MED12 mutations in leiomyosarcoma and extrauterine leiomyoma

Abstract

Leiomyoma and leiomyosarcoma share morphological features and smooth muscle differentiation, and both arise most frequently within the uterine corpus of middle-aged women. However, they are considered biologically unrelated tumors due to their disparate clinical, cytogenetic, and molecular features. MED12, the mediator complex subunit 12 gene, has been recently implicated as an oncogene in as many as 70% of sporadic uterine leiomyoma. In the present study, we show MED12 hotspot exon 2 mutations in extrauterine leiomyoma (3 of 19 cases) and in leiomyosarcoma (3 of 13 uterine cases). We also show that MED12 mutations are found in both primary and metastatic leiomyosarcoma. Immunoblotting studies demonstrated MED12 protein expression in 100% of leiomyomas (13) Keywords: fibroid; leiomyoma; leiomyosarcoma; MED12; oncogene; smooth muscle tumor; uterus Seventy percent of women in the general population develop uterine leiomyomas, 1 and B25% of women experience substantial symptoms from these tumors, leading to over 200 000 hysterectomies annually in the United States. 1 By contrast, uterine leiomyosarcomas are infrequent, with an estimated incidence of 0.64 per 100 000 women. Nonetheless, uterine leiomyosarcomas are among the most common sarcomas, accounting for 2-5% of tumors of the uterine body. [2][3][4] There is substantial morphological overlap between leiomyoma and low-grade spindle cell leiomyosarcoma, and diagnostic distinction between these entities relies on histopathological criteria, including nuclear atypia, mitotic activity, and tumor cell necrosis. 5 Morphological variants and unusual features can further complicate the diagnosis between leiomyoma versus leiomyosarcoma, as in smooth muscle tumors of uncertain malignant potential that cannot be unequivocally classified as benign or malignant. 6 Recently, somatic mutations affecting MED12 (the mediator complex subunit 12 gene) were discovered in B70% of sporadic uterine leiomyoma. 7,8 Mediator is a modular protein complex of 25 subunits that regulates RNA polymerase II-mediated transcription, thereby orchestrating cell development and survival in cooperation with CDK8. 9,10 MED12 is located on chromosome sub-band Xq13.1 and is composed of 45 exons, although all MED12 mutations thus far described in uterine leiomyoma have affected exon 2 exclusively, with mutation hotspots in codons 36-44.In the present study, we analyzed leiomyomas and leiomyosarcomas of various biological behaviors and anatomical locations to better determine the relevance of MED12 exon 2 mutations across a broad spectrum of smooth muscle neoplasia. In these studies, we also determined whether MED12 expression is dysregulated in smooth muscle neoplasia compared with a normal myometrium control. These studies demonstrate that MED12 mutations are the first known oncogenic mechanism shared by uterine and extrauterine leiomyoma and uterine leiomyosarcoma.

Exploring chromosomal abnormalities and genetic changes in uterine smooth muscle tumors

“…34 Sequencing of exon 2 of the MED12 gene, where the most frequently mutated codon 44 is located, revealed mutations in 47% of cases in the leiomyoma group in our study. This is in concordance with the literature reporting MED12 mutations in frequencies between 48 and 92%.…”

“…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 and uterine smooth muscle oncogenesis: State of the art and perspectives

“…Oncogenic mutations in exon 2 of the MED12 subunit [1] represent the most common genetic anomaly in leiomyoma, occurring in 37% [30] to 85.5% [31] (mean 64%) of uterine leiomyoma (Table 1), irrespective of ethnicity [32,33]. Together with HMGA (high mobility group AT-hook) 1 and 2 alterations, they may account for 80-90% of all uterine leiomyomas.…”

“…Of note, MED12 mutational status does not correlate with protein expression in particular in uterine leiomyoma [30,40,43]. Perot et al found MED12 protein expression by immunohistochemistry (IHC) in both MED12 mutated (6/9) and MED12 wild type uterine leiomyomas [40].…”

No REST for fibroids

“…Somatic mutations are present in MED12 in sporadic leiomyoma and are present in between 37% and 70% of samples analyzed (12)(13)(14), providing ample evidence to suggest a role of MED12 as a potential oncogene. Importantly, these mutations are shared by uterine leiomyoma and uterine leiomyosarcoma (14), which clinically are considered very different diseases.…”