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Systematic molecular and clinical analysis of uterine leiomyomas from fertile-aged women undergoing myomectomy.
Hum Reprod. 2020 Oct 01; 35(10):2237-2244.HR

Abstract

STUDY QUESTION

What are the distributions and associated clinical characteristics of mediator complex subunit 12 (MED12), high mobility group AT-hook 2 (HMGA2) and fumarate hydratase (FH) aberrations in uterine leiomyomas from fertile-aged myomectomy patients?

SUMMARY ANSWER

These driver mutations account for the majority (83%) of tumours in fertile-aged patients.

WHAT IS KNOWN ALREADY

Alterations affecting MED12, HMGA2 and FH account for 80-90% of uterine leiomyomas from middle-aged hysterectomy patients, while the molecular background of tumours from young myomectomy patients has not been systematically studied.

STUDY DESIGN, SIZE, DURATION

A retrospective series of 361 archival uterine leiomyoma samples from 234 women aged ≤45 years undergoing myomectomy in 2009-2014 was examined. Associations between the molecular data and detailed clinical information of the patients and tumours were analysed.

PARTICIPANTS/MATERIALS, SETTING, METHODS

DNA was extracted from formalin-fixed paraffin-embedded samples and MED12 exons 1 and 2 were sequenced to identify mutations. Level of HMGA2 expression was evaluated by immunohistochemistry. Biallelic FH inactivation was analysed with 2-succinylcysteine staining, which is an indirect method of assessing FH deficiency. All patients' medical histories were reviewed, and clinical information of patients and tumours was combined with molecular data.

MAIN RESULTS AND THE ROLE OF CHANCE

The median age at operation was 34 years. The majority (58%) of patients were operated on for a single leiomyoma. Known driver mutations were identified in 83% of tumours (71% MED12; 9% HMGA2; 3% FH). In solitary leiomyomas, the MED12 mutation frequency was only 43%, and 29% were wild-type for all driver alterations. MED12 mutations were associated with multiple tumours, smaller tumour size and subserosal location.

LIMITATIONS, REASONS FOR CAUTION

Although comprehensive, the study is retrospective in nature and all samples have been collected for routine diagnostic purposes. The use of paraffin-embedded samples and immunohistochemistry may have led to an underestimation of mutations. Due to the limited sample size and rarity of especially FH-deficient leiomyomas, the data are partly descriptive.

WIDER IMPLICATIONS OF THE FINDINGS

The contribution of driver mutations in leiomyomas from young myomectomy patients is comparable to tumours obtained from hysterectomies of mostly middle-aged women. Our results support the earlier findings that MED12 mutations are associated with multiple tumours, smaller tumour size and subserosal location. The study emphasizes the distinct molecular background of solitary leiomyomas, and more research is needed to clarify the underlying causes of the notable proportion of wild-type leiomyomas.

STUDY FUNDING/COMPETING INTEREST(S)

The study was supported by the Academy of Finland (307773), the Sigrid Jusélius Foundation, the Cancer Foundation Finland and the iCAN Digital Precision Cancer Medicine Flagship. The authors declare no conflicts of interest.

TRIAL REGISTRATION NUMBER

N/A.

Authors+Show Affiliations

Applied Tumor Genomics Research Program and Department of Medical and Clinical Genetics, Faculty of Medicine, University of Helsinki, Helsinki, Finland. Department of Obstetrics and Gynaecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.Applied Tumor Genomics Research Program and Department of Medical and Clinical Genetics, Faculty of Medicine, University of Helsinki, Helsinki, Finland. iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Helsinki, Finland.Applied Tumor Genomics Research Program and Department of Medical and Clinical Genetics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.Department of Obstetrics and Gynaecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.Department of Obstetrics and Gynaecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.Applied Tumor Genomics Research Program and Department of Medical and Clinical Genetics, Faculty of Medicine, University of Helsinki, Helsinki, Finland. iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Helsinki, Finland.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32829387

Citation

Äyräväinen, A, et al. "Systematic Molecular and Clinical Analysis of Uterine Leiomyomas From Fertile-aged Women Undergoing Myomectomy." Human Reproduction (Oxford, England), vol. 35, no. 10, 2020, pp. 2237-2244.
Äyräväinen A, Pasanen A, Ahvenainen T, et al. Systematic molecular and clinical analysis of uterine leiomyomas from fertile-aged women undergoing myomectomy. Hum Reprod. 2020;35(10):2237-2244.
Äyräväinen, A., Pasanen, A., Ahvenainen, T., Heikkinen, T., Pakarinen, P., Härkki, P., & Vahteristo, P. (2020). Systematic molecular and clinical analysis of uterine leiomyomas from fertile-aged women undergoing myomectomy. Human Reproduction (Oxford, England), 35(10), 2237-2244. https://doi.org/10.1093/humrep/deaa187
Äyräväinen A, et al. Systematic Molecular and Clinical Analysis of Uterine Leiomyomas From Fertile-aged Women Undergoing Myomectomy. Hum Reprod. 2020 Oct 1;35(10):2237-2244. PubMed PMID: 32829387.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Systematic molecular and clinical analysis of uterine leiomyomas from fertile-aged women undergoing myomectomy. AU - Äyräväinen,A, AU - Pasanen,A, AU - Ahvenainen,T, AU - Heikkinen,T, AU - Pakarinen,P, AU - Härkki,P, AU - Vahteristo,P, PY - 2020/01/17/received PY - 2020/06/12/revised PY - 2020/8/24/pubmed PY - 2020/8/24/medline PY - 2020/8/24/entrez KW - fumarate hydratase (FH) KW - high mobility group AT-hook 2 (HMGA2) KW - mediator complex subunit 12 (MED12) KW - myomectomy KW - uterine leiomyoma SP - 2237 EP - 2244 JF - Human reproduction (Oxford, England) JO - Hum. Reprod. VL - 35 IS - 10 N2 - STUDY QUESTION: What are the distributions and associated clinical characteristics of mediator complex subunit 12 (MED12), high mobility group AT-hook 2 (HMGA2) and fumarate hydratase (FH) aberrations in uterine leiomyomas from fertile-aged myomectomy patients? SUMMARY ANSWER: These driver mutations account for the majority (83%) of tumours in fertile-aged patients. WHAT IS KNOWN ALREADY: Alterations affecting MED12, HMGA2 and FH account for 80-90% of uterine leiomyomas from middle-aged hysterectomy patients, while the molecular background of tumours from young myomectomy patients has not been systematically studied. STUDY DESIGN, SIZE, DURATION: A retrospective series of 361 archival uterine leiomyoma samples from 234 women aged ≤45 years undergoing myomectomy in 2009-2014 was examined. Associations between the molecular data and detailed clinical information of the patients and tumours were analysed. PARTICIPANTS/MATERIALS, SETTING, METHODS: DNA was extracted from formalin-fixed paraffin-embedded samples and MED12 exons 1 and 2 were sequenced to identify mutations. Level of HMGA2 expression was evaluated by immunohistochemistry. Biallelic FH inactivation was analysed with 2-succinylcysteine staining, which is an indirect method of assessing FH deficiency. All patients' medical histories were reviewed, and clinical information of patients and tumours was combined with molecular data. MAIN RESULTS AND THE ROLE OF CHANCE: The median age at operation was 34 years. The majority (58%) of patients were operated on for a single leiomyoma. Known driver mutations were identified in 83% of tumours (71% MED12; 9% HMGA2; 3% FH). In solitary leiomyomas, the MED12 mutation frequency was only 43%, and 29% were wild-type for all driver alterations. MED12 mutations were associated with multiple tumours, smaller tumour size and subserosal location. LIMITATIONS, REASONS FOR CAUTION: Although comprehensive, the study is retrospective in nature and all samples have been collected for routine diagnostic purposes. The use of paraffin-embedded samples and immunohistochemistry may have led to an underestimation of mutations. Due to the limited sample size and rarity of especially FH-deficient leiomyomas, the data are partly descriptive. WIDER IMPLICATIONS OF THE FINDINGS: The contribution of driver mutations in leiomyomas from young myomectomy patients is comparable to tumours obtained from hysterectomies of mostly middle-aged women. Our results support the earlier findings that MED12 mutations are associated with multiple tumours, smaller tumour size and subserosal location. The study emphasizes the distinct molecular background of solitary leiomyomas, and more research is needed to clarify the underlying causes of the notable proportion of wild-type leiomyomas. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by the Academy of Finland (307773), the Sigrid Jusélius Foundation, the Cancer Foundation Finland and the iCAN Digital Precision Cancer Medicine Flagship. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A. SN - 1460-2350 UR - https://www.unboundmedicine.com/medline/citation/32829387/Systematic_molecular_and_clinical_analysis_of_uterine_leiomyomas_from_fertile_aged_women_undergoing_myomectomy_ L2 - https://academic.oup.com/humrep/article-lookup/doi/10.1093/humrep/deaa187 DB - PRIME DP - Unbound Medicine ER -
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