Characterization of MED12, HMGA2, and FH alterations reveals molecular variability in uterine smooth muscle tumors

Molecular Cancer

Ralf Bützow¹  Norma Frizzell²  Pia Vahteristo³  Kati Kämpjärvi³  Netta Mäkinen³ 

[1] Department of Pathology, Laboratory of Helsinki University Hospital (HUSLAB), Helsinki University Hospital and Medicum, FIN-00014 University of Helsinki;Department of Pharmacology, Physiology and Neuroscience, USC School of Medicine, University of South Carolina;Research Programs Unit, Genome-Scale Biology Research Program and Medicum, Department of Medical and Clinical Genetics, FIN-00014 University of Helsinki;

关键词: Uterine leiomyoma;    Histopathological uterine leiomyoma variants;    Uterine leiomyosarcoma;    MED12;    HMGA2;    FH;   

DOI  :  10.1186/s12943-017-0672-1

来源: DOAJ

【 摘 要 】

Abstract Uterine smooth muscle tumors range from benign leiomyomas to malignant leiomyosarcomas. Based on numerous molecular studies, leiomyomas and leiomyosarcomas mostly lack shared mutations and the majority of tumors are believed to develop through distinct mechanisms. To further characterize the molecular variability among uterine smooth muscle tumors, and simultaneously insinuate their potential malignant progression, we examined the frequency of known genetic leiomyoma driver alterations (MED12 mutations, HMGA2 overexpression, biallelic FH inactivation) in 65 conventional leiomyomas, 94 histopathological leiomyoma variants (18 leiomyomas with bizarre nuclei, 22 cellular, 29 highly cellular, and 25 mitotically active leiomyomas), and 51 leiomyosarcomas. Of the 210 tumors analyzed, 107 had mutations in one of the three driver genes. No tumor had more than one mutation confirming that all alterations are mutually exclusive. MED12 mutations were the most common alterations in conventional and mitotically active leiomyomas and leiomyosarcomas, while leiomyomas with bizarre nuclei were most often FH deficient and cellular tumors showed frequent HMGA2 overexpression. Highly cellular leiomyomas displayed the least amount of alterations leaving the majority of tumors with no known driver aberration. Our results indicate that based on the molecular background, histopathological leiomyoma subtypes do not only differ from conventional leiomyomas, but also from each other. The presence of leiomyoma driver alterations in nearly one third of leiomyosarcomas suggests that some tumors arise through leiomyoma precursor lesion or that these mutations provide growth advantage also to highly aggressive cancers. It is clinically relevant to understand the molecular background of various smooth muscle tumor subtypes, as it may lead to improved diagnosis and personalized treatments in the future.

【 授权许可】

Unknown