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Mutations in Exon 1 highlight the role of MED12 in uterine leiomyomas.
Hum Mutat. 2014 Sep; 35(9):1136-41.HM

Abstract

Mediator regulates transcription by connecting gene-specific transcription factors to the RNA polymerase II initiation complex. We recently discovered by exome sequencing that specific exon 2 mutations in mediator complex subunit 12 (MED12) are extremely common in uterine leiomyomas. Subsequent screening studies have focused on this mutational hot spot, and mutations have been detected in uterine leiomyosarcomas, extrauterine leiomyomas and leiomyosarcomas, endometrial polyps, and colorectal cancers. All mutations have been missense changes or in-frame insertions/deletions. Here, we have analyzed 611 samples representing all above-mentioned tumor types for possible exon 1 mutations. Five mutations were observed, all of which were in-frame insertion/deletions in uterine leiomyomas. Transcriptome-wide expression data revealed that MED12 exon 1 and exon 2 mutations lead to the same unique global gene expression pattern with RAD51B being the most upregulated gene. Immunoprecipitation and kinase activity assays showed that both exon 1 and exon 2 mutations disrupt the interaction between MED12 and Cyclin C and CDK8/19 and abolish the mediator-associated CDK kinase activity. These results further emphasize the role of MED12 in uterine leiomyomas, show that exon 1 and exon 2 exert their tumorigenic effect in similar manner, and stress that exon 1 should be included in subsequent MED12 screenings.

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Authors+Show Affiliations

Kämpjärvi K
Department of Medical Genetics, Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland.
Park MJ
No affiliation info available
Mehine M
No affiliation info available
Kim NH
No affiliation info available
Clark AD
No affiliation info available
Bützow R
No affiliation info available
Böhling T
No affiliation info available
Böhm J
No affiliation info available
Mecklin JP
No affiliation info available
Järvinen H
No affiliation info available
Tomlinson IP
No affiliation info available
van der Spuy ZM
No affiliation info available
Sjöberg J
No affiliation info available
Boyer TG
No affiliation info available
Vahteristo P
No affiliation info available

MeSH

Cell LineCluster AnalysisExonsFemaleGene Expression ProfilingGene Expression Regulation, NeoplasticGenetic Association StudiesHumansLeiomyomaMediator ComplexMutationProtein BindingUterine Neoplasms

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24980722

Citation

Kämpjärvi, Kati, et al. "Mutations in Exon 1 Highlight the Role of MED12 in Uterine Leiomyomas." Human Mutation, vol. 35, no. 9, 2014, pp. 1136-41.
Kämpjärvi K, Park MJ, Mehine M, et al. Mutations in Exon 1 highlight the role of MED12 in uterine leiomyomas. Hum Mutat. 2014;35(9):1136-41.
Kämpjärvi, K., Park, M. J., Mehine, M., Kim, N. H., Clark, A. D., Bützow, R., Böhling, T., Böhm, J., Mecklin, J. P., Järvinen, H., Tomlinson, I. P., van der Spuy, Z. M., Sjöberg, J., Boyer, T. G., & Vahteristo, P. (2014). Mutations in Exon 1 highlight the role of MED12 in uterine leiomyomas. Human Mutation, 35(9), 1136-41. https://doi.org/10.1002/humu.22612
Kämpjärvi K, et al. Mutations in Exon 1 Highlight the Role of MED12 in Uterine Leiomyomas. Hum Mutat. 2014;35(9):1136-41. PubMed PMID: 24980722.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mutations in Exon 1 highlight the role of MED12 in uterine leiomyomas. AU - Kämpjärvi,Kati, AU - Park,Min Ju, AU - Mehine,Miika, AU - Kim,Nam Hee, AU - Clark,Alison D, AU - Bützow,Ralf, AU - Böhling,Tom, AU - Böhm,Jan, AU - Mecklin,Jukka-Pekka, AU - Järvinen,Heikki, AU - Tomlinson,Ian P M, AU - van der Spuy,Zephne M, AU - Sjöberg,Jari, AU - Boyer,Thomas G, AU - Vahteristo,Pia, Y1 - 2014/07/21/ PY - 2014/04/15/received PY - 2014/06/17/accepted PY - 2014/7/2/entrez PY - 2014/7/2/pubmed PY - 2015/5/12/medline KW - MED12 KW - benign tumor KW - cancer KW - somatic mutation KW - uterine leiomyoma SP - 1136 EP - 41 JF - Human mutation JO - Hum Mutat VL - 35 IS - 9 N2 - Mediator regulates transcription by connecting gene-specific transcription factors to the RNA polymerase II initiation complex. We recently discovered by exome sequencing that specific exon 2 mutations in mediator complex subunit 12 (MED12) are extremely common in uterine leiomyomas. Subsequent screening studies have focused on this mutational hot spot, and mutations have been detected in uterine leiomyosarcomas, extrauterine leiomyomas and leiomyosarcomas, endometrial polyps, and colorectal cancers. All mutations have been missense changes or in-frame insertions/deletions. Here, we have analyzed 611 samples representing all above-mentioned tumor types for possible exon 1 mutations. Five mutations were observed, all of which were in-frame insertion/deletions in uterine leiomyomas. Transcriptome-wide expression data revealed that MED12 exon 1 and exon 2 mutations lead to the same unique global gene expression pattern with RAD51B being the most upregulated gene. Immunoprecipitation and kinase activity assays showed that both exon 1 and exon 2 mutations disrupt the interaction between MED12 and Cyclin C and CDK8/19 and abolish the mediator-associated CDK kinase activity. These results further emphasize the role of MED12 in uterine leiomyomas, show that exon 1 and exon 2 exert their tumorigenic effect in similar manner, and stress that exon 1 should be included in subsequent MED12 screenings. SN - 1098-1004 UR - https://www.unboundmedicine.com/medline/citation/24980722/Mutations_in_Exon_1_highlight_the_role_of_MED12_in_uterine_leiomyomas_ L2 - https://doi.org/10.1002/humu.22612 DB - PRIME DP - Unbound Medicine ER -