title: Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America.
abstract: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder characterized by smooth-muscle tumors of the skin and uterus and/or renal cancer. Although the identification of germline mutations in the fumarate hydratase (FH) gene in European families supports it as the susceptibility gene for HLRCC, its role in families in North America has not been studied. We screened for germline mutations in FH in 35 families with cutaneous leiomyomas. Sequence analysis revealed mutations in FH in 31 families (89%). Twenty different mutations in FH were identified, of which 18 were novel. Of these 20 mutations, 2 were insertions, 5 were small deletions that caused frameshifts leading to premature truncation of the protein, and 13 were missense mutations. Eleven unrelated families shared a common mutation: R190H. Eighty-one individuals (47 women and 34 men) had cutaneous leiomyomas. Ninety-eight percent (46/47) of women with cutaneous leiomyomas also had uterine leiomyomas. Eighty-nine percent (41/46) of women with cutaneous and uterine leiomyomas had a total hysterectomy, 44% at age < or =30 years. We identified 13 individuals in 5 families with unilateral and solitary renal tumors. Seven individuals from four families had papillary type II renal cell carcinoma, and another individual from one of these families had collecting duct carcinoma of the kidney. The present study shows that mutations in FH are associated with HLRCC in North America. HLRCC is associated with clinically significant uterine fibroids and aggressive renal tumors. The present study also expands the histologic spectrum of renal tumors and FH mutations associated with HLRCC.
authors.affiliation: Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, Executive Plaza South, Rockville, MD 20892, USA. torojo@exchange.nih.gov
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Toro
authors.forename: Michael L
authors.initials: ML
authors.lastname: Nickerson
authors.forename: Ming-Hui
authors.initials: MH
authors.lastname: Wei
authors.forename: Michelle B
authors.initials: MB
authors.lastname: Warren
authors.forename: Gladys M
authors.initials: GM
authors.lastname: Glenn
authors.forename: Maria L
authors.initials: ML
authors.lastname: Turner
authors.forename: Laveta
authors.initials: L
authors.lastname: Stewart
authors.forename: Paul
authors.initials: P
authors.lastname: Duray
authors.forename: Ousman
authors.initials: O
authors.lastname: Tourre
authors.forename: Nirmala
authors.initials: N
authors.lastname: Sharma
authors.forename: Peter
authors.initials: P
authors.lastname: Choyke
authors.forename: Pamela
authors.initials: P
authors.lastname: Stratton
authors.forename: Maria
authors.initials: M
authors.lastname: Merino
authors.forename: McClellan M
authors.initials: MM
authors.lastname: Walther
authors.forename: W Marston
authors.initials: WM
authors.lastname: Linehan
authors.forename: Laura S
authors.initials: LS
authors.lastname: Schmidt
authors.forename: Berton
authors.initials: B
authors.lastname: Zbar
mesh_terms: D002292:Carcinoma, Renal Cell / Q000235:genetics*; D005260:Female; D005649:Fumarate Hydratase / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics*; D018231:Leiomyomatosis / Q000235:genetics*; D008297:Male; D009154:Mutation; D009656:North America; D010375:Pedigree
chemical_list: D005649:Fumarate Hydratase