Exome Sequencing of Uterine Leiomyosarcomas Identifies Frequent Mutations in TP53, ATRX, and MED12

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Makinen , N , Aavikko , M , Heikkinen , T , Taipale , M , Taipale , J , Koivisto-Korander , R , Butzow , R & Vahteristo , P 2016 , ' Exome Sequencing of Uterine Leiomyosarcomas Identifies Frequent Mutations in TP53, ATRX, and MED12 ' , PLoS Genetics , vol. 12 , no. 2 , 1005850 . https://doi.org/10.1371/journal.pgen.1005850

Title: Exome Sequencing of Uterine Leiomyosarcomas Identifies Frequent Mutations in TP53, ATRX, and MED12
Author: Makinen, Netta; Aavikko, Mervi; Heikkinen, Tuomas; Taipale, Minna; Taipale, Jussi; Koivisto-Korander, Riitta; Butzow, Ralf; Vahteristo, Pia
Contributor organization: Research Programs Unit
Lauri Antti Aaltonen / Principal Investigator
Genome-Scale Biology (GSB) Research Program
Department of Medical and Clinical Genetics
Jussi Taipale / Principal Investigator
Department of Obstetrics and Gynecology
Department of Pathology
HUS Gynecology and Obstetrics
Date: 2016-02
Language: eng
Number of pages: 13
Belongs to series: PLoS Genetics
ISSN: 1553-7404
DOI: https://doi.org/10.1371/journal.pgen.1005850
URI: http://hdl.handle.net/10138/161303
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.
3111 Biomedicine
Peer reviewed: Yes
Usage restriction: openAccess
Self-archived version: publishedVersion

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