Biallelic Inactivation of Fumarate Hydratase (FH) Occurs in Nonsyndromic Uterine Leiomyomas but Is Rare in Other Tumors

Rainer Lehtonen, Maija Ht Kiuru, Sakari Vanharanta, Jari Sjöberg, Leena Maija Aaltonen, Kristiina Aittomäki, Johanna Arola, Ralf Butzow, Charis Eng, Kirsti Husgafvel-Pursiainen, Jorma Isola, Heikki Järvinen, Pasi Koivisto, Jukka Pekka Mecklin, Päivi Peltomäki, Reijo Salovaara, Veli Matti Wasenius, Auli Karhu, Virpi Launonen, Nina N. NupponenLauri A. Aaltonen

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Abstract

Germline mutations in the fumarate hydratase (FH) gene at 1q43 predispose to dominantly inherited cutaneous and uterine leiomyomas, uterine leiomyosarcoma, and papillary renal cell cancer (HLRCC syndrome). To evaluate the role of FH inactivation in sporadic tumorigenesis, we analyzed a series of 299 malignant tumors representing 10 different malignant tumor types for FH mutations. Additionally, 153 uterine leiomyomas from 46 unselected individuals were subjected to and informative in loss of heterozygosity analysis at the FH locus, and the five (3.3%) tumors displaying loss of heterozygosity were subjected to FH mutation analysis. Although mutation search in the 299 malignant tumors was negative, somatic FH mutations were found in two nonsyndromic leiomyomas; a splice site change IVS4 + 3A>G, leading to deletion of exon four, and a missense mutation Ala196Thr. The occurrence of somatic mutations strongly suggests that FH is a true target of the 1q43 deletions. Although uterine leiomyomas are the most common tumors of women, specific inactivating somatic mutations contributing to the formation of nonsyndromic leiomyomas have not been reported previously. Taking into account the apparent risk of uterine leiomyosarcoma associated with FH germline mutations, the finding raises the possibility that also some nonsyndromic leiomyomas may have a genetic profile that is more prone to malignant degeneration. Our data also indicate that somatic FH mutations appear to be limited to tumor types observed in hereditary leiomyomatosis and renal cell cancer.

Original languageEnglish (US)
Pages (from-to)17-22
Number of pages6
JournalAmerican Journal of Pathology
Volume164
Issue number1
StatePublished - Jan 2004
Externally publishedYes

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Fumarate Hydratase
Leiomyoma
Mutation
Neoplasms
Leiomyosarcoma
Germ-Line Mutation
Loss of Heterozygosity
Missense Mutation
Renal Cell Carcinoma
Exons
Carcinogenesis

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Lehtonen, R., Kiuru, M. H., Vanharanta, S., Sjöberg, J., Aaltonen, L. M., Aittomäki, K., ... Aaltonen, L. A. (2004). Biallelic Inactivation of Fumarate Hydratase (FH) Occurs in Nonsyndromic Uterine Leiomyomas but Is Rare in Other Tumors. American Journal of Pathology, 164(1), 17-22.

Biallelic Inactivation of Fumarate Hydratase (FH) Occurs in Nonsyndromic Uterine Leiomyomas but Is Rare in Other Tumors. / Lehtonen, Rainer; Kiuru, Maija Ht; Vanharanta, Sakari; Sjöberg, Jari; Aaltonen, Leena Maija; Aittomäki, Kristiina; Arola, Johanna; Butzow, Ralf; Eng, Charis; Husgafvel-Pursiainen, Kirsti; Isola, Jorma; Järvinen, Heikki; Koivisto, Pasi; Mecklin, Jukka Pekka; Peltomäki, Päivi; Salovaara, Reijo; Wasenius, Veli Matti; Karhu, Auli; Launonen, Virpi; Nupponen, Nina N.; Aaltonen, Lauri A.

In: American Journal of Pathology, Vol. 164, No. 1, 01.2004, p. 17-22.

Research output: Contribution to journalArticle

Lehtonen, R, Kiuru, MH, Vanharanta, S, Sjöberg, J, Aaltonen, LM, Aittomäki, K, Arola, J, Butzow, R, Eng, C, Husgafvel-Pursiainen, K, Isola, J, Järvinen, H, Koivisto, P, Mecklin, JP, Peltomäki, P, Salovaara, R, Wasenius, VM, Karhu, A, Launonen, V, Nupponen, NN & Aaltonen, LA 2004, 'Biallelic Inactivation of Fumarate Hydratase (FH) Occurs in Nonsyndromic Uterine Leiomyomas but Is Rare in Other Tumors', American Journal of Pathology, vol. 164, no. 1, pp. 17-22.
Lehtonen, Rainer ; Kiuru, Maija Ht ; Vanharanta, Sakari ; Sjöberg, Jari ; Aaltonen, Leena Maija ; Aittomäki, Kristiina ; Arola, Johanna ; Butzow, Ralf ; Eng, Charis ; Husgafvel-Pursiainen, Kirsti ; Isola, Jorma ; Järvinen, Heikki ; Koivisto, Pasi ; Mecklin, Jukka Pekka ; Peltomäki, Päivi ; Salovaara, Reijo ; Wasenius, Veli Matti ; Karhu, Auli ; Launonen, Virpi ; Nupponen, Nina N. ; Aaltonen, Lauri A. / Biallelic Inactivation of Fumarate Hydratase (FH) Occurs in Nonsyndromic Uterine Leiomyomas but Is Rare in Other Tumors. In: American Journal of Pathology. 2004 ; Vol. 164, No. 1. pp. 17-22.
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abstract = "Germline mutations in the fumarate hydratase (FH) gene at 1q43 predispose to dominantly inherited cutaneous and uterine leiomyomas, uterine leiomyosarcoma, and papillary renal cell cancer (HLRCC syndrome). To evaluate the role of FH inactivation in sporadic tumorigenesis, we analyzed a series of 299 malignant tumors representing 10 different malignant tumor types for FH mutations. Additionally, 153 uterine leiomyomas from 46 unselected individuals were subjected to and informative in loss of heterozygosity analysis at the FH locus, and the five (3.3{\%}) tumors displaying loss of heterozygosity were subjected to FH mutation analysis. Although mutation search in the 299 malignant tumors was negative, somatic FH mutations were found in two nonsyndromic leiomyomas; a splice site change IVS4 + 3A>G, leading to deletion of exon four, and a missense mutation Ala196Thr. The occurrence of somatic mutations strongly suggests that FH is a true target of the 1q43 deletions. Although uterine leiomyomas are the most common tumors of women, specific inactivating somatic mutations contributing to the formation of nonsyndromic leiomyomas have not been reported previously. Taking into account the apparent risk of uterine leiomyosarcoma associated with FH germline mutations, the finding raises the possibility that also some nonsyndromic leiomyomas may have a genetic profile that is more prone to malignant degeneration. Our data also indicate that somatic FH mutations appear to be limited to tumor types observed in hereditary leiomyomatosis and renal cell cancer.",
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T1 - Biallelic Inactivation of Fumarate Hydratase (FH) Occurs in Nonsyndromic Uterine Leiomyomas but Is Rare in Other Tumors

AU - Lehtonen, Rainer

AU - Kiuru, Maija Ht

AU - Vanharanta, Sakari

AU - Sjöberg, Jari

AU - Aaltonen, Leena Maija

AU - Aittomäki, Kristiina

AU - Arola, Johanna

AU - Butzow, Ralf

AU - Eng, Charis

AU - Husgafvel-Pursiainen, Kirsti

AU - Isola, Jorma

AU - Järvinen, Heikki

AU - Koivisto, Pasi

AU - Mecklin, Jukka Pekka

AU - Peltomäki, Päivi

AU - Salovaara, Reijo

AU - Wasenius, Veli Matti

AU - Karhu, Auli

AU - Launonen, Virpi

AU - Nupponen, Nina N.

AU - Aaltonen, Lauri A.

PY - 2004/1

Y1 - 2004/1

N2 - Germline mutations in the fumarate hydratase (FH) gene at 1q43 predispose to dominantly inherited cutaneous and uterine leiomyomas, uterine leiomyosarcoma, and papillary renal cell cancer (HLRCC syndrome). To evaluate the role of FH inactivation in sporadic tumorigenesis, we analyzed a series of 299 malignant tumors representing 10 different malignant tumor types for FH mutations. Additionally, 153 uterine leiomyomas from 46 unselected individuals were subjected to and informative in loss of heterozygosity analysis at the FH locus, and the five (3.3%) tumors displaying loss of heterozygosity were subjected to FH mutation analysis. Although mutation search in the 299 malignant tumors was negative, somatic FH mutations were found in two nonsyndromic leiomyomas; a splice site change IVS4 + 3A>G, leading to deletion of exon four, and a missense mutation Ala196Thr. The occurrence of somatic mutations strongly suggests that FH is a true target of the 1q43 deletions. Although uterine leiomyomas are the most common tumors of women, specific inactivating somatic mutations contributing to the formation of nonsyndromic leiomyomas have not been reported previously. Taking into account the apparent risk of uterine leiomyosarcoma associated with FH germline mutations, the finding raises the possibility that also some nonsyndromic leiomyomas may have a genetic profile that is more prone to malignant degeneration. Our data also indicate that somatic FH mutations appear to be limited to tumor types observed in hereditary leiomyomatosis and renal cell cancer.

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