ReviewMED12 and uterine smooth muscle oncogenesis: State of the art and perspectives
Section snippets
MED12 and uterine leiomyomas
The link between MED12 mutations and uterine leiomyoma was first described by Mäkinen et al. in 2011 [1] by exome sequencing analysis of a series of 18 uterine leiomyomas. In a larger series with an additional 207 formalin-fixed and paraffin-embedded uterine leiomyomas, MED12 was mutated in 159/225 (70%) cases [1].
MED12, a 45-exon gene located on chromosome Xq13 [2] is a subunit of the Mediator multiprotein complex with 30 subunits, an evolutionary-conserved regulator of transcription acting as
MED12 in other uterine tumours (leiomyosarcomas and STUMP)
MED12 mutations are not restricted to benign smooth muscle tumours. Between 2% and 30% of uterine leiomyosarcomas reported in literature harbour MED12 mutations [30], [40], [41], [43], [47], [48], [49], [50] (Table 2). All except one [48] have been reported to be heterozygous and the mutated allele was expressed [40]. The presence of exon 2 MED12 mutations in up to 30% of uterine leiomyosarcomas may be a potential filiation between leiomyoma and leiomyosarcoma in some cases. Nevertheless,
MED12 in extra-uterine smooth muscle tumours
MED12 mutations were also reported in leiomyoma outside of the uterus (Table 1) [30], [48], [49], [50]. Among the 15 cases of MED12-mutated extra-uterine leiomyoma reported in the literature, 12 were point mutations [30], [50] and three were deletions [30], [50]. Even if the authors did not specify the oestrogen and progesterone receptor status or the WT-1 expression, the presence of MED12 mutations in these tumours suggests a Müllerian origin, as Schwetye et al. [50] argued, or the result of
MED12 in other miscellaneous tumours (benign and malignant)
MED12 mutations in tumours other than uterine leiomyoma are very rare (Table 3). Only 0.3% (1/389) [44] to 0.5% (2/392) [48] of colorectal tumours harboured MED12 mutations, suggesting that this is not a driver but a passenger mutation [44]. Five per cent (6/111) of prostate cancers harbours MED12 mutations but in a different codon [53], [54]. No MED12 mutations have been detected in breast and ovarian (two hormonal sensitive organs) [47], haematologic malignancies or other carcinomas [44].
MED12 in myometrium
Discordant data have been until reported in literature: while three papers did not find MED12 mutations in adjacent myometrium [33], [34], [41] a paper reported 15% (2/13) of mutated cases [50] (Table 1). The two MED12 alterations included a single nucleotide base-pair change in codon 44 and a small deletion around codon 40 [50]. The presence of MED12 mutations in normal myometrium could suggest a role of MED12 mutations in preneoplastic, normal myometrium [50]. Nevertheless, given the
The role of MED12 in tumourigenesis and related pathways
By affinity purification-mass spectrometry and western blot analysis Turunen et al. [46] demonstrated that mutated MED12 shows a minor binding affinity with Cdk8 and Cyclin C compared to wild type MED12. The ultimate consequence is the absence of inhibition of the transcription.
The pivotal role of MED12 (and the consequences of its mutation) in leiomyoma tumourigenesis is outlined by the absence of mutations in the other compounds of the Mediator complex. In a series of 70 MED12-negative
Conclusions and perspectives
Even if the discovery of MED12 mutations in leiomyoma has considerably improved our understanding on leiomyoma genesis, many questions remain. In particular, the relationship between MED12 mutations and uterine leiomyosarcoma and the lack of expression (by western blot or IHC) in most leiomyosarcoma is not correlated with mutational status. Additional studies are required to investigate the regulatory mechanism of MED12 expression as a repressor of transcription and inhibitor of translation.
Conflict of interest statement
None declared.
Acknowledgements
We thank Pippa Mckelvie-Sebileau and Jone Iriondo–Alberdi for medical writing assistance in English.
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2020, PathologyCitation Excerpt :MED12 mutations also frequently occur in benign smooth muscle tumours from the Müllerian system other than uterus and peritoneal/pelvic sites, but rarely in extra-pelvic sites.6 However, MED12 mutations are less frequently detected in uterine leiomyosarcomas (up to 30%), smooth muscle uterine tumours with uncertain malignant potential (STUMP) (approximately 10%) and some leiomyoma variants, such as cellular leiomyoma (8.96%), atypical leiomyoma (16.67%), mitotically active leiomyoma (38.46%) and leiomyomas from hereditary leiomyomatosis with renal cell carcinoma (HLRCC) (8.82%).6–8,14 In this study we demonstrated a high prevalence of MED12 mutations in concurrent common uterine leiomyomas (50%).