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MED12 mutations and fumarate hydratase inactivation in uterine adenomyomas.
Hum Reprod Open. 2018; 2018(4):hoy020.HR

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 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.

Authors+Show Affiliations

Research Programs Unit, Genome-Scale Biology Research Program and Medicum, Department of Medical and Clinical Genetics., FIN-00014 University of Helsinki, Helsinki, Finland.Research Programs Unit, Genome-Scale Biology Research Program and Medicum, Department of Medical and Clinical Genetics., FIN-00014 University of Helsinki, Helsinki, Finland. Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.Research Programs Unit, Genome-Scale Biology Research Program and Medicum, Department of Medical and Clinical Genetics., FIN-00014 University of Helsinki, Helsinki, Finland.Research Programs Unit, Genome-Scale Biology Research Program and Medicum, Department of Medical and Clinical Genetics., FIN-00014 University of Helsinki, Helsinki, Finland.Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.Research Programs Unit, Genome-Scale Biology Research Program and Medicum, Department of Medical and Clinical Genetics., FIN-00014 University of Helsinki, Helsinki, Finland.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30895261

Citation

Heikkinen, Tuomas, et al. "MED12 Mutations and Fumarate Hydratase Inactivation in Uterine Adenomyomas." Human Reproduction Open, vol. 2018, no. 4, 2018, pp. hoy020.
Heikkinen T, Äyräväinen A, Hänninen J, et al. MED12 mutations and fumarate hydratase inactivation in uterine adenomyomas. Human reproduction open. 2018;2018(4):hoy020.
Heikkinen, T., Äyräväinen, A., Hänninen, J., Ahvenainen, T., Bützow, R., Pasanen, A., & Vahteristo, P. (2018). MED12 mutations and fumarate hydratase inactivation in uterine adenomyomas. Human Reproduction Open, 2018(4), hoy020. https://doi.org/10.1093/hropen/hoy020
Heikkinen T, et al. MED12 Mutations and Fumarate Hydratase Inactivation in Uterine Adenomyomas. Human reproduction open. 2018;2018(4):hoy020. PubMed PMID: 30895261.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - MED12 mutations and fumarate hydratase inactivation in uterine adenomyomas. AU - Heikkinen,Tuomas, AU - Äyräväinen,Anna, AU - Hänninen,Janne, AU - Ahvenainen,Terhi, AU - Bützow,Ralf, AU - Pasanen,Annukka, AU - Vahteristo,Pia, Y1 - 2018/11/17/ PY - 2018/07/02/received PY - 2018/10/09/revised PY - 2018/10/26/accepted PY - 2019/3/22/entrez PY - 2019/3/22/pubmed PY - 2019/3/22/medline KW - FH KW - HLRCC KW - HMGA2 KW - MED12 mutations KW - fumarate hydratase KW - hereditary leiomyomatosis and renal cell cancer KW - high mobility group AT-hook KW - immunohistochemistry KW - mediator complex subunit 12 KW - uterine adenomyoma KW - uterine leiomyoma SP - hoy020 EP - hoy020 JF - Human reproduction open VL - 2018 IS - 4 N2 - 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. SN - 2399-3529 UR - https://www.unboundmedicine.com/medline/citation/30895261/MED12_mutations_and_fumarate_hydratase_inactivation_in_uterine_adenomyomas_ L2 - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/30895261/ DB - PRIME DP - Unbound Medicine ER -