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No fumarate hydratase (FH) mutations in hereditary prostate cancer
  1. R Lehtonen1,
  2. M Kiuru1,
  3. A Rökman2,
  4. T Ikonen2,
  5. J M Cunningham3,
  6. D J Schaid3,
  7. M Matikainen2,
  8. N N Nupponen1,
  9. A Karhu1,
  10. O-P Kallioniemi2,
  11. S N Thibodeau3,
  12. J Schleutker2,
  13. L A Aaltonen1
  1. 1Departments of Medical Genetics, Biomedicum Helsinki or Haartman Institute, FIN-00014 University of Helsinki, Finland
  2. 2Laboratory of Cancer Genetics, Institute of Medical Technology, University of Tampere and Tampere University Hospital, 33521 Tampere, Finland
  3. 3Departments of Laboratory Medicine and Pathology, Health Sciences Research, Mayo Clinic/Foundation, Rochester, MN, and Prostate Cancer Investigation Group, National Human Genome Research Institute, National Institutes of Health, Bethesda, MA, USA
  1. Correspondence to:
 Dr L A Aaltonen, Department of Medical Genetics, Biomedicum Helsinki, PO Box 63, FIN-00014 University of Helsinki, Finland;
 lauri.aaltonen{at}helsinki.fi

https://doi.org/10.1136/jmg.40.3.e19

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    Mutations in fumarate hydratase (fumarase, FH), a nuclear gene encoding a mitochondrial tricarboxylic acid cycle or Krebs cycle protein also present in the cytosol, have recently been shown to predispose to hereditary leiomyomatosis and renal cell cancer (HLRCC, OMIM 605839)1 or multiple cutaneous and uterine leiomyomatosis (MCL, OMIM 150800).2 In addition to leiomyomas of the skin and uterus, some subjects also develop papillary renal cell carcinoma of rare type II histology.3,4 Germline FH mutations were found in approximately 60% (24/42) of families segregating HLRCC.1 Mutations in FH have been recently observed in apparently sporadic tumours. In a series of lesions studied, one uterine leiomyosarcoma and one cutaneous leiomyoma harboured a germline mutation while one soft tissue sarcoma represented the first known purely somatic case.5 Homozygous germline FH mutations have been found to cause recessive fumarate hydratase deficiency (OMIM 136850).6–8 FH has been mapped to chromosome 1q43, between markers D1S2785 and D1S2842, within 500 kb of D1S2785.

    Key points

    • Mutations in nuclear genes encoding tricarboxylic acid (Krebs) cycle proteins fumarate hydratase (FH) and some subunits of succinate dehydrogenase complex have been associated with familial tumour predisposition and certain sporadic tumour types. The mechanisms by which FH defects promote tumorigenesis are unknown, but may involve activation of hypoxia pathways or alterations in citrate production through Krebs cycle. • FH is located in the same chromosomal region as one of the putative familial prostate cancer loci, PCAP at 1q42.2-43. Thus it is a positional candidate gene for PCAP.

    • We performed FH mutation analysis in a series of 89 HPRCA families. Our data set consisted of 19 US families showing suggestive linkage to the PCAP locus and 70 Finnish families in which PCAP linkage information was not available.

    • No mutations were found. The absence of mutations …

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