title: Exome Sequencing of Uterine Leiomyosarcomas Identifies Frequent Mutations in TP53, ATRX, and MED12.
abstract: Uterine leiomyosarcomas (ULMSs) are aggressive smooth muscle tumors associated with poor clinical outcome. Despite previous cytogenetic and molecular studies, their molecular background has remained elusive. To examine somatic variation in ULMS, we performed exome sequencing on 19 tumors. Altogether, 43 genes were mutated in at least two ULMSs. Most frequently mutated genes included tumor protein P53 (TP53; 6/19; 33%), alpha thalassemia/mental retardation syndrome X-linked (ATRX; 5/19; 26%), and mediator complex subunit 12 (MED12; 4/19; 21%). Unlike ATRX mutations, both TP53 and MED12 alterations have repeatedly been associated with ULMSs. All the observed ATRX alterations were either nonsense or frameshift mutations. ATRX protein levels were reliably analyzed by immunohistochemistry in altogether 44 ULMSs, and the majority of tumors (23/44; 52%) showed clearly reduced expression. Loss of ATRX expression has been associated with alternative lengthening of telomeres (ALT), and thus the telomere length was analyzed with telomere-specific fluorescence in situ hybridization. The ALT phenotype was confirmed in all ULMSs showing diminished ATRX expression. Exome data also revealed one nonsense mutation in death-domain associated protein (DAXX), another gene previously associated with ALT, and the tumor showed ALT positivity. In conclusion, exome sequencing revealed that TP53, ATRX, and MED12 are frequently mutated in ULMSs. ALT phenotype was commonly seen in tumors, indicating that ATR inhibitors, which were recently suggested as possible new drugs for ATRX-deficient tumors, could provide a potential novel therapeutic option for ULMS.
authors.affiliation: Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.|Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.
authors.forename: Netta
authors.initials: N
authors.lastname: Mäkinen
authors.affiliation: Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.|Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.
authors.forename: Mervi
authors.initials: M
authors.lastname: Aavikko
authors.affiliation: Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.|Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.
authors.forename: Tuomas
authors.initials: T
authors.lastname: Heikkinen
authors.affiliation: Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.|Science for Life Laboratory, Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Minna
authors.initials: M
authors.lastname: Taipale
authors.affiliation: Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.|Science for Life Laboratory, Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jussi
authors.initials: J
authors.lastname: Taipale
authors.affiliation: Department of Obstetrics and Gynecology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
authors.forename: Riitta
authors.initials: R
authors.lastname: Koivisto-Korander
authors.affiliation: Department of Pathology, The Laboratory of Helsinki University Hospital (HUSLAB), Helsinki University Hospital and Medicum, University of Helsinki, Helsinki, Finland.
authors.forename: Ralf
authors.initials: R
authors.lastname: Bützow
authors.affiliation: Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.|Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.
authors.forename: Pia
authors.initials: P
authors.lastname: Vahteristo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D056970:Co-Repressor Proteins; D004265:DNA Helicases / Q000235:genetics*; D059472:Exome; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007890:Leiomyosarcoma / Q000235:genetics* / Q000401:mortality; D056892:Mediator Complex / Q000235:genetics*; D008875:Middle Aged; D018832:Molecular Chaperones; D059645:Mutation Rate; D009687:Nuclear Proteins / Q000235:genetics*; D059505:Telomere Homeostasis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D014594:Uterine Neoplasms / Q000235:genetics* / Q000401:mortality; D000075924:X-linked Nuclear Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; C460107:MED12 protein, human; D056892:Mediator Complex; D018832:Molecular Chaperones; D009687:Nuclear Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein