mutations and fumarate hydratase inactivation in uterine adenomyomas.

STUDY QUESTION

Do the uterine leiomyoma driver events - mediator complex subunit 12 () mutations, high mobility group AT-hook (HMGA2) overexpression, and fumarate hydratase (FH) inactivation - also contribute to the development of uterine adenomyomas?

SUMMARY ANSWER

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 , and 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 . Expression levels of HMGA2 and 2SC, a robust indirect method to detect FH inactivation, were analysed by immunohistochemistry (IHC). The coding region of 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

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 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 INTERESTS: This study was supported by The Academy of Finland, the Sigrid Jusélius Foundation, and the Cancer Society of Finland. The authors declare no conflict of interest.