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FH – Leiomyosarcoma

Biallelic inactivation of the FH gene has been reported in uterine leiomyosarcoma, with one comprehensive cohort identifying the splice‐site variant c.739-2A>G leading to FH deficiency in 16 of 51 leiomyosarcomas (PMID:28592321). However, a series of 26 sporadic leiomyosarcomas showed no somatic FH mutations, indicating that FH alterations are not a ubiquitous driver in this malignancy (PMID:12177782). A case of metastatic pulmonary leiomyosarcoma arising from an FH-deficient uterine leiomyoma demonstrated a somatic homozygous FH deletion and clonal progression, supporting a potential, albeit rare, role of FH loss in malignant transformation (PMID:35367216). No familial segregation or germline predisposition to leiomyosarcoma has been reported, and the prevailing evidence derives from somatic events in tumors.

Functional assessments in FH-deficient smooth muscle tumors reveal a characteristic gene expression signature and loss of FH immunoreactivity in histopathological variants, but mechanistic studies in leiomyosarcoma cells are lacking. The absence of FH mutations or loss in the majority of sporadic leiomyosarcomas, coupled with limited functional modeling, underscores the need for further investigation. Nonetheless, FH inactivation may define a molecular subset of leiomyosarcoma with potential diagnostic and therapeutic implications. Key take-home: FH loss occurs in a restricted subset of leiomyosarcomas, highlighting its limited but actionable biomarker potential.

References

  • Experimental and Molecular Pathology • 2022 • Lung metastases and subsequent malignant transformation of a fumarate hydratase -deficient uterine leiomyoma PMID:35367216
  • British Journal of Cancer • 2002 • Low frequency of somatic mutations in the FH/multiple cutaneous leiomyomatosis gene in sporadic leiomyosarcomas and uterine leiomyomas PMID:12177782
  • Molecular Cancer • 2017 • Characterization of MED12, HMGA2, and FH alterations reveals molecular variability in uterine smooth muscle tumors PMID:28592321

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Somatic biallelic FH inactivation in ~31% of uterine leiomyosarcomas in 51 cases (PMID:28592321); case report of metastatic FH-deficient leiomyosarcoma (PMID:35367216); absence of FH mutations in 26 sporadic LMS (PMID:12177782).

Genetic Evidence

Limited

Somatic splice-site variant c.739-2A>G in 16/51 LMS (PMID:28592321) and one homozygous deletion in metastatic case (PMID:35367216); no familial or germline segregation.

Functional Evidence

Limited

Gene expression profiling and FH immunohistochemistry loss in FH-deficient smooth muscle tumors (PMID:35367216); lack of mechanistic models in leiomyosarcoma.