MED12 mutations and fumarate hydratase inactivation in uterine adenomyomas

Abstract

STUDY QUESTION Do the uterine leiomyoma driver events – mediator complex subunit 12 ( MED12 ) mutations, high mobility group AT-hook (HMGA2) overexpression, and fumarate hydratase (FH) inactivation – also contribute to the development of uterine adenomyomas? SUMMARY ANSWER MED12 mutations and FH deficiency occur in a subset of uterine adenomyomas, but at lower frequencies than in leiomyomas. WHAT IS KNOWN ALREADY Uterine adenomyomas are benign tumours with clinical features very similar to uterine leiomyomas. Mutations affecting MED12 , HMGA2 and FH account for up to 80–90% of leiomyomas, but their contribution to adenomyomas is not known. STUDY DESIGN, SIZE, DURATION Formalin-fixed paraffin-embedded adenomyoma samples from 21 patients operated on during 2012–2014 were collected at the pathology department’s archives and analysed for uterine leiomyoma driver events. PARTICIPANTS/MATERIALS, SETTING, METHODS Adenomyoma diagnoses were verified by a specialized pathologist and representative areas were marked on haematoxylin-eosin slides. DNA was extracted from the tissue samples and sequenced to detect mutations in MED12 . Expression levels of HMGA2 and 2SC, a robust indirect method to detect FH inactivation, were analysed by immunohistochemistry (IHC). The coding region of FH was sequenced in one adenomyoma sample showing strong 2SC staining as well as in the same patient’s normal tissue sample. All patients’ medical histories were collected and reviewed. MAIN RESULTS AND THE ROLE OF CHANCE MED12 mutation c.131G > A, p.G44D, the most common mutation in uterine leiomyomas, was identified in two samples (2/21; 9.5%). One adenomyoma displayed strong 2SC positivity and subsequent sequencing revealed a frameshift FH mutation c.911delC, p.P304fs in the tumour. The mutation was also present in the patient’s normal tissue sample, indicating that she has a hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. HMGA2 protein expression was normal in all adenomyomas. LIMITATIONS, REASONS FOR CAUTION Restricted sample size limits the determination of exact mutation frequencies of the studied aberrations in adenomyomas. WIDER IMPLICATIONS OF THE FINDINGS Uterine leiomyoma driver mutations do contribute to the development of some adenomyomas. We also report an adenomyoma in the context of hereditary HLRCC syndrome. Despite clinical similarities, the pathogenic mechanisms of adenomyomas and leiomyomas are likely different. Large-scale genomic analyses are warranted to elucidate the complete molecular background of adenomyomas. STUDY FUNDING/COMPETING INTERE...

Systematic molecular and clinical analysis of uterine leiomyomas from fertile-aged women undergoing myomectomy

“…Mutation screening revealed FH mutations in 8 out of 11 tumours. Four of the mutations have been reported earlier (Heikkinen et al, 2018;Kiuru et al, 2002;Bayley et al, 2008), and in silico predictions for the novel variants indicated three of them to be pathogenic (Kopanos et al, 2019). Limitations of the direct sequencing method in recognizing large deletions, insertions, or changes in the regulatory regions probably explain why a mutation was not identified in the remaining three samples.…”

“…MED12 mutations lead to the uncoupling of Cyclin C and CDK8/19 from the core Mediator, loss of Mediator associated CDK kinase activity, and a unique global gene expression pattern (Mehine et al, 2013;Turunen et al, 2014;Kämpjärvi et al, 2014). In addition to uterine leiomyomas, MED12 mutations have been reported in other female hormone-dependent tumours such as breast fibroadenomas (Chang et al, 2020), phyllodes tumours, and uterine adenomyomas (Heikkinen et al, 2018). Roughly 10% of leiomyomas show high mobility group AT-hook 2 (HMGA2) overexpression.…”

Postmenopausal giant uterine adenomyoma with adipose metaplasia: A case report and literature review

“…It has been shown that DNA mutations in uterine smooth muscle tumors are also found in a subgroup of UAs and that driver mutations contribute to the development of some adenomyomas; however, the pathogenesis may be different, and large-scale genomic analyses are needed to elucidate the complete molecular background of UAs. [12] The diagnosis of UA still requires histopathological examination, in which endometrial glands and mesenchyme are seen microscopically in an insular distribution in the myometrium, and the basal layer of ectopic endometrium usually forms a complex structure of horizontally interconnected glands, which is different from the glands in functional endometrium, which are isolated, unbranched, and longitudinally arranged. However, the gold standard for the histopathologic definition is still controversial.…”

“…It has been shown that DNA mutations in uterine smooth muscle tumors are also found in a subgroup of UAs and that driver mutations contribute to the development of some adenomyomas; however, the pathogenesis may be different, and large-scale genomic analyses are needed to elucidate the complete molecular background of UAs. [12]…”

Pathogenomics of Uterine Fibroids Development

“…Somatic mutations of the MED12 gene are detected in 70%-75% of patients with LM [26,27] and arise de novo directly in myoblasts. In addition to LM cells, MED12 gene mutations also occur in adenomyosis (internal endometriosis) [28] and in mammary adenomyoma cells [25]. When mutations of the MED12 gene occur in ontogeny remains unknown.…”