MED12 mutations in human diseases

Wang, Hua; Qin, Shen; Ye, Lihua; Ye, Jun

doi:10.1007/s13238-013-3048-3

Cited by 23 publications

(18 citation statements)

References 36 publications

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“…MED12 is part of a large multiprotein complex known as the mediator complex, which functions as a protein bridge between transcription factors and RNA polymerase II to initiate transcription (21). This complex also affects later stages of the transcription process, including elongation and termination.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Discussionmentioning

confidence: 99%

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Recurrent PRDM10 Gene Fusions in Undifferentiated Pleomorphic Sarcoma

Hofvander

Tayebwa

Nilsson

et al. 2015

Clinical Cancer Research

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Purpose: Undifferentiated pleomorphic sarcoma (UPS) is defined as a sarcoma with cellular pleomorphism and no identifiable line of differentiation. It is typically a high-grade lesion with a metastatic rate of about one third. No tumor-specific rearrangement has been identified, and genetic markers that could be used for treatment stratification are lacking. We performed transcriptome sequencing (RNA-Seq) to search for novel gene fusions.Experimental design: RNA-Seq, FISH, and/or various PCR methodologies were used to search for gene fusions and rearrangements of the PRDM10 gene in 84 soft tissue sarcomas.Results: Using RNA-Seq, two cases of UPS were found to display novel gene fusions, both involving the transcription factor PRDM10 as the 3 0 partner and either MED12 or CITED2 as the 5 0 partner gene. Further screening of 82 soft tissue sarcomas for rearrangements of the PRDM10 locus revealed one more UPS with a MED12/PRDM10 fusion. None of these genes has been implicated in neoplasia-associated gene fusions before. Conclusions: Our results suggest that PRDM10 fusions are present in around 5% of UPS. Although the fusion-positive cases in our series showed the same nuclear pleomorphism and lack of differentiation as other UPS, it is noteworthy that all three were morphologically low grade and that none of the patients developed metastases. Thus, PRDM10 fusion-positive sarcomas may constitute a clinically important subset of UPS.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Recurrent PRDM10 Gene Fusions in Undifferentiated Pleomorphic Sarcoma

Hofvander

Tayebwa

Nilsson

et al. 2015

Clinical Cancer Research

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“…MED12 is part of the CDK8 module, which, upon activation by cyclin C, phosphorylates the C-terminal domain of the large subunit of RNA polymerase II and inhibits formation of the transcriptional initiation complex. 73 Mice expressing the c.131G > A MED12 mutation in the uterus show uterine hyperplasia, UL-like tumor formation, and genomic instability, demonstrating the importance of this mutation in UL etiology. 74 However, the mechanisms that lead to MED12 mutations in the otherwise quiescent myometrial tissue is still unknown.…”

Section: Cytogenetic Abnormalities In Uterine Leiomyomamentioning

confidence: 99%

Recent Advances in Uterine Fibroid Etiology

2017

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Uterine fibroids, also known as uterine leiomyoma (UL), are monoclonal tumors of the smooth muscle tissue layer (myometrium) of the uterus. Although ULs are considered benign, uterine fibroids are the source of major quality-of-life issues for approximately 25% of all women, who suffer from clinically significant symptoms of UL. Despite the prevalence of UL, there is no treatment option for UL which is long term, cost-effective, and leaves fertility intact. The lack of understanding about the etiology of UL contributes to the scarcity of medical therapies available. Studies have identified an important role for sex steroid hormones in the pathogenesis of UL, and have driven the use of hormonal treatment for fibroids, with mixed results. Dysregulation of cell signaling pathways, miRNA expression, and cytogenetic abnormalities have also been implicated in UL etiology. Recent discoveries on the etiology of UL and the development of relevant genetically modified rodent models of UL have started to revitalize UL research. This review outlines the major characteristics of fibroids; major contributors to UL etiology, including steroid hormones; and available preclinical animal models for UL.

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“…MED12 is a gene on the X chromosome that encodes the Mediator complex subunit 12, which is a multiprotein complex widely involved in transcriptional regulation of gene expression 9. Since our initial publication, there have been additional reports of MED12 mutations in fibroadenomas as well as phyllodes tumours,10–14 with some demonstrating a lower frequency of MED12 mutations in malignant than benign and borderline phyllodes tumours 11 13.…”

Section: Introductionmentioning

confidence: 99%

MED12is frequently mutated in breast phyllodes tumours: a study of 112 cases

Tan

Ong

et al. 2015

J Clin Pathol

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AimTo determine the frequency of MED12 mutations in a series of 112 breast phyllodes tumours, and to correlate the findings with clinicopathological parameters and survival outcomes. Methods Phyllodes tumours from the Department of Pathology, Singapore General Hospital, were classified into benign, borderline and malignant categories. Genomic DNA from formalin-fixed paraffin-embedded phyllodes tumours was extracted, purified and subjected to ultra-deep-targeted amplicon sequencing across exon 2 of the MED12 gene. Sequencing was performed on the Illumina MiSeq next-generation sequencing platform and bioinformatics analysis applied. Appropriate statistical analyses were carried out. Results There were 66 benign, 32 borderline and 14 malignant tumours, with 43 (65.1%), 21 (65.6%) and 6 (42.8%) disclosing MED12 mutations (missense, splice site, indel), respectively. For 97 cases with available follow-up, there were 10 (10.3%) recurrences. Patients with phyllodes tumours that harboured MED12 mutations experienced improved disease-free survivals, with higher recurrence likelihood in those without MED12 mutations (HR 9.99, 95% CIs 1.55 to 64.42, p=0.015). Conclusions Similar to fibroadenomas, phyllodes tumours show a high frequency of MED12 mutations, affirming the close biological relationship between these fibroepithelial neoplasms.

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MED12 mutations in human diseases

Cited by 23 publications

References 36 publications

Recurrent PRDM10 Gene Fusions in Undifferentiated Pleomorphic Sarcoma

Recurrent PRDM10 Gene Fusions in Undifferentiated Pleomorphic Sarcoma

Recent Advances in Uterine Fibroid Etiology

MED12is frequently mutated in breast phyllodes tumours: a study of 112 cases

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