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MED12 mutations and fumarate hydratase inactivation in uterine adenomyomas
Tuomas Heikkinen1, Anna Äyräväinen1,2, Janne Hänninen1
1Research Programs Unit, Genome-Scale Biology Research Program and Medicum, Department of Medical and Clinical Genetics., FIN-00014 University of Helsinki, Helsinki, Finland.
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 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.
Insights
Mediator complex subunit 12 (MED12) mutations and fumarate hydratase (FH) deficiency are found in some uterine adenomyomas, though less frequently than in uterine leiomyomas. These findings suggest distinct molecular pathways for these similar-appearing tumors.
Area of Science:
- Gynecologic pathology
- Molecular oncology
- Uterine tumors
Background:
- Uterine adenomyomas and leiomyomas share clinical similarities but have unknown etiological links.
- Key driver events in leiomyomas include MED12 mutations, HMGA2 overexpression, and FH inactivation.
- The contribution of these leiomyoma driver events to adenomyoma development remains uncharacterized.
Purpose of the Study:
- To investigate the presence and frequency of uterine leiomyoma driver events in uterine adenomyomas.
- To determine if MED12 mutations, HMGA2 overexpression, or FH inactivation contribute to adenomyoma pathogenesis.
- To explore potential molecular differences between adenomyomas and leiomyomas.
Main Methods:
- Analysis of 21 formalin-fixed paraffin-embedded adenomyoma samples.
- MED12 mutation detection via DNA sequencing.
- Immunohistochemistry (IHC) for HMGA2 expression and 2SC staining (as a marker for FH inactivation).
- FH gene sequencing in samples with strong 2SC positivity.
Main Results:
- MED12 mutations were identified in 9.5% (2/21) of adenomyoma samples.
- One adenomyoma showed strong 2SC positivity, linked to a frameshift FH mutation, indicating hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome.
- Normal HMGA2 protein expression was observed in all adenomyomas.
Conclusions:
- MED12 mutations and FH deficiency occur in a subset of uterine adenomyomas, albeit at lower frequencies than in leiomyomas.
- The study identified an adenomyoma associated with hereditary HLRCC syndrome.
- Distinct pathogenic mechanisms likely underlie adenomyomas and leiomyomas, necessitating further large-scale genomic studies.
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