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(American Journal of Pathology. 2004;164:17-22.)
© 2004 American Society for Investigative Pathology

Short Communication

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

Rainer Lehtonen^*, 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^* and Lauri A. Aaltonen^*

From the Departments of Medical Genetics,^* Virology, and Pathology,^¶Haartman Institute, University of Helsinki, Finland; the Department of Obstetrics and Gynecology, Clinical Genetics, and Oncology,|||| the Second Department of Surgery, and the Department of Otorhinolaryngology,^*** Head and Neck Surgery, Helsinki University Central Hospital, Helsinki, Finland; the Department of Industrial Hygiene and Toxicology,^** Finnish Institute of Occupational Health, Helsinki, Finland; the Laboratory of Cancer Genetics, Institute of Medical Technology, and the Department of Clinical Genetics, University of Tampere and Tampere University Hospital, Tampere, Finland; the Department of Surgery,^¶¶ Jyväskylä Central Hospital, Jyväskylä, Finland; and the Department of Internal Medicine,^|| Clinical Cancer Genetics Program, Human Cancer Genetics Program, Comprehensive Cancer Center, and Division of Human Genetics, The Ohio State University, Columbus, Ohio

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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