{"database":"EGA","file_versions":[],"scores":null,"additional":{"omics_type":["Genomics"],"dataset_type":["N/A"],"full_dataset_link":["https://ega-archive.org/datasets/EGAD00001000714"],"sample_count":["102"],"description":["EGA dataset EGAD00001000714"],"repository":["EGA"],"title":["The UCSF Low Grade Glioma Genome Project #1"],"pubmed_abstract":["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.","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."],"pubmed_title":["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."],"pubmed_authors":["Johnson 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 JF","van 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 JF"],"name_synonyms":["Data Set."],"description_synonyms":["Desc, Description, Descriptive, Provide., Supplied, Supply, Descriptor, description, Provided, Product Description/Appearance, DESCR"],"pubmed_title_synonyms":["1-d)-1, treatment, Therapy, me75, cou, CCRG81045, TMZA-HE, NSC 362856, Temozolomide Hexyl Ester, NSC-362856, M&B39831, M&B 39831, TMZ-Bioshuttle, Tl3, Temodar, Tl2, D17Mit170, M&B-39831, NSC362856, Treatments, T1, 5-tetrazin-4(3H)-one, 8-Carbamoyl-3-methylimidazo(5, Temodal, disease management., Lr, Therapeutic, CCRG 81045, DNA Damage Response, Bra, Therapies, Methazolastone, CCRG-81045, 2, 3, Treatment, Low, TMZ Bioshuttle"],"pubmed_abstract_synonyms":["mismatch repair cancer syndrome 1, mismatch repair cancer syndrome 3, mismatch repair cancer syndrome 2, PRKBA, mismatch repair cancer syndrome 4, Akt/PKB, 2610315D21Rik, Materials, MMRCS1, O6-alkylguanine-DNA alkyltransferase, PhrB photolyase activity, selection process, DAKT1/PKB, FKBP12-rapamycin complex-associated protein, cd206, MMRCS2, AKT1, l(2)k03905, Tumor, MMRCS3, pigmented epithelium, MMRCS4, Astrocytomas, Repair, DmTOR, CNS tumors with familial polyposis of the colon, DNA-6-O-methylguanine:protein-L-cysteine S-methyltransferase activity, Mutations, Roles, Concepts, DNA-6-O-methylguanine:[protein]-L-cysteine S-methyltransferase activity, Methazolastone, 2, Mismatch Repair Cancer Syndrome, 3, NUP96, RAFT1, Mammalian target of rapamycin, epithelium, treatment, increased, me75, thymus nucleic acid, CCRG81045, pigmented retina, Brain Tumor-Polyposis Syndrome 1, M&B39831, Giant Cell Glioblastoma, D17Mit170, PKB|Akt, dtor, T1, DNA cyclobutane dipyrimidine photolyase activity, Astrocytoma, RacPK, SUPPRESSOR OF AUXIN RESISTANCE 3, genetic, grade IV adult Astrocytic tumor, Role Concepts, disease management, Therapies, mismatch repair deficiency., Double-Stranded DNA, Malignancies, deoxyribonucleic acids, DNAn, associated, CD206, Mismatch, dTOR, dTor, FK506-binding protein 12-rapamycin complex-associated protein 1, Tumors, 1-d)-1, Therapy, Mechanistic target of rapamycin, PRE, dakt, TMZA-HE, mutagenesis, deoxyribonucleic cyclobutane dipyrimidine photolyase activity, familial, mismatch repair cancer syndrome, Double-Stranded, Giant Cell, l(3)89Bq, Tl3, Tl2, M&B-39831, results, 5-tetrazin-4(3H)-one, glioma-polyposis syndrome, (Deoxyribonucleotide)n+m, DNA-6-O-methylguanine - [protein]-L-cysteine S-methyltransferase activity, Temodal, PKB/Akt, PKB/AKT, AKT/PKB, Role Concept, Benign, dAkt, dAKT, retinal pigment, primary glioblastoma multiforme, 6-O-methylguanine-DNA methyltransferase activity, Role, dipyrimidine photolyase (photosensitive), p-Akt, Genetic Materials, MMR, macrophage mannose receptor 1-like protein 1, brain tumor-polyposis syndrome, desoxyribose nucleic acid, DAkt, retinal pigment layer, CLEC13DL, RAPT1, Genetic Material, MMR Deficiency, 6-O-methylguanine-DNA methyltransferase, l(3)04226, DNA-6-O-methylguanine - protein-L-cysteine S-methyltransferase activity, long patch mismatch repair system, DPKB, MMRCS, Glioblastoma, Drives, O-6-methylguanine-DNA-alkyltransferase activity, mismatch repair, pAkt, spongioblastoma multiforme, Rapamycin and FKBP12 target 1, Mismatch Repair, NSC 362856, GBM, mmr, Benign Neoplasms, NSC-362856, INSDC_feature:gene, Temodar, dAKT/dPKB, PKB/dAKT, Treatments, Malignant Neoplasms, metastatic, phr A photolyase activity, MGMT, Agat, Dakt, DNA-photoreactivating enzyme, Grade IV Astrocytomas, Patient, Material, 5092, dPKB, ds DNA, AGT, Turcot syndrome, CCRG-81045, Cistron, inherited genetic, DNA, other neoplasm, accessory, RAC-ALPHA, DRAC-PK85, DmelCG4006, DNS, (Deoxyribonucleotide)n, Mismatch Repair Deficiency, CG5092, Neoplasms, Benign Neoplasm, Temozolomide Hexyl Ester, Gene, TMZ-Bioshuttle, Grade IV, photoreactivating enzyme activity, C-type lectin domain family 13 member D-like, Malignant, l(2)k17004, supernumerary, Deoxyribonucleic acids, Dpkb, CNS tumors with Familial polyposis of the colon, Deoxyribonucleic Acid, CCRG 81045, resistance, MMR deficiency, glioblastoma, stratum pigmentosa retinae, Low, TOR, TMZ Bioshuttle, Giant Cell Glioblastomas, DmelCG8274, MOS3, deoxyribocyclobutadipyrimidine pyrimidine-lyase activity, grade IV adult astrocytic tumor, MutS/MutL/MutH pathway, Bx34, Genetic, clec13d, Malignancy, PRECOCIOUS, malignant tumors of the central nervous system associated with familial polyposis of the colon, scattered, DNA Mismatch, F23A5.3, Double Stranded, Deoxyribonucleic acid, flat, tor, Tpr, TPR, malignant tumours of the central nervous system associated with familial polyposis of the colon, MRC1L1, Neoplasias, Glioblastoma Multiforme, AKT, Akt, Clients, DRAC-PK, Grade IV Astrocytoma, (Deoxyribonucleotide)m, Frap1, constitutitional genetic, CT24817, Methylations, F23A5_3, AI267024, Cancer, grade IV adult astrocytic tumour, cou, Malignant Neoplasm, diffuse, akt, DNAn+1, CNS tumours with familial polyposis of the colon, DAkt1, FRAP1, DAKT1, FRAP2, M&B 39831, mTOR, methylated-DNA-protein-cysteine S-methyltransferase activity, FRAP/TOR, DmelCG5092, Cistrons, Client, Cell, Concept, 8-Carbamoyl-3-methylimidazo(5, adult glioblastoma multiforme, 2.7.11.1, MODIFIER OF SNC1, Lr, PKB, CWS6, PKB-ALPHA, deoxyribonucleic photolyase activity, Mutageneses, Neoplasm, D-Akt, CG4006, methylation, ds-DNA, Dakt1, glioblastoma multiforme, O-6-methylguanine-DNA-alkyltransferase, RPE, akt1, dAkt1, photolyase activity, increased number, DRAC-PK66, Glioblastomas, CT24745, Rapamycin target protein 1, MutL-like pathway, AI327068, Cancers, FRAP, NSC362856, p. pigmentosa retinae, present in greater numbers in organism, dAkt/PKB, 2.1.1.63, dakt1, CLEC13D, CT16317, childhood cancer syndrome, Therapeutic, CG8274, PKBalpha, MTOR, Bra, Desoxyribonukleinsaeure, Treatment, dAKT1, deoxyribonucleate pyrimidine dimer lyase (photosensitive), RAC, Rac, hereditary, Neoplasia"],"additional_accession":[]},"is_claimable":false,"name":"J_Costello_20130912_dataset - samples","description":"Description not provided","dates":{"updated":"2019-10-31 12:52:10"},"accession":"EGAD00001000714","cross_references":{"TAXONOMY":["9606"],"pubmed":["25724300","24336570"],"EGA":["EGAC00001000153","EGAS00001000579"]}}