EGAGenomicsILLUMINA, Illumina HiSeq 2500, HiSeq X Ten, Illumina HiSeq 2000Otherhttps://ega-archive.org/studies/EGAS00001002437EGAEGA study EGAS00001002437Exome sequencing data for LMS tumor and control samplesRNA-seq data of LMS tumorswhole genome sequencing data of LMS cell linesrestrictedEGALeiomyosarcoma (LMS) is an aggressive mesenchymal malignancy with few therapeutic options. The mechanisms underlying LMS development, including clinically actionable genetic vulnerabilities, are largely unknown. Here we show, using whole-exome and transcriptome sequencing, that LMS tumors are characterized by substantial mutational heterogeneity, near-universal inactivation of TP53 and RB1, widespread DNA copy number alterations including chromothripsis, and frequent whole-genome duplication. Furthermore, we detect alternative telomere lengthening in 78% of cases and identify recurrent alterations in telomere maintenance genes such as ATRX, RBL2, and SP100, providing insight into the genetic basis of this mechanism. Finally, most tumors display hallmarks of "BRCAness", including alterations in homologous recombination DNA repair genes, multiple structural rearrangements, and enrichment of specific mutational signatures, and cultured LMS cells are sensitive towards olaparib and cisplatin. This comprehensive study of LMS genomics has uncovered key biological features that may inform future experimental research and enable the design of novel therapies.Integrative genomic and transcriptomic analysis of leiomyosarcoma.Chudasama Priya P, Mughal Sadaf S SS, Sanders Mathijs A MA, Hübschmann Daniel D, Chung Inn I, Deeg Katharina I KI, Wong Siao-Han SH, Rabe Sophie S, Hlevnjak Mario M, Zapatka Marc M, Ernst Aurélie A, Kleinheinz Kortine K, Schlesner Matthias M, Sieverling Lina L, Klink Barbara B, Schröck Evelin E, Hoogenboezem Remco M RM, Kasper Bernd B, Heilig Christoph E CE, Egerer Gerlinde G, Wolf Stephan S, von Kalle Christof C, Eils Roland R, Stenzinger Albrecht A, Weichert Wilko W, Glimm Hanno H, Gröschel Stefan S, Kopp Hans-Georg HG, Omlor Georg G, Lehner Burkhard B, Bauer Sebastian S, Schimmack Simon S, Ulrich Alexis A, Mechtersheimer Gunhild G, Rippe Karsten K, Brors Benedikt B, Hutter Barbara B, Renner Marcus M, Hohenberger Peter P, Scholl Claudia C, Fröhling Stefan SEpithelioid Leiomyosarcomas, Myxoid Leiomyosarcoma, determination, Leiomyosarcomas, leiomyosarcoma - not uterine, malignant, chemical analysis, adult stage, leiomyosarcoma, Epithelioid Leiomyosarcoma, assay, Leiomyosarcoma, Myxoid, leiomyosarcoma (excluding uterine leiomyosarcoma), Adults, adult, Epithelioid., Myxoid Leiomyosarcomas, EpithelioidRB1, chromosomal crossover, telomere, Materials, Platinol, single-organism developmental process, cis-Diamminedichloroplatinum(II), cis-Dichlorodiammineplatinum(II), Activity, Laboratory, Randa, postnatal development, AZD 2281, Gene Expression Profile, (SP-4-2)-, growth and development, Profiles, RBF, ALPHA-thalassemia/mental retardation syndrome, Tumor, Xnp, XNP, Tp53, RBR, Recombinations, XLMR hypotonic face syndrome, B(p51B), bbl, TP73L, RB, rb, Peyrone's chloride, nuclear chromosome, RETINOBLASTOMA PROTEIN, rbf, Research Activity, Alpha-thalassemia-X-linked intellectual disability syndrome, Laboratory Research, KET, Peyrone's salt, Priorities, thymus nucleic acid, OFC8, BCC7, Genomes, pp110, Homologous, B(p51A), cis-diamminedichloridoplatinum(II), Comparative Genomics, p73H, cis-DDP, Rb, Myxoid, Briplatin, Signatures, genetic, allergic reaction, high frequency, Expression Signature, leiomyosarcoma - not uterine, Cisplatin, Transcriptomes, Shattering, (SP-4-2)-diamminedichloroplatinum, Malignancies, CG7413, Double-Stranded DNA, lysp100b, deoxyribonucleic acids, Research Priority, DNAn, INSDC_feature:telomere, somatic mutation, Hp1bp38, Tumors, ATR, Lynparza, retinoblastoma-related 1, Genomics, LNMS, DP, rbf1, NSC-119875, Comparative, Expression Profiles, familial, Research Priorities, retinoblastoma, Alpha thalassemia mental retardation syndrome, Alpha thalassemia intellectual disability syndrome, Double-Stranded, Functional Genomics, cis Platinum, telomeric sequence, RETINOBLASTOMA 1, diamminedichloro-, hereditary retinoblastoma, SHS, (Deoxyribonucleotide)n+m, Gene Expression, Benign, ectrodactyly, Expression Signatures, MRXS3, Alpha-thalassemia/mental retardation syndrome, Epithelioid Leiomyosarcoma, ATRBR1, Genetic Materials, CDDP, p73L, bfy, Chromosome Shattering, desoxyribose nucleic acid, ATRX syndrome, Expression Profile, Genetic Material, Transcriptome Profiles, Research and Development, pRb, Recombination, DmelCG7413, EEC3, MRXHF1, Dichlorodiammineplatinum, Exomes, [PtCl2(NH3)2], Platinum Diamminodichloride, Benign Neoplasms, ZNF-HX, whole genome, RAD54L, RHS, Malignant Neoplasms, experimental procedures, Activities, Epithelioid Leiomyosarcomas, p105-Rb, ALPHA-thalassemia/intellectual disability syndrome, familial retinoblastoma, Chromosome, Material, p40, Platidiam, ds DNA, P53, telomeric DNA, Laurence-Moon-Biedl syndrome, p44, bhy, Lms, LMS, Cistron, inherited genetic, cisplatinum, DNA, EG:34F3.3, Rbf1, RBF1, whole exome, telomeric region, DNS, X-linked, (Deoxyribonucleotide)n, experimental, Transcriptome Profile, FBF, p51, Neoplasms, p53, leiomyosarcoma, Benign Neoplasm, number, Gene, AZD221, Malignant, LFS1, autosomal dominant, dRBF, presence, Myxoid Leiomyosarcomas, NBP, Deoxyribonucleic acids, 4833408C14Rik, AZD-2281, LMNS, eye cancer, Structural, Deoxyribonucleic Acid, nondeletion type, HP1-BP38, AIS, sensitive, p63, RHOMBOID-like 2, OSRC, DNA Damage Response, Functional, SFM1, mammary hypoplasia, Leiomyosarcoma, AZD2281, sensitivity, Laurence-MOON syndrome, study, XH2, methods, telomeres, Genetic, cis-Diamminedichloroplatinum, Malignancy, Research, experimental section, Profile, Chromothripses, cis-Platinum, Double Stranded, Deoxyribonucleic acid, leiomyosarcoma (excluding uterine leiomyosarcoma), Lederplatin, Research Activities., Platamine, Neoplasias, AI447451, Trp53, SHFM4, Chromosome Shatterings, heterogeneity, JMS, (Deoxyribonucleotide)m, Development and Research, TRP53, constitutitional genetic, Cancer, F16M19_4, Transcriptome, Malignant Neoplasm, Cismaplat, malignant, ATR2, Homologous Recombinations, DNAn+1, and other hand/foot anomalies, PRB2, Cistrons, Cell, Xp53, Alpha-thalassemia/intellectual disability syndrome, development, count in organism, Priority, MT, ATRX, Myxoid Leiomyosarcoma, F16M19.4, Gene Expression Signatures, (SP-4-2)-diamminedichloridoplatinum, Neoplasm, PPP1R130, Telomeres, Gene Expression Signature, TP53L, ds-DNA, p53CP, Epithelioid, cis-diammineplatinum(II) dichloride, cis-diamminedichloroplatinum, regulation of telomere length, cis-platin, Nondeletion type, cis-[PtCl2(NH3)2], frequent, cis-diamminedichloroplatinum(II), cis-dichlorodiammineplatinum(II), Leiomyosarcomas, Neoplatin, reciprocal DNA recombination, TP53CP, Diamminodichloride, postnatal growth, Rb-1, cis Diamminedichloroplatinum, Platinum, cisplatine, Cancers, P130, cisplatin, cisplatino, Rb1, DXHXS6677E, Rb2, Hp1bp2, Rad54, RBR-2, Gene Expression Profiles, Alpha-thalassemia X-linked intellectual disability syndrome, A430075G10Rik, p130, cardinality, Biocisplatinum, RETINOBLASTOMA-RELATED PROTEIN 1, RETINOBLASTOMA-RELATED, Desoxyribonukleinsaeure, Platino, Structural Genomics, RAD54, Signature, RbF, trilateral, ATRBL2, growth, hereditary, Neoplasia, PlatinexEpithelioid Leiomyosarcomas, Myxoid Leiomyosarcoma, determination, Leiomyosarcomas, leiomyosarcoma - not uterine, malignant, chemical analysis, leiomyosarcoma, Epithelioid Leiomyosarcoma, assay, Leiomyosarcoma, Myxoid, leiomyosarcoma (excluding uterine leiomyosarcoma), Epithelioid., Myxoid Leiomyosarcomas, EpithelioidRB1, chromosomal crossover, Materials, Platinol, single-organism developmental process, cis-Diamminedichloroplatinum(II), cis-Dichlorodiammineplatinum(II), Activity, Laboratory, acetylglucosaminyltransferase-like protein, Randa, postnatal development, AZD 2281, Mbp1, (SP-4-2)-, growth and development, RBF, ALPHA-thalassemia/mental retardation syndrome, Tumor, RPA194, Xnp, XNP, Tp53, BUF2, RBR, RPA 70, Recombinations, XLMR hypotonic face syndrome, diseases, B(p51B), bbl, TP73L, RB, rb, Peyrone's chloride, diseases and disorders, RETINOBLASTOMA PROTEIN, rbf, Research Activity, Alpha-thalassemia-X-linked intellectual disability syndrome, myd, Laboratory Research, KET, Peyrone's salt, Priorities, treatment, thymus nucleic acid, DmelCG9633, human disease, OFC8, like-acetylglucosaminyltransferase, BCC7, Genomes, mst075, pp110, Homologous, B(p51A), cis-diamminedichloridoplatinum(II), p73H, cis-DDP, Rb, Mbp-1, RP-A, Myxoid, Briplatin, T1, RPO1-4, genetic, bs34h02.y1, allergic reaction, high frequency, leiomyosarcoma - not uterine, Rpo1-4, dmrpa1, Cisplatin, disease management, Therapies, Shattering, (SP-4-2)-diamminedichloroplatinum, Homo sapiens disease, Malignancies, CG7413, Double-Stranded DNA, deoxyribonucleic acids, Research Priority, DNAn, somatic mutation, Hp1bp38, AA589576, Tumors, ATR, Lynparza, Ssb-70, rad11, Therapy, retinoblastoma-related 1, RplP2, LNMS, gyltl1b-b, DP, rbf1, NSC-119875, familial, Research Priorities, retinoblastoma, FUN3, Alpha thalassemia mental retardation syndrome, Alpha thalassemia intellectual disability syndrome, Double-Stranded, RpP1, cis Platinum, rpa1, RETINOBLASTOMA 1, diamminedichloro-, hereditary retinoblastoma, SHS, (Deoxyribonucleotide)n+m, 5031405K23Rik, Benign, rp-a, hssb, ectrodactyly, MDDGA6, mKIAA0609, Diseases, MRXS3, Alpha-thalassemia/mental retardation syndrome, Epithelioid Leiomyosarcoma, ATRBR1, Genetic Materials, CDDP, p73L, bfy, Chromosome Shattering, KIAA0609, desoxyribose nucleic acid, ATRX syndrome, HSSB, acetylglucosaminyltransferase-like 1A, Genetic Material, Research and Development, fg, pRb, Recombination, gyltl1b, DmelCG7413, RpA1, RF-A, EEC3, mdc1d, MRXHF1, Dichlorodiammineplatinum, [PtCl2(NH3)2], Platinum Diamminodichloride, Benign Neoplasms, ZNF-HX, whole genome, RAD54L, LARGE_HUMAN, RHS, Treatments, Malignant Neoplasms, experimental procedures, Activities, Epithelioid Leiomyosarcomas, MDC1D, p105-Rb, ALPHA-thalassemia/intellectual disability syndrome, disease, enr, Rpa1, RPA1, familial retinoblastoma, Chromosome, Material, p40, Platidiam, ds DNA, P53, Laurence-Moon-Biedl syndrome, p44, bhy, Lms, LMS, Cistron, medical condition., inherited genetic, cisplatinum, DNA, CG9633, EG:34F3.3, rpA1, Rbf1, RBF1, MST075, other disease, DNS, X-linked, (Deoxyribonucleotide)n, D-SSB, experimental, FBF, RpA70, p51, Neoplasms, p53, leiomyosarcoma, Benign Neoplasm, number, DmelCG4918, Gene, Tp1, RPA 70 kDa, AZD221, Malignant, LFS1, LARGE1, autosomal dominant, dRBF, presence, Myxoid Leiomyosarcomas, NBP, RPO14, froggy, Deoxyribonucleic acids, Gyltl1a, 4833408C14Rik, AZD-2281, LMNS, eye cancer, Deoxyribonucleic Acid, nondeletion type, HP1-BP38, AIS, sensitive, p63, RHOMBOID-like 2, LP2, OSRC, DNA Damage Response, SFM1, disease or disorder, mammary hypoplasia, Leiomyosarcoma, A190, AZD2281, repa1, sensitivity, rf-a, Laurence-MOON syndrome, study, XH2, methods, telomeres, Genetic, cis-Diamminedichloroplatinum, Malignancy, Research, MDDGB6, experimental section, Chromothripses, DRP-A, cis-Platinum, Double Stranded, LARGE, Deoxyribonucleic acid, leiomyosarcoma (excluding uterine leiomyosarcoma), Lederplatin, Platamine, non-neoplastic, Neoplasias, BPFD#36, AI447451, Trp53, Rpa-70, SHFM4, Chromosome Shatterings, heterogeneity, JMS, dRP-A, disorder, RPA70, (Deoxyribonucleotide)m, Development and Research, TRP53, constitutitional genetic, Cancer, F16M19_4, CG4918, rpa70, Malignant Neoplasm, D-RPA70, DmRPA, Cismaplat, malignant, ATR2, Homologous Recombinations, DNAn+1, disorders, and other hand/foot anomalies, i164, PRB2, RLA2_DROME, Cistrons, Cell, Xp53, Alpha-thalassemia/intellectual disability syndrome, development, count in organism, Priority, MT, ATRX, Myxoid Leiomyosarcoma, F16M19.4, (SP-4-2)-diamminedichloridoplatinum, Research Activities, Neoplasm, PPP1R130, AW557552, Telomeres, condition, TP53L, ds-DNA, p53CP, Epithelioid, cis-diammineplatinum(II) dichloride, cis-diamminedichloroplatinum, regulation of telomere length, BcDNA:SD22208, RPA, Rpa, cis-platin, Nondeletion type, cis-[PtCl2(NH3)2], frequent, cis-diamminedichloroplatinum(II), cis-dichlorodiammineplatinum(II), Leiomyosarcomas, Neoplatin, reciprocal DNA recombination, TP53CP, Diamminodichloride, postnatal growth, 70kDa, Rb-1, cis Diamminedichloroplatinum, Platinum, cisplatine, Cancers, P130, cisplatin, cisplatino, Rb1, rpa, DXHXS6677E, Rb2, Hp1bp2, Rad54, RBR-2, like-glycosyltransferase, REPA1, Therapeutic, Alpha-thalassemia X-linked intellectual disability syndrome, p130, cardinality, Biocisplatinum, RETINOBLASTOMA-RELATED PROTEIN 1, RETINOBLASTOMA-RELATED, Desoxyribonukleinsaeure, Platino, Treatment, RAD54, RbF, trilateral, ATRBL2, growth, hereditary, Neoplasia, glycosyltransferase-like protein LARGE1, PlatinexfalseIntegrative genomic and transcriptomic analysis of adult leiomyosarcoma (HIPO-028, HIPO-018, HIPO-021)Leiomyosarcoma (LMS) is an aggressive mesenchmyal malignancy with few therapeutic options. The mechanisms underlying LMS development, including clinically actionable genetic vulnerabilities, are largely unknown. We performed genomic and transcriptomic profiling of a large cohort of LMS tumors and identified substantial mutational heterogeneity, near-universal inactivation of TP53 and RB1, widespread DNA copy number alterations, chromothripsis, and frequent whole-genome duplication. Furthermore, we discovered recurrent alterations in telomere maintenance genes such as ATRX, RBL2, and RPA1, resulting in alternative lengthening of telomeres in 78% of cases. Finally, most tumors displayed hallmarks of “BRCAness”, including alterations in various homologous recombination DNA repair genes, multiple structural rearrangements, and enrichment of specific mutational signatures, and cultured LMS cells were sensitive towards olaparib and cisplatin treatment. This first comprehensive study of genetic alterations in LMS has uncovered key biological features that may inform future experimental research and enable the design of novel therapeutic strategies for this disease.2018-03-15 14:50:57EGAS00001002437960629321523EGAD00001003828EGAD00001003827EGAD00001003829EGAC00001000452