Abstract
Mediator Subcomplex 12 (MED12) is part of the transcriptional preinitiation machinery. Mutations of its gene predominantly occur in two types of highly frequent benign tumors, uterine leiomyomas and fibroadenomas of the breast, where they apparently act as driver mutations. Nevertheless, their presence is not restricted to benign tumors having been found at considerable frequencies in uterine leiomyosarcomas, malignant phyllodes tumors, and chronic lymphocytic leukemia also. Most of the mutations are located within exon 2 of the gene but in rare cases the intron 1/exon 2 boundary or exon 1 are affected. As to their type, predominantly single nucleotide exchanges with a hotspot in one codon are found, but small deletions clustering around that hotspot also are not uncommon. According to their presumed classification as gain-of-function mutations, these latter deletions are leaving the open reading frame intact. As to the types of mutations, so far no apparent differences between the tumor entities affected have emerged. Interestingly, this pattern with small deletions clustered around the hotspot of single nucleotide exchanges resembles that seen as a result of targeted gene editing. In contrast to other driver mutations the percentage of MED12-mutation positive tumors of independent clonal origin increases with the number of tumors per patient suggesting unknown etiological factors supporting site specific mutagenesis. These factors may act by inducing simultaneous site-specific double strand breaks the erroneous repair of which may lead to corresponding mutations. As inducers of DNA damage and its repair such as foreign nucleic acids of the microbiome displaying sequence homology to the putative target site might play a role. Interestingly, a 16 base pair homology of the hotspot to a putative terminator base-paired hairpin sequence of a Staphylococcus aureus tRNA gene cluster has been noted which might form R-loop like structures with its target sequence thus inducing said changes.
Highlights
The most common mutation in human tumors does not affect one of the famous suspects in the field (for review see (Vogelstein et al, 2013)) but the much less well-known gene encoding Mediator Subcomplex 12 (MED12)
As in the benign tumors, mutations of that gene occur as apparent driver mutations in a predominant subset of uterine leiomyomas (Mäkinen et al, 2011; Markowski et al, 2012; McGuire et al, 2012), constituting the by far most frequent human symptomatic tumors of all. These mutations are found in a large subset of fibroadenomas of the breast (Lim et al, 2014; Piscuoglio et al, 2015; Yoshida et al, 2015), another frequent benign tumor which occurs predominantly in young and middle-aged women
Apart from solid tumors, MED12 mutations recently were detected in a significant percentage of roughly 5–9% of chronic lymphocytic leukemias (CLL) (Guièze et al, 2015; Kämpjärvi et al, 2015; Wu et al, 2017a)
Summary
The most common mutation in human tumors does not affect one of the famous suspects in the field (for review see (Vogelstein et al, 2013)) but the much less well-known gene encoding Mediator Subcomplex 12 (MED12). Keywords Mediator subcomplex 12 (MED12), mutations, uterine leiomyomas, fibroadenomas of the breast, chronic lymphocytic leukemia (CLL), multiple tumors, DNA-RNA hybrids, Staphylococcus aureus
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