MED12 Mutations and Fumarate Hydratase Inactivation in Uterine Adenomyomas

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.