Somatic MED12 mutations in uterine leiomyosarcoma and colorectal cancer

Abstract

Background:Mediator complex participates in transcriptional regulation by connecting regulatory DNA sequences to the RNA polymerase II initiation complex. 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). In this work, we examined the role of MED12 exon 2 mutations in other tumour types.Methods:The frequency of MED12 exon 2 mutations was analysed in altogether 1158 tumours by direct sequencing. The tumour spectrum included mesenchymal tumours (extrauterine leiomyomas, endometrial polyps, lipomas, uterine leiomyosarcomas, other sarcomas, gastro-intestinal stromal tumours), hormone-dependent tumours (breast and ovarian cancers), haematological malignancies (acute myeloid leukaemias, acute lymphoid leukaemias, myeloproliferative neoplasms), and tumours associated with abnormal Wnt-signalling (colorectal cancers (CRC)).Results:Five somatic alterations were observed: three in uterine leiomyosarcomas (3/41, 7% Gly44Ser, Ala38_Leu39ins7, Glu35_Leu36delinsVal), and two in CRC (2/392, 0.5% Gly44Cys, Ala67Val).Conclusion:Somatic MED12 exon 2 mutations were observed in uterine leiomyosarcomas, suggesting that a subgroup of these malignant tumours may develop from a leiomyoma precursor. Mutations in CRC samples indicate that MED12 may, albeit rarely, contribute to CRC tumorigenesis.

Cyclin-dependent Kinase 8 Module Expression Profiling Reveals Requirement of Mediator Subunits 12 and 13 for Transcription of Serpent-dependent Innate Immunity Genes in Drosophila

“…Furthermore, the finding that Cdk8-CycC can act opposite to Med12-Med13 although being Med12-Med13-dependent indicates that e.g. loss of Med12 could lead to similar phenotypes as gain of Cdk8; both genetic alterations have been noted in human colorectal cancer (13,52). Taken together, these results are consistent with the notion (2, 3, 25) that Cdk8-CycC mediates gene regulation primarily through interaction with Mediator through Med12-Med13, whereas Med12-Med13 can regulate transcription independently of Cdk8-CycC.…”

Recurrent PRDM10 Gene Fusions in Undifferentiated Pleomorphic Sarcoma

“…MED12 regulates the kinase activity of the Cdk8 module and mutations in MED12 are associated with several diseases, including neoplasia. Mutations, especially in exon 2, are found at high frequencies in uterine leiomyoma and fibroadenoma of the breast (25,26), as well as in malignancies, such as colorectal cancer, leiomyosarcoma, and prostate cancer (21,27). CITED2 is a non-DNA-binding transcriptional coactivator that affects the activity of multiple genes by recruiting CBP/p300 to chromatin via the DNA-binding transcription factor AP2.…”

MED12 and uterine smooth muscle oncogenesis: State of the art and perspectives

“…For the most part, MED12 mutations occur in exon 2 (94% [43]), with 71% occurring in the highly-conserved codon 44 [43] (essentially in the region encompassing codons [36][37][38][39][40][41][42][43][44][45][46][47]. In the majority of MED12-mutated cases reported in the literature, mutations were the most frequent alteration (75-90%) followed by deletions (10-25%) [1,40,44].…”