Uterine
leiomyomas, or
fibroids, are the most common human
tumors. Based on histopathology, they can be divided into common
leiomyomas and various relatively rare subtypes that mimic
malignancy in one or more aspects. Recently, we showed that exon 2 of
mediator complex subunit 12 (MED12) is mutated in up to 70% of common
fibroids. To investigate the frequency of MED12 exon 2 mutations in histopathological uterine
leiomyoma variants, we screened altogether 206 lesions, including 69 histopathologically common
leiomyomas, 59 cellular (23 cellular and 36 highly cellular), 18 atypical and 26 mitotically active
leiomyomas, as well as 34
uterine fibroid samples from 14
hereditary leiomyomatosis and renal cell cancer patients with a heterozygous germ line mutation in
fumarate hydratase (FH). The uterine
leiomyoma variants harbored MED12 exon 2 mutations significantly less frequently than common
leiomyomas (P=2.93 × 10(-8)). In all, 6 mutations were detected among cellular
fibroids (6/67; 8.96%), 3 among atypical
fibroids (3/18; 16.67%) and 10 among mitotically active
fibroids (10/26; 38.46%). Only mitotically active
fibroids displayed a mutation frequency that was not statistically different from common
leiomyomas (P=0.11). Three MED12 exon 2 mutations were detected among 34
tumors with a heterozygous germ line FH mutation (P=5.28 × 10(-7)). None of these
tumors displayed biallelic inactivation of FH. Our results suggest that MED12 mutation positivity is a key characteristic of common
leiomyomas. Cellular and atypical
fibroids, in particular, may arise through different molecular mechanisms. The results also propose that MED12 and biallelic FH mutations may be mutually exclusive.