Prevalence of somatic and germline mutations of Fumarate hydratase in uterine leiomyomas from young patients

Autor:	Chengbao Liu, Jessica Dillon, Yuehua Liu, Chien Fu Hung, Russell Vang, Tzyy Choou Wu, Anna Beavis, Kara Lombardo, Jairo E. Garcia, Deyin Xing, Amanda N. Fader
Rok vydání:	2020
Předmět:	Adult 0301 basic medicine Skin Neoplasms Histology Adolescent DNA Mutational Analysis Bisulfite sequencing Germline Fumarate Hydratase Pathology and Forensic Medicine Young Adult 03 medical and health sciences Exon symbols.namesake 0302 clinical medicine Germline mutation Neoplastic Syndromes Hereditary Leiomyomatosis Prevalence Humans Medicine Epigenetics Gene Germ-Line Mutation Retrospective Studies Sanger sequencing Tissue microarray Leiomyoma business.industry General Medicine Immunohistochemistry 030104 developmental biology Tissue Array Analysis 030220 oncology & carcinogenesis Mutation Uterine Neoplasms Cancer research symbols Female business
Zdroj:	Histopathology. 76:354-365
ISSN:	1365-2559 0309-0167
Popis:	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.
Databáze:	OpenAIRE
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