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Prevalence of somatic and germline mutations of Fumarate hydratase in uterine leiomyomas from young patients.
Histopathology. 2020 Feb; 76(3):354-365.H

Abstract

AIMS

Hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome is caused by germline mutations in the Fumarate hydratase (FH) gene. In young women, the syndrome often presents with symptomatic uterine leiomyomas, leading to myomectomy or hysterectomy. In this study, we aimed to investigate the incidence and mutational profiles of FH-negative leiomyomas from young patients, thus allowing for early identification and triage of syndromic patients for surveillance.

METHODS AND RESULTS

We evaluated 153 cases of uterine leiomyomas from women aged up to 30 years for loss of FH expression by tissue microarray (TMA)-based immunohistochemical staining. Mutational analysis of tumours with loss of FH was carried out by polymerase chain reaction (PCR) amplification of 10 exons within the FH gene and subsequent Sanger sequencing. The status of promoter methylation was assessed by bisulphite sequencing. Loss of FH protein expression was detected in seven (4.6%) of 153 tested uterine leiomyomas from young patients. All FH-negative leiomyomas displayed staghorn vasculature and fibrillary/neurophil-like cytoplasm. We found that six (86%) of seven FH-negative tumours detected by immunohistochemistry harboured FH mutations, 50% of which contained germline mutations. In particular, the germline mutational rate in FH gene was 2.0% (three of 153 cases). Bisulphite sequencing analysis failed to detect promoter methylation in any of the seven tumours.

CONCLUSION

Our study showed a relatively high rate of FH germline mutation in FH-negative uterine leiomyomas from patients aged up to 30 years. While genetic mutations confer protein expression loss, epigenetic regulation of the FH gene appears to be unrelated to this phenotype.

Authors+Show Affiliations

Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.The Kelly Gynecologic Oncology Service, Department of Gynecology and Obstetrics, Johns Hopkins School of Medicine, Baltimore, MD, USA.Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.The Kelly Gynecologic Oncology Service, Department of Gynecology and Obstetrics, Johns Hopkins School of Medicine, Baltimore, MD, USA.Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA. Department of Gynecology and Obstetrics, The Johns Hopkins Medical Institutions, Baltimore, MD, USA. Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA. Department of Gynecology and Obstetrics, The Johns Hopkins Medical Institutions, Baltimore, MD, USA. Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA. Department of Gynecology and Obstetrics, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.Department of Gynecology and Obstetrics, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA. Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31564060

Citation

Liu, Chengbao, et al. "Prevalence of Somatic and Germline Mutations of Fumarate Hydratase in Uterine Leiomyomas From Young Patients." Histopathology, vol. 76, no. 3, 2020, pp. 354-365.
Liu C, Dillon J, Beavis AL, et al. Prevalence of somatic and germline mutations of Fumarate hydratase in uterine leiomyomas from young patients. Histopathology. 2020;76(3):354-365.
Liu, C., Dillon, J., Beavis, A. L., Liu, Y., Lombardo, K., Fader, A. N., Hung, C. F., Wu, T. C., Vang, R., Garcia, J. E., & Xing, D. (2020). Prevalence of somatic and germline mutations of Fumarate hydratase in uterine leiomyomas from young patients. Histopathology, 76(3), 354-365. https://doi.org/10.1111/his.14007
Liu C, et al. Prevalence of Somatic and Germline Mutations of Fumarate Hydratase in Uterine Leiomyomas From Young Patients. Histopathology. 2020;76(3):354-365. PubMed PMID: 31564060.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Prevalence of somatic and germline mutations of Fumarate hydratase in uterine leiomyomas from young patients. AU - Liu,Chengbao, AU - Dillon,Jessica, AU - Beavis,Anna L, AU - Liu,Yuehua, AU - Lombardo,Kara, AU - Fader,Amanda N, AU - Hung,Chien-Fu, AU - Wu,Tzyy-Choou, AU - Vang,Russell, AU - Garcia,Jairo E, AU - Xing,Deyin, Y1 - 2020/01/13/ PY - 2019/08/09/received PY - 2019/09/25/revised PY - 2019/09/26/accepted PY - 2019/9/30/pubmed PY - 2020/10/27/medline PY - 2019/9/30/entrez KW - fumarate hydratase KW - germline mutation KW - hereditary leiomyomatosis and renal cell cancer (HLRCC) KW - leiomyomas SP - 354 EP - 365 JF - Histopathology JO - Histopathology VL - 76 IS - 3 N2 - AIMS: Hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome is caused by germline mutations in the Fumarate hydratase (FH) gene. In young women, the syndrome often presents with symptomatic uterine leiomyomas, leading to myomectomy or hysterectomy. In this study, we aimed to investigate the incidence and mutational profiles of FH-negative leiomyomas from young patients, thus allowing for early identification and triage of syndromic patients for surveillance. METHODS AND RESULTS: We evaluated 153 cases of uterine leiomyomas from women aged up to 30 years for loss of FH expression by tissue microarray (TMA)-based immunohistochemical staining. Mutational analysis of tumours with loss of FH was carried out by polymerase chain reaction (PCR) amplification of 10 exons within the FH gene and subsequent Sanger sequencing. The status of promoter methylation was assessed by bisulphite sequencing. Loss of FH protein expression was detected in seven (4.6%) of 153 tested uterine leiomyomas from young patients. All FH-negative leiomyomas displayed staghorn vasculature and fibrillary/neurophil-like cytoplasm. We found that six (86%) of seven FH-negative tumours detected by immunohistochemistry harboured FH mutations, 50% of which contained germline mutations. In particular, the germline mutational rate in FH gene was 2.0% (three of 153 cases). Bisulphite sequencing analysis failed to detect promoter methylation in any of the seven tumours. CONCLUSION: Our study showed a relatively high rate of FH germline mutation in FH-negative uterine leiomyomas from patients aged up to 30 years. While genetic mutations confer protein expression loss, epigenetic regulation of the FH gene appears to be unrelated to this phenotype. SN - 1365-2559 UR - https://www.unboundmedicine.com/medline/citation/31564060/Prevalence_of_somatic_and_germline_mutations_of_Fumarate_hydratase_in_uterine_leiomyomas_from_young_patients_ L2 - https://doi.org/10.1111/his.14007 DB - PRIME DP - Unbound Medicine ER -