EGAGenomicsJoseph Costellohttps://ega-archive.org/dacs/EGAC00001000153EGAEGA DAC EGAC00001000153EGAjcostello@cc.ucsf.eduTERT promoter mutations reactivate telomerase, allowing for indefinite telomere maintenance and enabling cellular immortalization. These mutations specifically recruit the multimeric ETS factor GABP, which can form two functionally independent transcription factor species: a dimer or a tetramer. We show that genetic disruption of GABPβ1L (β1L), a tetramer-forming isoform of GABP that is dispensable for normal development, results in TERT silencing in a TERT promoter mutation-dependent manner. Reducing TERT expression by disrupting β1L culminates in telomere loss and cell death exclusively in TERT promoter mutant cells. Orthotopic xenografting of β1L-reduced, TERT promoter mutant glioblastoma cells rendered lower tumor burden and longer overall survival in mice. These results highlight the critical role of GABPβ1L in enabling immortality in TERT promoter mutant glioblastoma.Aberrant DNA hypomethylation may play an important role in the growth rate of glioblastoma (GBM), but the functional impact on transcription remains poorly understood. We assayed the GBM methylome with MeDIP-seq and MRE-seq, adjusting for copy number differences, in a small set of non-glioma CpG island methylator phenotype (non-G-CIMP) primary tumors. Recurrent hypomethylated loci were enriched within a region of chromosome 5p15 that is specified as a cancer amplicon and also encompasses TERT, encoding telomerase reverse transcriptase, which plays a critical role in tumorigenesis. Overall, 76 gene body promoters were recurrently hypomethylated, including TERT and the oncogenes GLI3 and TP73. Recurring hypomethylation also affected previously unannotated alternative promoters, and luciferase reporter assays for three of four of these promoters confirmed strong promoter activity in GBM cells. Histone H3 lysine 4 trimethylation (H3K4me3) ChIP-seq on tissue from the GBMs uncovered peaks that coincide precisely with tumor-specific decrease of DNA methylation at 200 loci, 133 of which are in gene bodies. Detailed investigation of TP73 and TERT gene body hypomethylation demonstrated increased expression of corresponding alternate transcripts, which in TP73 encodes a truncated p73 protein with oncogenic function and in TERT encodes a putative reverse transcriptase-null protein. Our findings suggest that recurring gene body promoter hypomethylation events, along with histone H3K4 trimethylation, alter the transcriptional landscape of GBM through the activation of a limited number of normally silenced promoters within gene bodies, in at least one case leading to expression of an oncogenic protein.Temozolomide (TMZ) increases the overall survival of patients with glioblastoma (GBM), but its role in the clinical management of diffuse low-grade gliomas (LGG) is still being defined. DNA hypermethylation of the O (6) -methylguanine-DNA methyltransferase (MGMT) promoter is associated with an improved response to TMZ treatment, while inactivation of the DNA mismatch repair (MMR) pathway is associated with therapeutic resistance and TMZ-induced mutagenesis. We previously demonstrated that TMZ treatment of LGG induces driver mutations in the RB and AKT-mTOR pathways, which may drive malignant progression to secondary GBM. To better understand the mechanisms underlying TMZ-induced mutagenesis and malignant progression, we explored the evolution of MGMT methylation and genetic alterations affecting MMR genes in a cohort of 34 treatment-naïve LGGs and their recurrences. Recurrences with TMZ-associated hypermutation had increased MGMT methylation compared to their untreated initial tumors and higher overall MGMT methylation compared to TMZ-treated non-hypermutated recurrences. A TMZ-associated mutation in one or more MMR genes was observed in five out of six TMZ-treated hypermutated recurrences. In two cases, pre-existing heterozygous deletions encompassing MGMT, or an MMR gene, were followed by TMZ-associated mutations in one of the genes of interest. These results suggest that tumor cells with methylated MGMT may undergo positive selection during TMZ treatment in the context of MMR deficiency.Reactivation of telomerase reverse transcriptase (TERT) expression enables cells to overcome replicative senescence and escape apoptosis, which are fundamental steps in the initiation of human cancer. Multiple cancer types, including up to 83% of glioblastomas (GBMs), harbor highly recurrent TERT promoter mutations of unknown function but specific to two nucleotide positions. We identified the functional consequence of these mutations in GBMs to be recruitment of the multimeric GA-binding protein (GABP) transcription factor specifically to the mutant promoter. Allelic recruitment of GABP is consistently observed across four cancer types, highlighting a shared mechanism underlying TERT reactivation. Tandem flanking native E26 transformation-specific motifs critically cooperate with these mutations to activate TERT, probably by facilitating GABP heterotetramer binding. GABP thus directly links TERT promoter mutations to aberrant expression in multiple cancers.Tumor recurrence is a leading cause of cancer mortality. Therapies for recurrent disease may fail, at least in part, because the genomic alterations driving the growth of recurrences are distinct from those in the initial tumor. To explore this hypothesis, we sequenced the exomes of 23 initial low-grade gliomas and recurrent tumors resected from the same patients. In 43% of cases, at least half of the mutations in the initial tumor were undetected at recurrence, including driver mutations in TP53, ATRX, SMARCA4, and BRAF; this suggests that recurrent tumors are often seeded by cells derived from the initial tumor at a very early stage of their evolution. Notably, tumors from 6 of 10 patients treated with the chemotherapeutic drug temozolomide (TMZ) followed an alternative evolutionary path to high-grade glioma. At recurrence, these tumors were hypermutated and harbored driver mutations in the RB (retinoblastoma) and Akt-mTOR (mammalian target of rapamycin) pathways that bore the signature of TMZ-induced mutagenesis.Cancer. The transcription factor GABP selectively binds and activates the mutant TERT promoter in cancer.Disruption of the β1L Isoform of GABP Reverses Glioblastoma Replicative Immortality in a TERT Promoter Mutation-Dependent Manner.Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment.Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma.Recurrent epimutations activate gene body promoters in primary glioblastoma.Mancini Andrew A, Xavier-Magalhães Ana A, Woods Wendy S WS, Nguyen Kien-Thiet KT, Amen Alexandra M AM, Hayes Josie L JL, Fellmann Christof C, Gapinske Michael M, McKinney Andrew M AM, Hong Chibo C, Jones Lindsey E LE, Walsh Kyle M KM, Bell Robert J A RJA, Doudna Jennifer A JA, Costa Bruno M BM, Song Jun S JS, Perez-Pinera Pablo P, Costello Joseph F JFNagarajan Raman P RP, Zhang Bo B, Bell Robert J A RJ, Johnson Brett E BE, Olshen Adam B AB, Sundaram Vasavi V, Li Daofeng D, Graham Ashley E AE, Diaz Aaron A, Fouse Shaun D SD, Smirnov Ivan I, Song Jun J, Paris Pamela L PL, Wang Ting T, Costello Joseph F JFJohnson Brett E BE, Mazor Tali T, Hong Chibo C, Barnes Michael M, Aihara Koki K, McLean Cory Y CY, Fouse Shaun D SD, Yamamoto Shogo S, Ueda Hiroki H, Tatsuno Kenji K, Asthana Saurabh S, Jalbert Llewellyn E LE, Nelson Sarah J SJ, Bollen Andrew W AW, Gustafson W Clay WC, Charron Elise E, Weiss William A WA, Smirnov Ivan V IV, Song Jun S JS, Olshen Adam B AB, Cha Soonmee S, Zhao Yongjun Y, Moore Richard A RA, Mungall Andrew J AJ, Jones Steven J M SJM, Hirst Martin M, Marra Marco A MA, Saito Nobuhito N, Aburatani Hiroyuki H, Mukasa Akitake A, Berger Mitchel S MS, Chang Susan M SM, Taylor Barry S BS, Costello Joseph F JFBell Robert J A RJ, Rube H Tomas HT, Kreig Alex A, Mancini Andrew A, Fouse Shaun D SD, Nagarajan Raman P RP, Choi Serah S, Hong Chibo C, He Daniel D, Pekmezci Melike M, Wiencke John K JK, Wrensch Margaret R MR, Chang Susan M SM, Walsh Kyle M KM, Myong Sua S, Song Jun S JS, Costello Joseph F JFvan Thuijl Hinke F HF, Mazor Tali T, Johnson Brett E BE, Fouse Shaun D SD, Aihara Koki K, Hong Chibo C, Malmström Annika A, Hallbeck Martin M, Heimans Jan J JJ, Kloezeman Jenneke J JJ, Stenmark-Askmalm Marie M, Lamfers Martine L M ML, Saito Nobuhito N, Aburatani Hiroyuki H, Mukasa Akitake A, Berger Mitchell S MS, Söderkvist Peter P, Taylor Barry S BS, Molinaro Annette M AM, Wesseling Pieter P, Reijneveld Jaap C JC, Chang Susan M SM, Ylstra Bauke B, Costello Joseph F JFGlioma 1, Glioma NOS, Glioma (except Nasal glioma, Genomics, GLM, glial tumors, malignant, Comparative, neuroglial tumor, obsolete_glioma, Mixed Glioma, Malignant Glioma, Neuroglial Tumor, Functional Genomics, tumour of the neuroglia, Tumor, Malignant, neoplasm of neuroglia, Structural, [M]Glioma NOS (morphologic abnormality), tumor of the neuroglia, Functional, [M]Gliomas (morphologic abnormality), Gliomas, Mixed, Glial Cell Tumor, [M]Glioma NOS, Mixed Gliomas, Glial Tumor, NOS (except Nasal glioma, Neuroglial Neoplasm, glioma (morphologic abnormality), Neuroglial Neoplasms, Glioma NOS (morphologic abnormality), neuroglial tumour, Glial Cell, Malignant glioma, Neoplasm of the Neuroglia, Tumor of Neuroglia, Glial Neoplasm, neuroglial neoplasm, tumor of neuroglia, Neoplasm of Neuroglia, Comparative Genomics., glial tumor, no ICD-O subtype, Tumor of the Neuroglia, tumour of neuroglia, glial tumour, Glial Cell Tumors, not neoplastic), Gliomas (morphologic abnormality), Malignant Gliomas, Structural Genomics, Glioma, glial neoplasm, [M]Gliomas, malignant (morphologic abnormality), glioma, Tumors of Neuroglia, neoplasm of the neuroglia, Neoplasms of Neuroglia, TumorsRNA polymerase II core promoter proximal region sequence-specific binding, T-cell leukemia, Malignant Neoplasm, Neoplasms, AGL4, Benign Neoplasm, zinc ion regulated core promoter proximal region sequence-specific DNA binding RNA polymerase II transcription factor activity, homeobox 1, Factor, TRT, SEPALLATA 2, Tumor, metal ion regulated sequence-specific DNA binding RNA polymerase II transcription factor activity, Malignant, Transcription Factor, hTRT, transcription factor activity, MT, Benign, zinc ion regulated core promoter proximal region sequence-specific DNA binding, EST2, RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activity, hEST2, DKCB4, Neoplasm, RNA polymerase II transcription factor activity, sequence-specific distal enhancer binding RNA polymerase II transcription factor activity, TP2, metal ion regulated core promoter proximal region sequence-specific DNA binding RNA polymerase II transcription factor activity, KNOTTED1-like homeobox gene 5, INSDC_feature:regulatory, F14P3.4, Transcription, primary cancer, Factors, Malignancy, TCS1, DKCA2, F14P3_4, F10N7_150, Benign Neoplasms, Cancers, metal ion regulated core promoter proximal region sequence-specific binding, copper ion regulated core promoter proximal region sequence-specific binding, RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity, malignant tumor, Transcription factor, F10N7.150, Malignant Neoplasms, Neoplasias, CMM9, PFBMFT1, malignant neoplasm, RNA polymerase II proximal promoter sequence-specific DNA binding, copper ion regulated proximal promoter sequence-specific DNA binding, copper ion regulated core promoter proximal region sequence-specific DNA binding RNA polymerase II transcription factor activity, AGAMOUS-like 4, Malignancies, zinc ion regulated proximal promoter sequence-specific DNA binding, sequence-specific transcription regulatory region DNA binding RNA polymerase II transcription factor recruiting transcription factor activity, metal ion regulated sequence-specific DNA binding, Neoplasia, metal ion regulated proximal promoter sequence-specific DNA binding, TRANSCRIPTION FACTOR, TR, Cancer, Tumors, RNA polymerase II distal enhancer sequence-specific binding, Malignant Neoplasms.Forms, T-cell leukemia, telomere, single-organism developmental process, Burden, Laboratory, Heterograft, PNT-P1, Tumor Weight, DmelCG17077, postnatal development, Mus domesticus, CG6338, AGL4, Splice Variants, EY3-1, growth and development, CASP-14, Pnt, Tumor, Protein Splice, Astrocytomas, House Mouse, hTRT, Heterograft Transplantation, d-elg, Mutations, png, Roles, Telomerase Catalytic, RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activity, hEST2, DKCB4, nuclear chromosome, Concepts, Volume, D-ets-2, 3520, Pnt-P1, average, D-elg, Protein Splice Variant, DKCA2, Subunit, Loads, hypoplasia, F10N7_150, Weights, Swiss Mice, Protein Isoform, Giant Cell Glioblastoma, RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity, Astrocytoma, genetic, Telomerase Reverse Transcriptase Catalytic Subunit, grade IV adult Astrocytic tumor, Role Concepts, AGAMOUS-like 4, zinc ion regulated proximal promoter sequence-specific DNA binding, sequence-specific transcription regulatory region DNA binding RNA polymerase II transcription factor recruiting transcription factor activity, necrosis, Tumor Volume, INSDC_feature:telomere, Grade IV., Tumor Loads, TRANSCRIPTION FACTOR, TR, RNA polymerase II distal enhancer sequence-specific binding, Elg, RNA polymerase II core promoter proximal region sequence-specific binding, familial, CASP14, mouse, Telomerase Reverse, D-Ets-2, ets94F, 0123/09, Isoform, Giant Cell, metal ion regulated sequence-specific DNA binding RNA polymerase II transcription factor activity, telomeric sequence, Telomerase, elg, D-Elg, DmelCG6338, Role Concept, primary glioblastoma multiforme, Weight, Mini-ICE, Role, sequence-specific distal enhancer binding RNA polymerase II transcription factor activity, F14P3.4, Xenograft, Mus musculus, pntP2, Xenotransplantation, Factors, Glioblastoma, Pointed-P1, Caspase-14 subunit p10, TCS1, Transplantation, spongioblastoma multiforme, mice, Ets94F, Swiss Mouse, F14P3_4, GBM, Caspase-14 subunit p19, MICE, Transcription factor, domesticus, ptd, PntP2, Grade IV Astrocytomas, PntP1, E(E2F)3D, telomeric DNA, copper ion regulated core promoter proximal region sequence-specific DNA binding RNA polymerase II transcription factor activity, PNTP2, inherited genetic, Mouse, metal ion regulated sequence-specific DNA binding, PNTP1, metal ion regulated proximal promoter sequence-specific DNA binding, 3.4.22.-, 0998/12, telomeric region, ETS2, Ets2, Xenograft Transplantation, mini-ICE, SEPALLATA 2, Grade IV, Transcription Factor, Tumor Weights, Load, DMPOINT1A, pntegfr, 0608/07, zinc ion regulated core promoter proximal region sequence-specific DNA binding, reduced, tne, House, Variant, Mus musculus domesticus, Xenografting, glioblastoma, Tumor Load, tiny, TP2, Isoforms, Giant Cell Glioblastomas, Mice, Splice Variant, tny, Transcription, telomeres, grade IV adult astrocytic tumor, pointed-RC, Swiss, Protein Splice Variants, EK3-2, l(3)07825, Glioblastoma Multiforme, Reverse Transcriptase, Catalytic Subunit, CMM9, RNA polymerase II proximal promoter sequence-specific DNA binding, Telomerase Catalytic Subunit, copper ion regulated proximal promoter sequence-specific DNA binding, accidental cell death, CG17077, species, Grade IV Astrocytoma, constitutitional genetic, l(3)j1B7, small, Telomerase Reverse Transcriptase, grade IV adult astrocytic tumour, Ets, Heterologous Transplantation, zinc ion regulated core promoter proximal region sequence-specific DNA binding RNA polymerase II transcription factor activity, homeobox 1, TRT, Factor, Cell, Concept, transcription factor activity, development, DELG, adult glioblastoma multiforme, Mus, EST2, Protein, RNA polymerase II transcription factor activity, Telomeres, Death, pnt-P1, metal ion regulated core promoter proximal region sequence-specific DNA binding RNA polymerase II transcription factor activity, pnt-P2, KNOTTED1-like homeobox gene 5, INSDC_feature:regulatory, l(3)s118306, regulation of telomere length, glioblastoma multiforme, underdeveloped, postnatal growth, Glioblastomas, House Mice, metal ion regulated core promoter proximal region sequence-specific binding, copper ion regulated core promoter proximal region sequence-specific binding, F10N7.150, Laboratory Mice, Ets58AB, PFBMFT1, Transcriptase, Heterografting, Variants, hereditary, growth, Laboratory Mouse, POINT, Delg, CG8705falseGlioma Genomics CommitteeData Access Committee EGAC00001000153

2025-1-9

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