A novel pathogenic variant of the FH gene in a family with hereditary leiomyomatosis and renal cell carcinoma

Abstract

Hereditary leiomyomatosis and renal cell carcinoma caused by loss-of-function germline variants of the FH gene can develop into aggressive renal cell carcinoma (RCC). We report the case of a 27-year-old man who died of RCC. Genetic testing revealed a novel pathogenic variant of FH, NM_000143.3:c.1013_1014del (p.Ile338Serfs*3), that was also identified in healthy siblings. Identification of genetic causes in the proband helped us to provide relatives with precise genetic counseling and appropriate surveillance programs.

PI3K/AKT/mTOR Dysregulation and Reprogramming Metabolic Pathways in Renal Cancer: Crosstalk with the VHL/HIF Axis

“…Smaller tumors are associated with the overexpression of PRUNE 2 gene (prune homolog 2 with BCH domain) [79] and thus of having a better prognosis, while in large tumors PRUNE 2 gene is downregulated, which is correlated with a worse prognosis. Alterations of FH (Fumarate Hydrase) gene [80,81] can also be present in renal sarcomas. At the same time, 17q duplication is associated with low-risk metastases, longer survival, and better prognosis [82].…”

Fumarate hydratase (FH) and cancer: a paradigm of oncometabolism

“…Notably, renal tumours in HLRCC patients are the most aggressive form of renal cancer, characterised by early metastasis (even with a small primary tumour size) and poor clinical outcome [17]. Although pathogenic variants of FH have been identified and provide precise genetic and surveillance programs to HLRCC families, there is no association between mutation sites and clinical outcomes in patients [17][18][19]. Still, FH variants in HLRCC patients lead to loss of function, and the consequent LOH in the tumour tissue causes the complete loss of its enzymatic activity [20].…”