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Comparative Study
. 2004 Jan;164(1):17-22.
doi: 10.1016/S0002-9440(10)63091-X.

Biallelic inactivation of fumarate hydratase (FH) occurs in nonsyndromic uterine leiomyomas but is rare in other tumors

Rainer Lehtonen  1 , Maija 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 Nupponen, Lauri A Aaltonen
Affiliations
Comparative Study

Biallelic inactivation of fumarate hydratase (FH) occurs in nonsyndromic uterine leiomyomas but is rare in other tumors

Rainer Lehtonen et al. Am J Pathol. 2004 Jan.

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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Figures

Figure 1
Figure 1
LOH flanking FH locus was analyzed by two microsatellite markers. Allelic loss was observed in myoma P4M3 (b) and in P32M1 (d) by markers FH-T and FH-C, respectively. Alleles of normal tissue samples are presented above the tumor samples (a and c). Myomas from three additional individuals harbored allelic imbalance in at least one of these markers at the FH locus (data not shown).
Figure 2
Figure 2
Sequences of FH mutations detected in uterine leiomyomas Ala196Thr (a) and IVS4 + 3A>G (c) and the chromatographs of the corresponding normal tissues (b and d, respectively). LOH at the splice site change (c) is noticeable by the lower wild-type allele signal in the presence of normal tissue contamination.
See this image and copyright information in PMC

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