{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T08:56:34Z","timestamp":1789721794378,"version":"4.0.1"},"reference-count":31,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2020,1,13]],"date-time":"2020-01-13T00:00:00Z","timestamp":1578873600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Histopathology"],"published-print":{"date-parts":[[2020,2]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>Hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome is caused by germline mutations in the <jats:italic>Fumarate hydratase<\/jats:italic> (<jats:italic>FH<\/jats:italic>) 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\u2010negative leiomyomas from young patients, thus allowing for early identification and triage of syndromic patients for surveillance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and results<\/jats:title><jats:p>We evaluated 153 cases of uterine leiomyomas from women aged up to 30\u00a0years for loss of FH expression by tissue microarray (TMA)\u2010based immunohistochemical staining. Mutational analysis of tumours with loss of FH was carried out by polymerase chain reaction (PCR) amplification of 10 exons within the <jats:italic>FH<\/jats:italic> 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\u2010negative leiomyomas displayed staghorn vasculature and fibrillary\/neurophil\u2010like cytoplasm. We found that six (86%) of seven FH\u2010negative tumours detected by immunohistochemistry harboured <jats:italic>FH<\/jats:italic> mutations, 50% of which contained germline mutations. In particular, the germline mutational rate in <jats:italic>FH<\/jats:italic> gene was 2.0% (three of 153 cases). Bisulphite sequencing analysis failed to detect promoter methylation in any of the seven tumours.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our study showed a relatively high rate of <jats:italic>FH<\/jats:italic> germline mutation in FH\u2010negative uterine leiomyomas from patients aged up to 30\u00a0years. While genetic mutations confer protein expression loss, epigenetic regulation of the <jats:italic>FH<\/jats:italic> gene appears to be unrelated to this phenotype.<\/jats:p><\/jats:sec>","DOI":"10.1111\/his.14007","type":"journal-article","created":{"date-parts":[[2019,9,29]],"date-time":"2019-09-29T00:43:58Z","timestamp":1569717838000},"page":"354-365","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Prevalence of somatic and germline mutations of <i>Fumarate hydratase<\/i> in uterine leiomyomas from young patients"],"prefix":"10.1111","volume":"76","author":[{"given":"Chengbao","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Pathology The Johns Hopkins Medical Institutions Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Dillon","sequence":"additional","affiliation":[{"name":"Department of Pathology The Johns Hopkins Medical Institutions Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna L","family":"Beavis","sequence":"additional","affiliation":[{"name":"The Kelly Gynecologic Oncology Service Department of Gynecology and Obstetrics Johns Hopkins School of Medicine Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuehua","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pathology The Johns Hopkins Medical Institutions Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kara","family":"Lombardo","sequence":"additional","affiliation":[{"name":"Department of Pathology The Johns Hopkins Medical Institutions Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda N","family":"Fader","sequence":"additional","affiliation":[{"name":"The Kelly Gynecologic Oncology Service Department of Gynecology and Obstetrics Johns Hopkins School of Medicine Baltimore MD 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