................................................................................................................................................... 7 REVIEW OF THE LITERATURE .............................................................................................................. 9 1. UTERINE LEIOMYOMAS ....................................................................................................................... 9 1.1. Epidemiology ............................................................................................................................ 9 1.2. Clinical course ........................................................................................................................ 10 1.3. Histopathology ........................................................................................................................ 13 2. TUMORIGENESIS ................................................................................................................................ 14 2.1. Leiomyomagenesis ................................................................................................................. 15 2.2. Genetics of leiomyomas .......................................................................................................... 17 2.2.1. Genetic predisposition ..................................................................................................................... 17 2.2.2. Somatic chromosomal aberrations .................................................................................................. 18 2.2.3. High mobility group AT-hook 2 (HMGA2) ...................................................................................... 19 2.2.4. Fumarate hydratase (FH) ................................................................................................................ 19 2.2.5. Mediator complex subunit 12 (MED12) .......................................................................................... 20 AIMS OF THE STUDY ............................................................................................................................... 22 MATERIALS AND METHODS ................................................................................................................. 23 1. ETHICS APPROVAL (I-IV) .................................................................................................................. 23 2. SAMPLES (I-IV) ................................................................................................................................. 23 3. MUTATION SCREENING (I-IV) ........................................................................................................... 24 4. HMGA2 QPCR (IV) .......................................................................................................................... 25 5. GENE EXPRESSION DATA (IV) ........................................................................................................... 25 6. METABOLOMIC PROFILING (IV) ........................................................................................................ 25 7. STATISTICAL ANALYSES (I-IV) ......................................................................................................... 26 RESULTS ...................................................................................................................................................... 28 1. MED12 MUTATIONS IN LEIOMYOMAS (I-III) .................................................................................... 28 1.1. MED12 mutations in different sample series (I-III) ............................................................... 28 1.2. MED12-mutation status and clinical characteristics (I-III)................................................... 28 2. METABOLOMIC PROFILE OF LEIOMYOMAS (IV) ................................................................................ 30 DISCUSSION ................................................................................................................................................ 34 1. MED12 MUTATIONS IN TUMORIGENESIS .......................................................................................... 34 1.1. MED12 mutations in leiomyomas and other neoplasms ........................................................ 34 1.2. MED12 mutations and clinical features ................................................................................. 37 1.3. Tumorigenic mechanism of MED12 mutations ...................................................................... 38 2. METABOLOMIC ALTERATIONS IN LEIOMYOMAS ................................................................................ 40