title: Mutations in Exon 1 highlight the role of MED12 in uterine leiomyomas.
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.
authors: Department of Medical Genetics, Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland.
authors: Kati
authors: K
authors: Kämpjärvi
authors: Min Ju
authors: MJ
authors: Park
authors: Miika
authors: M
authors: Mehine
authors: Nam Hee
authors: NH
authors: Kim
authors: Alison D
authors: AD
authors: Clark
authors: Ralf
authors: R
authors: Bützow
authors: Tom
authors: T
authors: Böhling
authors: Jan
authors: J
authors: Böhm
authors: Jukka-Pekka
authors: JP
authors: Mecklin
authors: Heikki
authors: H
authors: Järvinen
authors: Ian P M
authors: IP
authors: Tomlinson
authors: Zephne M
authors: ZM
authors: van der Spuy
authors: Jari
authors: J
authors: Sjöberg
authors: Thomas G
authors: TG
authors: Boyer
authors: Pia
authors: P
authors: Vahteristo
mesh_terms: D002460:Cell Line; D016000:Cluster Analysis; D005091:Exons; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D056726:Genetic Association Studies; D006801:Humans; D007889:Leiomyoma / Q000235:genetics* / Q000473:pathology; D056892:Mediator Complex / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D011485:Protein Binding; D014594:Uterine Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: C460107:MED12 protein, human; D056892:Mediator Complex
keywords: MED12; benign tumor; cancer; somatic mutation; uterine leiomyoma