title: MED12 alterations in both human benign and malignant uterine soft tissue tumors.
abstract: The relationship between benign uterine leiomyomas and their malignant counterparts, i.e. leiomyosarcomas and smooth muscle tumors of uncertain malignant potential (STUMP), is still poorly understood. The idea that a leiomyosarcoma could derive from a leiomyoma is still controversial. Recently MED12 mutations have been reported in uterine leiomyomas. In this study we asked whether such mutations could also be involved in leiomyosarcomas and STUMP oncogenesis. For this purpose we examined 33 uterine mesenchymal tumors by sequencing the hot-spot mutation region of MED12. We determined that MED12 is altered in 66.6% of typical leiomyomas as previously reported but also in 11% of STUMP and 20% of leiomyosarcomas. The mutated allele is predominantly expressed in leiomyomas and STUMP. Interestingly all classical leiomyomas exhibit MED12 protein expression while 40% of atypical leiomyomas, 50% of STUMP and 80% of leiomyosarcomas (among them the two mutated ones) do not express MED12. All these tumors without protein expression exhibit complex genomic profiles. No mutations and no expression loss were identified in an additional series of 38 non-uterine leiomyosarcomas. MED12 mutations are not exclusive to leiomyomas but seem to be specific to uterine malignancies. A previous study has suggested that MED12 mutations in leiomyomas could lead to Wnt/β-catenin pathway activation however our immunohistochemistry results show that there is no association between MED12 status and β-catenin nuclear/cytoplasmic localization. Collectively, our results show that subgroups of benign and malignant tumors share a common genetics. We propose here that MED12 alterations could be implicated in the development of smooth muscle tumor and that its expression could be inhibited in malignant tumors.
authors: INSERM U916, Institut Bergonié Cancer Institute, Bordeaux, France.
authors: Gaëlle
authors: G
authors: Pérot
authors: Sabrina
authors: S
authors: Croce
authors: Agnès
authors: A
authors: Ribeiro
authors: Pauline
authors: P
authors: Lagarde
authors: Valérie
authors: V
authors: Velasco
authors: Agnès
authors: A
authors: Neuville
authors: Jean-Michel
authors: JM
authors: Coindre
authors: Eberhard
authors: E
authors: Stoeckle
authors: Anne
authors: A
authors: Floquet
authors: Gaëtan
authors: G
authors: MacGrogan
authors: Frédéric
authors: F
authors: Chibon
mesh_terms: D000483:Alleles; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D007889:Leiomyoma / Q000235:genetics / Q000473:pathology; D056892:Mediator Complex / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D021381:Protein Transport; D018235:Smooth Muscle Tumor / Q000235:genetics / Q000473:pathology; D012983:Soft Tissue Neoplasms / Q000235:genetics* / Q000473:pathology; D014594:Uterine Neoplasms / Q000235:genetics* / Q000473:pathology; D060449:Wnt Signaling Pathway / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism
chemical_list: D018076:DNA, Complementary; C460107:MED12 protein, human; D056892:Mediator Complex; D051176:beta Catenin