade by the glucocorticoid receptor (GR). In contrast to fixed genomic alterations, here we show that GR-mediated antiandrogen resistance is adaptive and reversible due to regulation of GR expression by a tissue-specific enhancer. GR expression is silenced in prostate cancer by a combination of AR binding and EZH2-mediated repression at the GR locus, but is restored in advanced prostate cancers upon reversion of both repressive signals. Remarkably, BET bromodomain inhibition resensitizes drug-resistant tumors to Enz by selectively impairing the GR signaling axis via this enhancer. In addition to revealing an underlying molecular mechanism of GR-driven drug resistance, these data suggest that inhibitors of broadly active chromatin-readers could have utility in nuanced clinical contexts of acquired drug resistance with a more favorable therapeutic index.
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    Mutational heterogeneity in cancer and the search for new cancer genes
    (2014) Lawrence, Michael S.; Stojanov, Petar; Polak, Paz; Kryukov, Gregory V.; Cibulskis, Kristian; Sivachenko, Andrey; Carter, Scott L.; Stewart, Chip; Mermel, Craig; Roberts, Steven A.; Kiezun, Adam; Hammerman, Peter S.; McKenna, Aaron; Drier, Yotam; Zou, Lihua; Ramos, Alex H.; Pugh, Trevor J.; Stransky, Nicolas; Helman, Elena; Kim, Jaegil; Sougnez, Carrie; Ambrogio, Lauren; Nickerson, Elizabeth; Shefler, Erica; Cortés, Maria L.; Auclair, Daniel; Saksena, Gordon; Voet, Douglas; Noble, Michael; DiCara, Daniel; Lin, Pei; Lichtenstein, Lee; Heiman, David I.; Fennell, Timothy; Imielinski, Marcin; Hernandez, Bryan; Hodis, Eran; Baca, Sylvan; Dulak, Austin M.; Lohr, Jens; Landau, Dan-Avi; Wu, Catherine; Melendez-Zajgla, Jorge; Hidalgo-Miranda, Alfredo; Koren, Amnon; McCarroll, Steven; Mora, Jaume; Crompton, Brian; Onofrio, Robert; Parkin, Melissa; Winckler, Wendy; Ardlie, Kristin; Gabriel, Stacey B.; Roberts, Charles W. M.; Biegel, Jaclyn A.; Stegmaier, Kimberly; Bass, Adam; Garraway, Levi; Meyerson, Matthew; Golub, Todd; Gordenin, Dmitry A.; Sunyaev, Shamil; Lander, Eric; Getz, Gad
    Major international projects are now underway aimed at creating a comprehensive catalog of all genes responsible for the initiation and progression of cancer. These studies involve sequencing of matched tumor–normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here, we describe a fundamental problem with cancer genome studies: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds. The list includes many implausible genes (such as those encoding olfactory receptors and the muscle protein titin), suggesting extensive false positive findings that overshadow true driver events. Here, we show that this problem stems largely from mutational heterogeneity and provide a novel analytical methodology, MutSigCV, for resolving the problem. We apply MutSigCV to exome sequences from 3,083 tumor-normal pairs and discover extraordinary variation in (i) mutation frequency and spectrum within cancer types, which shed light on mutational processes and disease etiology, and (ii) mutation frequency across the genome, which is strongly correlated with DNA replication timing and also with transcriptional activity. By incorporating mutational heterogeneity into the analyses, MutSigCV is able to eliminate most of the apparent artefactual findings and allow true cancer genes to rise to attention.
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    An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma
    (2016) Drier, Yotam; Cotton, Matthew J.; Williamson, Kaylyn; Gillespie, Shawn M.; Ryan, Russell J.H.; Kluk, Michael J.; Carey, Christopher D.; Rodig, Scott; Sholl, Lynette; Afrogheh, Amir H.; Faquin, William; Queimado, Lurdes; Qi, Jun; Wick, Michael J.; El-Naggar, Adel K.; Bradner, James E; Moskaluk, Christopher A.; Aster, Jon; Knoechel, Birgit; Bernstein, Bradley
    Translocation events are frequent in cancer and may create chimeric fusions or ‘regulatory rearrangements’ that drive oncogene overexpression. Here we identify super-enhancer translocations that drive overexpression of the oncogenic transcription factor MYB as a recurrent theme in adenoid cystic carcinoma (ACC). Whole-genome sequencing data and chromatin maps reveal distinct chromosomal rearrangements that juxtapose super-enhancers to the MYB locus. Chromosome conformation capture confirms that the translocated enhancers interact with the MYB promoter. Remarkably, MYB protein binds to the translocated enhancers, creating a positive feedback loop that sustains its expression. MYB also binds enhancers that drive different regulatory programs in alternate cell lineages in ACC, cooperating with TP63 in myoepithelial cells and a Notch program in luminal epithelial cells. Bromodomain inhibitors slow tumor growth in ACC primagraft models in vivo. Thus, our study identifies super-enhancer translocations that drive MYB expression and provides insight into downstream MYB functions in the alternate ACC lineages.
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    Insulator dysfunction and oncogene activation in IDH mutant gliomas
    (2015) Flavahan, William A.; Drier, Yotam; Liau, Brian; Gillespie, Shawn M.; Venteicher, Andrew S; Stemmer-Rachamimov, Anat; Suva, Mario; Bernstein, Bradley
    Gain-of-function IDH mutations are initiating events that define major clinical and prognostic classes of gliomas1,2. Mutant IDH protein produces a novel onco-metabolite, 2-hydroxyglutarate (2-HG), that interferes with iron-dependent hydroxylases, including the TET family of 5′-methylcytosine hydroxylases3–7. TET enzymes catalyze a key step in the removal of DNA methylation8,9. IDH mutant gliomas thus manifest a CpG island methylator phenotype (G-CIMP)10,11, though the functional significance of this altered epigenetic state remains unclear. Here we show that IDH mutant gliomas exhibit hyper-methylation at CTCF binding sites, compromising binding of this methylation-sensitive insulator protein. Reduced CTCF binding is associated with loss of insulation between topological domains and aberrant gene activation. We specifically demonstrate that loss of CTCF at a domain boundary permits a constitutive enhancer to aberrantly interact with the receptor tyrosine kinase gene PDGFRA, a prominent glioma oncogene. Treatment of IDH mutant gliomaspheres with demethylating agent partially restores insulator function and down-regulates PDGFRA. Conversely, CRISPR-mediated disruption of the CTCF motif in IDH wildtype gliomaspheres up-regulates PDGFRA and increases proliferation. Our study suggests that IDH mutations promote gliomagenesis by disrupting chromosomal topology and allowing aberrant regulatory interactions that induce oncogene expression.
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    SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation
    (2016) Wang, Xiaofeng; Lee, Ryan; Alver, Burak; Haswell, Jeffrey; Wang, Su; Mieczkowski, Jakub; Drier, Yotam; Gillespie, Shawn M.; Archer, Tenley; Wu, Jennifer; Tzvetkov, Evgeni P.; Troisi, Emma C.; Pomeroy, Scott; Biegel, Jaclyn A.; Tolstorukov, Michael; Bernstein, Bradley; Park, Peter; Roberts, Charles W. M.
    SMARCB1 (SNF5/INI1/BAF47), a core subunit of the SWI/SNF (BAF) chromatin remodeling complex1,2, is inactivated in nearly all pediatric rhabdoid tumors3–5. These aggressive cancers are among the most genomically stable6–8, suggesting an epigenetic mechanism by which SMARCB1 loss drives transformation. Here, we show that despite indistinguishable mutational landscapes, human rhabdoid tumors show distinct enhancer H3K27ac signatures, which reveal remnants of differentiation programs. We show that SMARCB1 is required for the integrity of SWI/SNF complexes and that its loss alters enhancer targeting – markedly impairing SWI/SNF binding to typical enhancers, particularly those required for differentiation, while maintaining SWI/SNF binding at super-enhancers. We show that these retained super-enhancers are essential for rhabdoid tumor survival, including some that are shared across all subtypes, such as SPRY1, and other lineage-specific super-enhancers, like SOX2 in brain-derived rhabdoid tumors. Taken together, our findings reveal a novel chromatin-based epigenetic mechanism underlying the tumor suppressive activity of SMARCB1.
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    Melanoma genome sequencing reveals frequent PREX2 mutations
    (2012) Berger, Michael F.; Hodis, Eran; Heffernan, Timothy P.; Deribe, Yonathan Lissanu; Lawrence, Michael S.; Protopopov, Alexei; Ivanova, Elena; Watson, Ian; Nickerson, Elizabeth; Ghosh, Papia; Zhang, Hailei; Zeid, Rhamy; Ren, Xiaojia; Cibulskis, Kristian; Sivachenko, Andrey Y.; Wagle, Nikhil; Sucker, Antje; Sougnez, Carrie; Onofrio, Roberto; Ambrogio, Lauren; Auclair, Daniel; Fennell, Timothy; Carter, Scott L.; Drier, Yotam; Stojanov, Petar; Singer, Meredith A.; Voet, Douglas; Jing, Rui; Saksena, Gordon; Barretina, Jordi; Ramos, Alex H.; Pugh, Trevor J.; Stransky, Nicolas; Parkin, Melissa Ann; Winckler, Wendy; Mahan, Scott; Ardlie, Kristin; Baldwin, Jennifer; Wargo, Jennifer Ann; Schadendorf, Dirk; Meyerson, Matthew; Gabriel, Stacey B.; Golub, Todd; Wagner, Stephan N.; Lander, Eric; Getz, Gad; Chin, Lynda; Garraway, Levi
    Melanoma is notable for its metastatic propensity, lethality in the advanced setting, and association with ultraviolet (UV) exposure early in life1. To obtain a comprehensive genomic view of melanoma, we sequenced the genomes of 25 metastatic melanomas and matched germline DNA. A wide range of point mutation rates was observed: lowest in melanomas whose primaries arose on non-UV exposed hairless skin of the extremities (3 and 14 per Mb genome), intermediate in those originating from hair-bearing skin of the trunk (range = 5 to 55 per Mb), and highest in a patient with a documented history of chronic sun exposure (111 per Mb). Analysis of whole-genome sequence data identified PREX2 - a PTEN-interacting protein and negative regulator of PTEN in breast cancer2 - as a significantly mutated gene with a mutation frequency of approximately 14% in an independent extension cohort of 107 human melanomas. PREX2 mutations are biologically relevant, as ectopic expression of mutant PREX2 accelerated tumor formation of immortalized human melanocytes in vivo. Thus, whole-genome sequencing of human melanoma tumors revealed genomic evidence of UV pathogenesis and discovered a new recurrently mutated gene in melanoma.
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    Enhancer Signatures Stratify and Predict Outcomes of Non-Functional Pancreatic Neuroendocrine Tumors
    (Springer Science and Business Media LLC, 2019-07-01) Cejas, Paloma; Drier, Yotam; Brosens, Lodewijk A. A.; Deshpande, Vikram; Morsink, Folkert H. M.; Graham, Mindy K.; Valk, Gerlof D.; Vriens, Menno R.; Fernandez-Del Castillo, Carlos; Fabiana Lucia da Silva, Annacarolina; Font-Tello, Alba; Heaphy, Christopher M.; Sicinska, Ewa; Dreijerink, Koen; Epstein, Charles; Conemans, Elfi; Ferrone, Cristina; Adar, Tomer; Bowden, Michaela; Whitton, Holly; Long, Henry; Gaskell, Elizabeth; Shoresh, Noam; Kulke, Matthew; Chung, Daniel; Bernstein, Bradley; Shivdasani, Ramesh
    Most pancreatic neuroendocrine tumors (PNETs) do not produce excess hormones and are therefore considered ‘non-functional’. As clinical behaviors vary widely and distant metastases are eventually lethal, biological classifications might guide treatment. Using enhancer maps to infer gene regulatory programs, we find that non-functional PNETs fall into two major sub-types whose epigenomes and transcriptomes partially resemble islet alpha and beta cells. Transcription factors ARX and PDX1 specify these normal cells, respectively, and 84% of 142 non-functional PNETs expressed one or the other factor, occasionally both. Among 103 cases, distant relapses occurred almost exclusively in patients with ARX+PDX1- tumors and, within this sub-type, in cases with alternative lengthening of telomeres (ALT). These markedly different outcomes belied similar clinical presentations and histology and, in one cohort, occurred irrespective of MEN1 mutation. This robust molecular stratification provides insight into cell lineage correlates of non-functional PNETs, accurately predicts disease course, and can inform post-operative clinical decisions.