MED12 Alterations in Both Human Benign and Malignant Uterine Soft Tissue Tumors

Abstract

The relationship between benign uterine leiomyomas and their malignant counterparts, i.e. leiomyosarcomas and smooth muscle tumors of uncertain malignant potential (STUMP), is still poorly understood. The idea that a leiomyosarcoma could derive from a leiomyoma is still controversial. Recently MED12 mutations have been reported in uterine leiomyomas. In this study we asked whether such mutations could also be involved in leiomyosarcomas and STUMP oncogenesis. For this purpose we examined 33 uterine mesenchymal tumors by sequencing the hot-spot mutation region of MED12. We determined that MED12 is altered in 66.6% of typical leiomyomas as previously reported but also in 11% of STUMP and 20% of leiomyosarcomas. The mutated allele is predominantly expressed in leiomyomas and STUMP. 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. All these tumors without protein expression exhibit complex genomic profiles. No mutations and no expression loss were identified in an additional series of 38 non-uterine leiomyosarcomas. MED12 mutations are not exclusive to leiomyomas but seem to be specific to uterine malignancies. A previous study has suggested that MED12 mutations in leiomyomas could lead to Wnt/β-catenin pathway activation however our immunohistochemistry results show that there is no association between MED12 status and β-catenin nuclear/cytoplasmic localization. Collectively, our results show that subgroups of benign and malignant tumors share a common genetics. We propose here that MED12 alterations could be implicated in the development of smooth muscle tumor and that its expression could be inhibited in malignant tumors.

Exploring chromosomal abnormalities and genetic changes in uterine smooth muscle tumors

“…28,29 Frequent loss of heterozygosity particularly for chromosomes 10 and 13 has been described. 30,31 Recently, the first recurrent somatic mutations of the Mediator Subcomplex 12 gene (MED12) have been demonstrated in benign and malignant uterine 32,33 and extrauterine smooth muscle tumors 34 indicating that MED12 mutations have a crucial role in tumors with smooth muscle differentiation. In addition, Fumarate Hydratase (FH)-deletions and rearrangements of high motility group protein 2 (HMGA2) have been proposed as independent somatic driver mutations in leiomyoma.…”

MED12 mutations in human diseases

“…Some mutations in leiomyoma are also found in leiomyosarcoma, though the mutations seem rare in malignant tumors (Perot et al, 2012). Moreover, MED12 is expressed in all typical leiomyoma but in only 60% of atypical leiomyoma, 50% of STUMP and 20% of leiomyosarcoma (Perot et al, 2012). These results implicate that while not all leiomyosarcoma and STUMP develop from leiomyomas, a subset of leiomyoma has the potential for malignant progression.…”

“…These results suggest that the MED12 mutation might be involved in the activation of the Wnt pathway that activates β-catenin, which is known to cause leiomyoma-like lesions in a mouse model. However, immunohistochemistry results showed that there is no correlation between MED12 status and β-catenin nuclear/cytoplasmic localization (Perot et al, 2012;Islam et al, 2013). Therefore, detailed mechanism for how MED12 mutations induce uterine leiomyoma awaits further investigation.…”

“…Analyses of the status of MED12 in leiomyosarcoma and STUMP should help to address whether they develop from leiomyoma. Studies on a hot spot region of MED12 in thirty-three patients suffering uterine stromal tumor revealed that 66.6% of typical uterine leiomyomas patients had MED12 mutations, but only 11% of STUMP patients and 20% of uterine leiomyosarcoma patients had MED12 mutations (Perot et al, 2012). Some mutations in leiomyoma are also found in leiomyosarcoma, though the mutations seem rare in malignant tumors (Perot et al, 2012).…”

“…Studies on a hot spot region of MED12 in thirty-three patients suffering uterine stromal tumor revealed that 66.6% of typical uterine leiomyomas patients had MED12 mutations, but only 11% of STUMP patients and 20% of uterine leiomyosarcoma patients had MED12 mutations (Perot et al, 2012). Some mutations in leiomyoma are also found in leiomyosarcoma, though the mutations seem rare in malignant tumors (Perot et al, 2012). Moreover, MED12 is expressed in all typical leiomyoma but in only 60% of atypical leiomyoma, 50% of STUMP and 20% of leiomyosarcoma (Perot et al, 2012).…”