title: Biallelic inactivation of fumarate hydratase (FH) occurs in nonsyndromic uterine leiomyomas but is rare in other tumors.
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.
authors.affiliation: Department of Medical Genetics, Haartman Institute, University of Helsinki, Finland.
authors.forename: Rainer
authors.initials: R
authors.lastname: Lehtonen
authors.forename: Maija
authors.initials: M
authors.lastname: Kiuru
authors.forename: Sakari
authors.initials: S
authors.lastname: Vanharanta
authors.forename: Jari
authors.initials: J
authors.lastname: Sjöberg
authors.forename: Leena-Maija
authors.initials: LM
authors.lastname: Aaltonen
authors.forename: Kristiina
authors.initials: K
authors.lastname: Aittomäki
authors.forename: Johanna
authors.initials: J
authors.lastname: Arola
authors.forename: Ralf
authors.initials: R
authors.lastname: Butzow
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
authors.forename: Kirsti
authors.initials: K
authors.lastname: Husgafvel-Pursiainen
authors.forename: Jorma
authors.initials: J
authors.lastname: Isola
authors.forename: Heikki
authors.initials: H
authors.lastname: Järvinen
authors.forename: Pasi
authors.initials: P
authors.lastname: Koivisto
authors.forename: Jukka-Pekka
authors.initials: JP
authors.lastname: Mecklin
authors.forename: Päivi
authors.initials: P
authors.lastname: Peltomäki
authors.forename: Reijo
authors.initials: R
authors.lastname: Salovaara
authors.forename: Veli-Matti
authors.initials: VM
authors.lastname: Wasenius
authors.forename: Auli
authors.initials: A
authors.lastname: Karhu
authors.forename: Virpi
authors.initials: V
authors.lastname: Launonen
authors.forename: Nina N
authors.initials: NN
authors.lastname: Nupponen
authors.forename: Lauri A
authors.initials: LA
authors.lastname: Aaltonen
mesh_terms: D001483:Base Sequence; D002292:Carcinoma, Renal Cell / Q000235:genetics; D002851:Chromatography, High Pressure Liquid; D004252:DNA Mutational Analysis; D005260:Female; D005649:Fumarate Hydratase / Q000235:genetics*; D006801:Humans; D007889:Leiomyoma / Q000235:genetics*; D019656:Loss of Heterozygosity; D008297:Male; D009154:Mutation; D016133:Polymerase Chain Reaction; D014594:Uterine Neoplasms / Q000235:genetics*
chemical_list: D005649:Fumarate Hydratase