Medical Research Society

Uterine fibroids, or leiomyomata, are the most common tumours in women during the reproductive years and represent a significant health issue, yet little is known about their pathogenesis. We mapped a predisposition gene for multiple fibroids, cutaneous leiomyomata and renal carcinoma to chromosome 1q42.3-q43 and refined the region of the gene by mapping critical recombinants and using FISH in patients with germline deletions. We identified heterozygous germline mutations in the fumarate hydratase (FH) gene, which codes for a component of the Kreb’s cycle, in 35 of 47 probands. Mutations resulted in truncated protein, aberrantly spliced transcripts, or substitutions or deletions of highly conserved amino acids. We carried out a functional assay of FH enzyme activity which showed reduced activity in lymphoblastoid cells from leiomyomatosis patients. We confirmed that FH acts as a tumour suppressor in familial leiomyomata, with loss of heterozygosity being the commonest ‘second hit’. Homozygous FH mutations have been reported in the autosomal recessive inborn error of metabolism, fumarase deficiency. We identified previously unreported leiomyomata in parents of FH deficiency patients. We collected detailed clinicopathological information on107 patients with multiple leiomyomatosis. FH mutations were found to be highly penetrant with affected females developing severely symptomatic fibroids requiring early hysterectomy. Fibroids were histologically indistinguishable from typical sporadic fibroids. Renal cell carcinoma and uterine leiomyosarcoma were uncommon associations. Evidence of FH dysfunction was found in almost all patients suggesting that this may be a genetically homogeneous condition. Thus, patients with skin leiomyomata should be screened for FH mutation and, if female, for uterine fibroids. Similarly, females presenting with fibroids, should be examined for skin leiomyomata. These results provide important clues about the pathogenesis of fibroids and renal cancers, and emphasise the role of housekeeping and mitochondrial proteins in tumorigenesis. Y2