Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America

Jorge R. Toro, Michael L. Nickerson, Ming Hui Wei, Michelle B. Warren, Gladys M. Glenn, Maria L. Turner, Laveta Stewart, Paul Duray, Ousman Tourre, Nirmala Sharma, Peter Choyke, Pamela Stratton, Maria Merino, McClellan M. Walther, W. Marston Linehan, Laura S. Schmidt, Berton Zbar

Research output: Contribution to journalArticle

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 ≤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.

Original languageEnglish (US)
Pages (from-to)95-106
Number of pages12
JournalAmerican Journal of Human Genetics
Volume73
Issue number1
DOIs
StatePublished - Jul 1 2003
Externally publishedYes

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Fumarate Hydratase
North America
Leiomyoma
Mutation
Genes
Skin
Germ-Line Mutation
Kidney
Renal Cell Carcinoma
Smooth Muscle Tumor
Neoplasms
Uterine Neoplasms
Hereditary leiomyomatosis and renal cell cancer
Kidney Neoplasms
Skin Neoplasms
Missense Mutation
Hysterectomy
Sequence Analysis

ASJC Scopus subject areas

  • Genetics

Cite this

Toro, J. R., Nickerson, M. L., Wei, M. H., Warren, M. B., Glenn, G. M., Turner, M. L., ... Zbar, B. (2003). Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. American Journal of Human Genetics, 73(1), 95-106. https://doi.org/10.1086/376435

Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. / Toro, Jorge R.; Nickerson, Michael L.; Wei, Ming Hui; Warren, Michelle B.; Glenn, Gladys M.; Turner, Maria L.; Stewart, Laveta; Duray, Paul; Tourre, Ousman; Sharma, Nirmala; Choyke, Peter; Stratton, Pamela; Merino, Maria; Walther, McClellan M.; Linehan, W. Marston; Schmidt, Laura S.; Zbar, Berton.

In: American Journal of Human Genetics, Vol. 73, No. 1, 01.07.2003, p. 95-106.

Research output: Contribution to journalArticle

Toro, JR, Nickerson, ML, Wei, MH, Warren, MB, Glenn, GM, Turner, ML, Stewart, L, Duray, P, Tourre, O, Sharma, N, Choyke, P, Stratton, P, Merino, M, Walther, MM, Linehan, WM, Schmidt, LS & Zbar, B 2003, 'Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America', American Journal of Human Genetics, vol. 73, no. 1, pp. 95-106. https://doi.org/10.1086/376435
Toro, Jorge R. ; Nickerson, Michael L. ; Wei, Ming Hui ; Warren, Michelle B. ; Glenn, Gladys M. ; Turner, Maria L. ; Stewart, Laveta ; Duray, Paul ; Tourre, Ousman ; Sharma, Nirmala ; Choyke, Peter ; Stratton, Pamela ; Merino, Maria ; Walther, McClellan M. ; Linehan, W. Marston ; Schmidt, Laura S. ; Zbar, Berton. / Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. In: American Journal of Human Genetics. 2003 ; Vol. 73, No. 1. pp. 95-106.
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AU - Turner, Maria L.

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AU - Sharma, Nirmala

AU - Choyke, Peter

AU - Stratton, Pamela

AU - Merino, Maria

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N2 - 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 ≤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.

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