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Mediator complex subunit 12 exon 2 mutation analysis in different subtypes of smooth muscle tumors confirms genetic heterogeneity.
Hum Pathol. 2013 Aug; 44(8):1597-604.HP

Abstract

Recently, heterozygous mutations in exon 2 of the mediator complex subunit 12 gene have been described in 50% to 70% of uterine leiomyomas; the recurrent nature of these mutations suggests an important role in their pathogenesis. Mediator complex subunit 12 is involved in regulation of transcription and Wnt signaling. So far, little is known about the pathogenesis of the different subtypes of extrauterine leiomyomas and leiomyosarcomas. We performed mutation analysis of mediator complex subunit 12 and immunohistochemistry for β-catenin, using 69 tumors of 64 patients including 19 uterine leiomyomas, 6 abdominal leiomyomas, 9 angioleiomyomas, 5 piloleiomyomas, and 7 uterine and 23 soft tissue leiomyosarcomas. In line with previous observations, 58% of uterine leiomyomas carried a mediator complex subunit 12 mutation. However, all other extrauterine leiomyomas were negative with the exception of 1 abdominal leiomyoma with a likely primary uterine origin. Of the 30 leiomyosarcomas, only 1 uterine tumor harbored a mutation. A new observation is the identification of 3 tumors with a homozygous mutation; a monosomy X or interstitial deletion was excluded. β-Catenin immunohistochemistry showed nuclear positivity in only 55% of the mediator complex subunit 12-mutated uterine leiomyomas, suggesting the involvement of pathways other than canonical Wnt signaling in tumorigenesis. Interestingly, 80% of mediator complex subunit 12 wild-type sporadic piloleiomyomas displayed nuclear β-catenin positivity, indicating its involvement in this leiomyoma subtype. The lack of mediator complex subunit 12 mutations in extrauterine leiomyomas and leiomyosarcomas indicates that these tumors arise through a different pathway, emphasizing the genetic heterogeneity of smooth muscle tumors.

Authors+Show Affiliations

Department of Pathology, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

23517922

Citation

de Graaff, Marieke A., et al. "Mediator Complex Subunit 12 Exon 2 Mutation Analysis in Different Subtypes of Smooth Muscle Tumors Confirms Genetic Heterogeneity." Human Pathology, vol. 44, no. 8, 2013, pp. 1597-604.
de Graaff MA, Cleton-Jansen AM, Szuhai K, et al. Mediator complex subunit 12 exon 2 mutation analysis in different subtypes of smooth muscle tumors confirms genetic heterogeneity. Hum Pathol. 2013;44(8):1597-604.
de Graaff, M. A., Cleton-Jansen, A. M., Szuhai, K., & Bovée, J. V. (2013). Mediator complex subunit 12 exon 2 mutation analysis in different subtypes of smooth muscle tumors confirms genetic heterogeneity. Human Pathology, 44(8), 1597-604. https://doi.org/10.1016/j.humpath.2013.01.006
de Graaff MA, et al. Mediator Complex Subunit 12 Exon 2 Mutation Analysis in Different Subtypes of Smooth Muscle Tumors Confirms Genetic Heterogeneity. Hum Pathol. 2013;44(8):1597-604. PubMed PMID: 23517922.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mediator complex subunit 12 exon 2 mutation analysis in different subtypes of smooth muscle tumors confirms genetic heterogeneity. AU - de Graaff,Marieke A, AU - Cleton-Jansen,Anne-Marie, AU - Szuhai,Károly, AU - Bovée,Judith V M G, Y1 - 2013/03/19/ PY - 2012/10/31/received PY - 2012/12/20/revised PY - 2013/01/02/accepted PY - 2013/3/23/entrez PY - 2013/3/23/pubmed PY - 2013/9/17/medline KW - Leiomyoma KW - Leiomyosarcoma KW - MED12 mutation KW - Wnt-pathway KW - β-catenin SP - 1597 EP - 604 JF - Human pathology JO - Hum. Pathol. VL - 44 IS - 8 N2 - Recently, heterozygous mutations in exon 2 of the mediator complex subunit 12 gene have been described in 50% to 70% of uterine leiomyomas; the recurrent nature of these mutations suggests an important role in their pathogenesis. Mediator complex subunit 12 is involved in regulation of transcription and Wnt signaling. So far, little is known about the pathogenesis of the different subtypes of extrauterine leiomyomas and leiomyosarcomas. We performed mutation analysis of mediator complex subunit 12 and immunohistochemistry for β-catenin, using 69 tumors of 64 patients including 19 uterine leiomyomas, 6 abdominal leiomyomas, 9 angioleiomyomas, 5 piloleiomyomas, and 7 uterine and 23 soft tissue leiomyosarcomas. In line with previous observations, 58% of uterine leiomyomas carried a mediator complex subunit 12 mutation. However, all other extrauterine leiomyomas were negative with the exception of 1 abdominal leiomyoma with a likely primary uterine origin. Of the 30 leiomyosarcomas, only 1 uterine tumor harbored a mutation. A new observation is the identification of 3 tumors with a homozygous mutation; a monosomy X or interstitial deletion was excluded. β-Catenin immunohistochemistry showed nuclear positivity in only 55% of the mediator complex subunit 12-mutated uterine leiomyomas, suggesting the involvement of pathways other than canonical Wnt signaling in tumorigenesis. Interestingly, 80% of mediator complex subunit 12 wild-type sporadic piloleiomyomas displayed nuclear β-catenin positivity, indicating its involvement in this leiomyoma subtype. The lack of mediator complex subunit 12 mutations in extrauterine leiomyomas and leiomyosarcomas indicates that these tumors arise through a different pathway, emphasizing the genetic heterogeneity of smooth muscle tumors. SN - 1532-8392 UR - https://www.unboundmedicine.com/medline/citation/23517922/Mediator_complex_subunit_12_exon_2_mutation_analysis_in_different_subtypes_of_smooth_muscle_tumors_confirms_genetic_heterogeneity_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0046-8177(13)00026-9 DB - PRIME DP - Unbound Medicine ER -