title: MED12 and HMGA2 mutations: two independent genetic events in uterine leiomyoma and leiomyosarcoma.
abstract: Recent identification of somatic MED12 mutations in most uterine leiomyomas brings a new venue for the study of the tumorigenesis of leiomyomas. We are particularly interested in the correlation of MED12 and HMGA2 gene products in leiomyomas and leiomyosarcomas with and without MED12 mutations. To address these issues, in this study we examined MED12 mutations in a large cohort of usual type leiomyomas (178 cases) and uterine leiomyosarcomas (32 cases). We found that 74.7% (133/178) of leiomyomas had MED12 mutations, which was consistent with several independent studies. In contrast, only 9.7% (3/32) of leiomyosarcomas harbored MED12 mutations. Expression analysis by western blot and immunohistochemistry revealed that those leiomyomas with complex MED12 mutations had significantly lower protein products than the matched myometrium. Interestingly, most leiomyosarcomas without MED12 mutations also had very low levels of MED12 expression in comparison to the matched myometrium. These findings suggest a potential functional role of MED12 in both benign and malignant uterine smooth muscle tumors. When we further examined HMGA2 expression in all leiomyomas and leiomyosarcomas, we found that HMGA2 overexpression was exclusively present in those leiomyomas with no MED12 mutation, accounting for 10.1% (18/178) of total leiomyomas and 40% (18/45) of non-MED12 mutant leiomyomas. Twenty-five percent (8/32) of leiomyosarcomas had HMGA2 overexpression, and no MED12 mutations were found in HMGA2 positive leiomyosarcoma. These findings strongly suggest that MED12 mutations and HMGA2 overexpression are independent genetic events that occur in leiomyomas, and they may act differently in the tumorigenesis of uterine leiomyomas.
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Bertsch
authors.affiliation: Department of Gynecology and Obstetrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Wenan
authors.initials: W
authors.lastname: Qiang
authors.affiliation: 1] Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA [2] Department of Gynecology and Obstetrics, Shandong University, Jinan, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Gynecology and Obstetrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Margarita
authors.initials: M
authors.lastname: Espona-Fiedler
authors.affiliation: Department of Gynecology and Obstetrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Stacy
authors.initials: S
authors.lastname: Druschitz
authors.affiliation: Department of Gynecology and Obstetrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pathology, Longue Medical School, New York University, New York, NY, USA.
authors.forename: Khush
authors.initials: K
authors.lastname: Mittal
authors.affiliation: Department of Gynecology and Obstetrics, Shandong University, Jinan, China.
authors.forename: Beihua
authors.initials: B
authors.lastname: Kong
authors.affiliation: Department of Gynecology and Obstetrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kurita
authors.affiliation: 1] Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA [2] Department of Gynecology and Obstetrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Wei
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics*; D015153:Blotting, Western; D004252:DNA Mutational Analysis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D025743:HMGA2 Protein / Q000032:analysis* / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D007889:Leiomyoma / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D007890:Leiomyosarcoma / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D056892:Mediator Complex / Q000032:analysis / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D014178:Translocation, Genetic; D015854:Up-Regulation; D014594:Uterine Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D025743:HMGA2 Protein; C460107:MED12 protein, human; D056892:Mediator Complex