Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer

Abstract

Uterine leiomyomata (fibroids) are common and clinically important tumors, but little is known about their etiology and pathogenesis. We previously mapped a gene that predisposes to multiple fibroids, cutaneous leiomyomata and renal cell carcinoma to chromosome 1q42.3-q43 (refs 4-6). Here we show, through a combination of mapping critical recombinants, identifying individuals with germline mutations and screening known and predicted transcripts, that this gene encodes fumarate hydratase, an enzyme of the tricarboxylic acid cycle. Leiomyomatosis-associated mutations are predicted to result in absent or truncated protein, or substitutions or deletions of highly conserved amino acids. Activity of fumarate hydratase is reduced in lymphoblastoid cells from individuals with leiomyomatosis. This enzyme acts as a tumor suppressor in familial leiomyomata, and its measured activity is very low or absent in tumors from individuals with leiomyomatosis. Mutations in FH also occur in the recessive condition fumarate hydratase deficiency, and some parents of people with this condition are susceptible to leiomyomata. Thus, heterozygous and homozygous or compound heterozygous mutants have very different clinical phenotypes. Our results provide clues to the pathogenesis of fibroids and emphasize the importance of mutations of housekeeping and mitochondrial proteins in the pathogenesis of common types of tumor.

Gastric Leiomyoma and Hyperplastic Polyposis Coli in a Patient with Multiple Cutaneous and Uterine Leiomyomatosis

“…Mutations of the FH gene are present in both MCUL and HLRCC patients. 10,13 As no significant genotype-phenotype correlation has been established, identification of families with renal cancer risk cannot rely on genetic testing. The FH gene encodes fumarate hydratase, an enzyme of the tricarboxylic acid (Krebs) cycle.…”

“…In the latter case, they usually represent an autosomal dominant inherited condition associated with uterine myomas: MCUL. 10 A subset of MCUL families has individuals affected with certain types of aggressive renal cancer, namely, type 2 papillary renal cell carcinomas and collecting duct carcinomas 4 : hereditary leiomyomatosis and renal cell cancer (HLRCC; OMIM #605839). Mutations of the FH gene are present in both MCUL and HLRCC patients.…”

“…9 We report the observation of a MCUL patient with a gastric leiomyoma and colonic polyposis carrying a new mutation of the fumarate hydratase (FH) gene. 10 …”

Mitochondrial metabolic remodeling in response to genetic and environmental perturbations

“…FH and SDH are bone fide tumor suppressor genes, inactivating mutations in which have been identified as causative in cancers such as renal clear‐cell carcinoma and paraganglioma 46, 47, 48, 49, 50. Mutations in IDH1 and IDH2 are common in a variety of diverse cancers, including adult gliomas51, 52 and acute myelogenous leukemia (AML),53, 54 but unlike FH and SDH , are genetic oncogenes.…”

“…FH , encoding the proximal downstream enzyme to SDH, is another mitochondrial tumor suppressor gene, the loss of which leads to hereditary leiomyomatosis and renal‐cell cancer (HLRCC) 46. FH‐deficient leiomyomas (a benign neoplasm) are highly penetrant, while RCC occurs slightly less frequently 74.…”