In order to elucidate molecular and genetic mechanisms responsible for the increased prevalence and morbidity associated with UL in black women, clinical, pathologic, cytogenetic, and select molecular profiling (MED12 mutation analysis) of 75 self-reported black women undergoing surgical treatment for UL was performed.
Interestingly all classical leiomyomas exhibit MED12 protein expression while 40% of atypical leiomyomas, 50% of STUMP and 80% of leiomyosarcomas (among them the two mutated ones) do not express MED12.
Most genetically mutated tumors (27/30; 90%) demonstrated only one type of genetic change, highlighting that even single allele change in MED12 can have profound impact in transforming the normal uterine myometrium to leiomyomas.
Mutations in the N-terminus of MED12 protein occur at high frequency in uterine leiomyomas and breast fibroepithelial tumours, and are frequently found in chronic lymphocytic leukaemia (CLL).
Normal myometrial stem cells may be transformed into tumor-initiating stem cells, causing UFs, due to unknown causes of somatic mutations in MED12, found in up to 85% of sporadically formed UFs.
On the basis of this finding, we suggest that the MED12 status stratifies the ULs into two mutually exclusive pathways of leiomyoma genesis, one with IGF-2 overexpression and the other with no IGF-2 activation.
Our results confirm the findings of similar recent studies and further show that pelvic and retroperitoneal leiomyomas harbor an increased frequency of MED12 mutations (34%) as compared with other extrauterine sites (0%; P = 0.0006), and that histologically unremarkable adjacent myometrium can harbor similar MED12 mutations.
Our results revealed that hsa_circ_0060927 was ectopically expressed in 33.33% of ULM tissues; although, this expression was independent of the MED12 mutation profile in the ULM samples.
Our study defined the proteome of uterine fibroids and identified that increased ECM protein expression, in particular periostin, is a hallmark of uterine fibroids regardless of MED12 mutation status.
Our study suggests that the MED12 mutations play unique roles in the pathogenesis of uterine leiomyomas and mutated MED12 could be therapeutically targeted in uterine leiomyomas.
RAD51 paralog B (RAD51B), the preferential translocation partner of HMGA2, was up-regulated in MED12 mutant lesions, suggesting a role for this gene in the genesis of leiomyomas.
Rather, a 51-nucleotide deletion mutation including partial exon 2 of mediator complex subunit 12 (MED12), a gene commonly mutated in leiomyoma, breast fibroadenoma and phyllodes tumor, was identified.
Recently, we discovered through exome sequencing that as many as 70% of uterine leiomyomas harbour specific mutations in exon 2 of mediator complex subunit 12 (MED12).
Somatic fibroid-causing mutations in mediator complex subunit 12 (MED12), the most frequent genetic alterations in UFs (up to 85% of tumors), are implicated in transforming normal myometrial stem cells (MSCs) into tumor-forming cells, though the underlying mechanism(s) leading to these mutations remains unknown.
Specific somatic MED12 mutations in prostate cancer and uterine leiomyomas accumulate in two separate regions of the gene and promote tumorigenesis through clearly distinct mechanisms.
The complete lack of novel driver point mutations in the examined series highlights the unique role of MED12 mutations in genesis of uterine leiomyomas, and suggests that these mutations alone may be sufficient for tumor development.
The DEGs in the MED12 mutation and wild-type leiomyoma samples, and common DEGs were defined as group A, B and C. Gene Ontology (GO) and pathway enrichment analyses were performed using the Database for Annotation, Visualization and Integrated Discovery online tool.
The discovery of MED12 involvement in leiomyoma genesis has dramatically contributed to increasing our knowledge on leiomyomas, but many questions remain.
The fibroadenoma MED12 mutation spectrum is nearly identical to that of previously reported MED12 lesions in uterine leiomyoma but not those of other tumors.