MED12 mutations in uterine fibroids—their relationship to cytogenetic subgroups

Abstract

Recurrent chromosomal alterations are found in roughly 20% of all uterine fibroids but in the majority cytogenetic changes are lacking. Recently, mutations of the gene mediator subcomplex 12 (MED12) have been detected in a majority of fibroids but no information is available whether or not they co-occur with cytogenetic subtypes as, e.g., rearrangements of the genes encoding high mobility group AT-hook (HMGA) proteins. In a total of 80 cytogenetically characterized fibroids from 50 patients, we were not only able to confirm the frequent occurrence of MED12 mutations but also to stratify two mutually exclusive pathways of leiomyomagenesis with either rearrangements of HMGA2 reflected by clonal chromosome abnormalities affecting 12q14~15 or by mutations affecting exon 2 of MED12. On average the latter mutations were associated with a significantly smaller tumor size. However, G>A transitions of nucleotides c.130 or c.131 correlate with a significantly larger size of the fibroids compared to other MED12 mutations thus explaining the high prevalence of the former mutations among clinically detectable fibroids. Interestingly, fibroids with MED12 mutations expressed significantly higher levels of the gene encoding wingless-type MMTV integration site family, member 4 (WNT4). Based on these findings and data from the literature, we hypothesize that estrogen and the mutated MED12 cooperate in activating the Wnt pathway which in turn activates b-catenin known to cause leiomyoma-like lesions in a mouse model. The occurrence of a ''fibroid-type mutation'' in a rare histologic subtype of endometrial polyps suggests that this mechanism is not confined to uterine leiomyomas.Uterine leiomyomas (syn.: fibroids) are among the most frequent clinically relevant human tumors leading, e.g., to abdominal pain, bleeding and infertility. Their prevalence clearly differs depending on ethnicity but in most countries exceeds 50% of all women in their reproductive ages.

Integrated data analysis reveals uterine leiomyoma subtypes with distinct driver pathways and biomarkers

“…Some of these rearrangements have been reported to co-occur with MED12 mutations, suggesting that a subset of HMGA1 rearrangements are secondary events (7). Leiomyomas also may harbor recurrent deletions and rearrangements of 7q22, 22q, and 1p (8)(9)(10)(11).…”

“…Leiomyomas also may harbor recurrent deletions and rearrangements of 7q22, 22q, and 1p (8)(9)(10)(11). These deletions co-occur with other genetic alterations and may be secondary driver events, often present only in a subpopulation of tumor cells (4,7,8,(11)(12)(13).…”

MED12 mutations in human diseases

“…They also observed that significantly high levels of wingless-type MMTV integration site family member 4 (WNT4) is expressed in leiomyomas with MED12 mutations (Markowski et al, 2012). These results suggest that the MED12 mutation might be involved in the activation of the Wnt pathway that activates β-catenin, which is known to cause leiomyoma-like lesions in a mouse model.…”

“…It has been reported that in patients suffering from uterine leiomyoma, MED12 mutations are found in stem cells, which leads to unlimited growth and tumor. The mutation sites in MED12 are located in the second exon (Makinen et al, 2011a(Makinen et al, , 2011bJe et al, 2012;Markowski et al, 2012). It was recently reported that the second exon mutation occurs in 52.2% of uterine fi broid patients while the mutation is not found in other tumors (Je et al, 2012), implicating the involvement of MED12 in the disease.…”

“…Markowski et al reported that mutations of MED12 are strongly associated with fibroids not displaying primary karyotypic alterations (Markowski et al, 2012). They also observed that significantly high levels of wingless-type MMTV integration site family member 4 (WNT4) is expressed in leiomyomas with MED12 mutations (Markowski et al, 2012).…”