EGAGenomicsIllumina HiSeq 2000;https://ega-archive.org/datasets/EGAD00001001051200EGA dataset EGAD00001001051EGA<h4>Unlabelled</h4>Ewing sarcoma is a primary bone tumor initiated by EWSR1-ETS gene fusions. To identify secondary genetic lesions that contribute to tumor progression, we performed whole-genome sequencing of 112 Ewing sarcoma samples and matched germline DNA. Overall, Ewing sarcoma tumors had relatively few single-nucleotide variants, indels, structural variants, and copy-number alterations. Apart from whole chromosome arm copy-number changes, the most common somatic mutations were detected in STAG2 (17%), CDKN2A (12%), TP53 (7%), EZH2, BCOR, and ZMYM3 (2.7% each). Strikingly, STAG2 mutations and CDKN2A deletions were mutually exclusive, as confirmed in Ewing sarcoma cell lines. In an expanded cohort of 299 patients with clinical data, we discovered that STAG2 and TP53 mutations are often concurrent and are associated with poor outcome. Finally, we detected subclonal STAG2 mutations in diagnostic tumors and expansion of STAG2-immunonegative cells in relapsed tumors as compared with matched diagnostic samples.<h4>Significance</h4>Whole-genome sequencing reveals that the somatic mutation rate in Ewing sarcoma is low. Tumors that harbor STAG2 and TP53 mutations have a particularly dismal prognosis with current treatments and require alternative therapies. Novel drugs that target epigenetic regulators may constitute viable therapeutic strategies in a subset of patients with mutations in chromatin modifiers.Mutations in the P53 pathway are a hallmark of human cancer. The identification of pathways upon which p53-deficient cells depend could reveal therapeutic targets that may spare normal cells with intact p53. In contrast to P53 point mutations in other cancer, complete loss of P53 is a frequent event in osteosarcoma (OS), the most common cancer of bone. The consequences of p53 loss for osteoblastic cells and OS development are poorly understood. Here we use murine OS models to demonstrate that elevated Pthlh (Pthrp), cAMP levels and signalling via CREB1 are characteristic of both p53-deficient osteoblasts and OS. Normal osteoblasts survive depletion of both PTHrP and CREB1. In contrast, p53-deficient osteoblasts and OS depend upon continuous activation of this pathway and undergo proliferation arrest and apoptosis in the absence of PTHrP or CREB1. Our results identify the PTHrP-cAMP-CREB1 axis as an attractive pathway for therapeutic inhibition in OS.Ewing sarcoma is an aggressive neoplasm occurring predominantly in adolescent Caucasians. At the genome level, a pathognomonic EWSR1-ETS translocation is present. The resulting fusion protein acts as a molecular driver in the tumor development and interferes, amongst others, with endogenous transcription and splicing. The Ewing sarcoma cell shows a poorly differentiated, stem-cell like phenotype. Consequently, the cellular origin of Ewing sarcoma is still a hot discussed topic. To further characterize Ewing sarcoma and to further elucidate the role of EWSR1-ETS fusion protein multiple genome, epigenome and transcriptome level studies were performed. In this review, the data from these studies were combined into a comprehensive overview. Presently, classical morphological predictive markers are used in the clinic and the therapy is dominantly based on systemic chemotherapy in combination with surgical interventions. Using sequencing, novel predictive markers and candidates for immuno- and targeted therapy were identified which were summarized in this review.Activation of PTHrP-cAMP-CREB1 signaling following p53 loss is essential for osteosarcoma initiation and maintenance.Genomic landscape of Ewing sarcoma defines an aggressive subtype with co-association of STAG2 and TP53 mutations.Sequencing Overview of Ewing Sarcoma: A Journey across Genomic, Epigenomic and Transcriptomic Landscapes.Sand Laurens G L LG, Szuhai Karoly K, Hogendoorn Pancras C W PCTirode Franck F, Surdez Didier D, Ma Xiaotu X, Parker Matthew M, Le Deley Marie Cécile MC, Bahrami Armita A, Zhang Zhaojie Z, Lapouble Eve E, Grossetête-Lalami Sandrine S, Rusch Michael M, Reynaud Stéphanie S, Rio-Frio Thomas T, Hedlund Erin E, Wu Gang G, Chen Xiang X, Pierron Gaelle G, Oberlin Odile O, Zaidi Sakina S, Lemmon Gordon G, Gupta Pankaj P, Vadodaria Bhavin B, Easton John J, Gut Marta M, Ding Li L, Mardis Elaine R ER, Wilson Richard K RK, Shurtleff Sheila S, Laurence Valérie V, Michon Jean J, Marec-Bérard Perrine P, Gut Ivo I, Downing James J, Dyer Michael M, Zhang Jinghui J, Delattre Olivier OWalia Mannu K MK, Ho Patricia Mw PM, Taylor Scott S, Ng Alvin Jm AJ, Gupte Ankita A, Chalk Alistair M AM, Zannettino Andrew Cw AC, Martin T John TJ, Walkley Carl R CREwing's family localized tumor, peripheral primitive neuroectodermal tumour, Ewing's Family of Tumors, Ewing sarcoma, localized Ewing's sarcoma/peripheral primitive neuroectodermal tumor, Ewing's sarcoma/peripheral primitive neuroectodermal tumour, sarcoma, localised peripheral primitive neuroectodermal tumour, Ewings sarcoma-primitive neuroectodermal tumor, neuroepithelioma, Ewing's sarcoma, Ewings sarcoma, Ewing Tumor, localised Ewing sarcoma, localised Ewing's tumour, Ewing, Ewing's Sarcoma/Peripheral Primitive Neuroectodermal Tumor, Tumor, localized Ewing's tumor, localised Ewing's sarcoma, Ewing Family of Tumors, Ewing's Tumor, Ewings, Ewing's Family of Tumours, peripheral, localized peripheral primitive neuroectodermal tumor, Ewing's sarcoma/peripheral primitive neuroectodermal tumor, WGS., Sarcoma, PNET of Thoracopulmonary Region, Ewing's, Ewings Sarcoma, Ewing's Sarcoma, Ewing's tumour, localized Ewing's sarcoma, ES, Ewing tumor, Tumors of the Ewing's Family, Ewing's sarcoma (morphologic abnormality), localized Ewing sarcoma, localised Ewing's sarcoma/peripheral primitive neuroectodermal tumour, peripheral primitive neuroectodermal tumor, Ewing's tumor, Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor, Ewing Sarcoma, Ewings sarcoma-primitive neuroectodermal tumour, Ewings Tumor, Ewing tumourDesc, Description, Descriptive, Provide., Supplied, Supply, Descriptor, description, Provided, Product Description/Appearance, DESCRbeta[[3]]-Tub, Osteosarcoma of bone (disorder), Osteochondrosarcoma, CRAMP, DmelCG17117, dp53, Osteogenic Sarcomas, p50, FALL39, 5'-cyclic monophosphate, p53, 143391_i_at, beta3 TU, Tumor, LFS1, betaTub3, PTH-Related Peptide, Tp53, l(3)05745, 5'-Cyclic AMP, AV083133, Osteogenic Sarcoma, PTHrP[38-94], DMP53, Cyclic adenylic acid, PTHR, bbl, CAP-18, Dmp53, anon-EST:Liang-2.13, Osteoblastic osteosarcoma, C13orf8, Parathyroid Hormone Related Peptide, Sarcomas, 1323/07, PTHrP[107-139], clone 2.13, BCC7, HHM, cAMP, Creb, D.m.BETA-60D, Sarcoma of Bone, PTH-Like Protein, BDE2, beta-Tub6D, dmp53, PTH Like Protein, ZNF828, CREB, 3', T, DmP53, 1422/04, Hypercalcemic Factor, Osteoblastic sarcoma, Osseous Sarcoma, Parathyroid Hormone Like Tumor Factor, B3t, DmelCG3401, Sarcoma, Trp53, Parathyroid Hormone-Like Protein, PTH Related Peptide, Dp53, no ICD-O subtype (morphologic abnormality), PTHrP, betaTub60C, Parathyroid hormone-like protein, PTH-like, beta3-tubulin, Parathyroid Hormone-Related Peptide, beta[[3]]-tubulin, TRP53, CG17117, p50/tubulin, single organism signaling, Tumors, HSD26, beta-Tub60D, PTH-rP, CG10873, Osteosarcoma of bone, Dmbeta3, Dm-HTH, 3526402H21Rik, Osteogenic sarcoma, Osteosarcoma - disorder, PTHRP, 2310001E10Rik, BETA 60D, prac, beta3t, beta3-Tub, CAP18, Osteostatin, Osteogenic, 5'-phosphate, CAMP, Pthrp, Xp53, 3t, Tumor Hypercalcemic Factor, Cyclic AMP, 5'-cyclic phosphate, [M]Osteosarcoma NOS, p53/tubulin, NOS, bfy, beta[[3]] tubulin, activation, PTHrP[1-36], Tub60D, HTH, Hth, Osteosarcomas, Parathyroid Hormone Like Protein, CG33336, Skeletal sarcoma, Bone Sarcoma, beta-tub, Sarcoma of the Bone, LL37, FALL-39, CHAMP, Hormone-Related Protein, DmelCG33336, D-p53, beta60C, osteoid sarcoma, CG3401, initiation, Maintenances., beta3Tub, beta3TUB, PLP, 5'-(hydrogen phosphate), Dm-P53, l(3)86Ca, Osteosarcoma, beta3, Creb-1, 5'-CYCLIC-MONOPHOSPHATE, Parathyroid, dtl, bone tissue neoplasm, Tub, DTB3, PTH Like Tumor Factor, Meis1, hth1, hth2, no ICD-O subtype, signalling process, betatub60D, Hypercalcemic Hormone of Malignancy, Adenosine 3', ADENOSINE-3', P53, p44, Parathyroid Hormone Related Protein, bhy, Osteosarcoma Tumors, Osteosarcoma Tumor, adenosine 3', CG31325, betaTub, osteosarcomaEwing's family localized tumor, 8430401K06Rik, localized Ewing's sarcoma/peripheral primitive neuroectodermal tumor, bone tumor, p19<ARF>, Product, PNT-P1, ezh2, ezh1, EZH2b, EY3-1, osseous tumour, Tumor, CG3629, Ewing tumor cell, beta-cat, Mutation Frequency, MYM, Mutations, Alternative, bbl, ARF-INK4a, Mutation Frequencies, EWSR1, D-ets-2, 3520, Alternative Medicine, p16(INK4a), Ewings Tumor, D930024N20Rik, beta-Cat, D-elg, thymus nucleic acid, chromosome scaffold., Genomes, BCC7, SA-2, CG3606, localized Ewing's tumor, Dm Arm, D17Mit170, Epigenomic, Ewing's Family of Tumours, Ba, Upper, ZNF261, XSA2, medicine, osseous tumor, Medicine, localised Ewing's sarcoma/peripheral primitive neuroectodermal tumour, Pen19, Nucleotide, EZH1, Tumors, Elg, MAA2, dl, familial, SAP2, localised Ewing's sarcoma, Tl3, Tl2, bone tumour, ANOP2, Expanded, elg, l(2)01092, D-Elg, KU-MEL-1, DmelCG6338, Benign, 1270, ES, bfy, desoxyribose nucleic acid, Ewings sarcoma-primitive neuroectodermal tumour, XFIM, nucleotides, DLL, pntP2, bK984G1.4, Pointed-P1, Ewing Tumor, Ets94F, expanded, Ex, Benign Neoplasms, whole genome, EG:86E4.6, E(Arp), Ewings, Malignant Neoplasms, DXS6673E, dll, Chromosome, Brachiums, betacat, ds DNA, localized Ewing sarcoma, bhy, DNA, Epigenetics, other neoplasm, INK4A, CDKN2, mKIAA4065, peripheral primitive neuroectodermal tumour, big, 0998/12, DNS, primary bone cancer, (Deoxyribonucleotide)n, INK4, enx1, Neoplasms, localised Ewing sarcoma, number, SCC3B, Prognostic Factors, LFS1, Complementary Medicine, BcorR, large, DMPOINT1A, DmelCG4114, Rate, Deoxyribonucleic Acid, l(2)387, tne, KMT6A, Upper Arm, tny, ENX-1, pointed-RC, MCOPS2, Double Stranded, WVS, Deoxyribonucleic acid, EK3-2, Ewing's Tumor, Neoplasias, l(3)07825, ENX1, drugs, p19ARF, CG17077, bA517O1.1, (Deoxyribonucleotide)m, WVS2, constitutitional genetic, 2.7, Cancer, Pharmaceuticals, Ewing's Family of Tumors, Products, Ets, TP16, ALR, Malignant Neoplasm, cou, DNAn+1, CG4114, Factor, Ewing Family of Tumors, BcDNA:GM09207, p19-lt-ARF-gt-, p16INK4a, Cell, AU018891, peripheral, l(1)arm, Ewing's sarcoma/peripheral primitive neuroectodermal tumor, DELG, prophase chromosome, Lr, Arms, Complementary Therapy, P14ARF, Ewing sarcoma cell, Mutation Rates, Neoplasm, ZNF198L2, pnt-P1, pnt-P2, Mutation, P16INK4A, EWS cell, Pharmaceutic Preparations, Ewings sarcoma-primitive neuroectodermal tumor, interphase chromosome, Ewing, Ewing's Sarcoma/Peripheral Primitive Neuroectodermal Tumor, Cancers, BCoR, rare bone tumour, upper extremity, Ews, EWS, CG11579, INK4a-ARF, l(2)01270, Ewing's, Fusions, Desoxyribonukleinsaeure, Bra, Pharmaceutical Products, hereditary, POINT, Delg, Neoplasia, CG8705, MTS1, l(1)G0410, Ewing's tumor of bone, beta-cat-arm, Ewing's sarcoma, DmelCG17077, CG6338, Pctr1, Ewing's sarcoma of bone, Pnt, Tp53, brl, d-elg, ETB cell, png, Ewing's tumour, Pharmaceutical Product, Arf, ARF, mKIAA1575, ARM, Chromatins, Fusion, Arm, Pnt-P1, Art, Ewing's sarcoma/peripheral primitive neuroectodermal tumour, me75, Prognoses, MTS-1, chromatid, arm, T1, genetic, Sarcoma, Pharmaceutical, Therapies, peripheral primitive neuroectodermal tumor, P14, Malignancies, Double-Stranded DNA, P16, deoxyribonucleic acids, DNAn, P19, Frequency, P16-INK4A, nuclear chromatin, Therapy, Upper Arms, Ewsh, RGD1562735, anon-Pen19, MLM, localised Ewing's tumour, D-Ets-2, p16, ets94F, 0123/09, beta-catenin/Arm, Double-Stranded, p19, localized peripheral primitive neuroectodermal tumor, (Deoxyribonucleotide)n+m, Ewings Sarcoma, Ewing's Sarcoma, Frequencies, DmelCG3629, Gene Fusions, BcDNA:LP01770, Enx-1, Pharmaceutic, B230112I07Rik, l(1)G0234, Factors, Epigenetic, neuroepithelioma, Prognostic, En(Arp), Treatments, NS21, ptd, PntP2, metastatic, enlarged, Patient, t12687 ALR Dm, PntP1, E(E2F)3D, localized Ewing's sarcoma, Ewing tumor, DmelCG3606, ALDR1, P53, Ewing's sarcoma (morphologic abnormality), p44, l(2)ey, PNTP2, inherited genetic, DmelCG11579, sa2-a, Ewing Sarcoma, PNTP1, Prognostic Factor, cytoplasmic chromatin, ETS2, Ets2, p53, enx-1, Benign Neoplasm, Gene, kmt6, primary malignant neoplasm of bone, bone neoplasm, Malignant, presence, Deoxyribonucleic acids, pntegfr, 5830466J11Rik, 0608/07, brachium, xez, Low, SARFH, Sarfh, Drugs, Malignancy, Complementary, Brachium, pen19, Alternative Therapies, Trp53, Enx1h, Ink4a|Arf, KMT6, Clients, great, CMM2, Ewing's tumor, Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor, TRP53, Preparation, l(1)2Bv, l(3)j1B7, sarcoma, P16INK4, rare bone tumor, Medications, Client, HEL-S-6, Xp53, PNET of Thoracopulmonary Region, count in organism, SA2, sa2, Tumors of the Ewing's Family, Ink4a/Arf, TFIID, DD3, ds-DNA, l(3)s118306, Caz, Ewing tumour, Ewing sarcoma, Rates, localised peripheral primitive neuroectodermal tumour, Ewings sarcoma, CDK4I, cas, l(1)G0192, Drug, Preparations, Ets58AB, Therapeutic, P19ARF, cardinality, Treatment, Pharmaceutical Preparation, 9230105L23RikfalseEwing sarcoma - WGS - samplesDescription not provided2019-10-31 12:52:11EGAD000010010519606252237342707046226193259EGAC00001000010EGAS00001000855