Human Molecular Genetics Advance Access published online on June 29, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi227
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1 Molecular and Population Genetics Laboratory, London Research Institute, Cancer Research UK, 44, Lincoln's Inn Fields, London WC2A 3PX, UK
* To whom correspondence should be addressed. The nuclear-encoded Krebs cycle enzymes fumarate hydratase (FH) and succinate dehydrogenase (SDHB, -C and -D) act as tumour suppressors. Germline mutations in FH predispose individuals to leiomyomas and renal cell cancer (HLRCC) whereas mutations in SDH cause paragangliomas and phaeochromocytomas (HPGL). In this study, we have shown that FH-deficient cells and tumours accumulate fumarate and, to a lesser extent, succinate. SDH-deficient tumours principally accumulate succinate. In situ analyses showed that these tumours also have over-expression of hypoxia-inducible factor 1
Received May 13, 2005
Revised June 3, 2005
Accepted June 23, 2005
Article
Accumulation of Krebs cycle intermediates and over-expression of HIF1
in tumours which result from germline FH and SDH mutations
2 INSERM U676, Hopital Robert Debre, 48 Bd Serurier, 75019 Paris, France
3 Molecular and Population Genetics Laboratory, London Research Institute, Cancer Research UK, 44, Lincoln's Inn Fields, London WC2A 3PX, UK; St John's Institute of Dermatology, The Guy's, King's and St Thomas' Medical School, St Thomas' Hospital, London, UK
4 Department of Clinical Genetics, St Georges Hospital, London SW17 ORE, UK; Department of Clinical Genetics, Guy's Hospital, London, SE1 9RT, UK
5 Histopathology Unit and In Situ Hybridisation Service, London Research Institute, Cancer Research UK, 44, Lincoln's Inn Fields, London WC2A 3PX, UK
6 Computational Genome Analysis Laboratory, London Research Institute, Cancer Research UK, 44, Lincoln's Inn Fields, London WC2A 3PX, UK
7 Neonatal Screening and Chemical Pathology, Sheffield Children's Hospital, Sheffield, S10 2TH, UK
8 Department of Medical Biochemistry and Immunology, University Hospital of Wales, Heath Park, Cardiff, CF14 4XW, UK
9 Neurometabolic Unit, National Hospital, Queen Square, London WC1N 3BG, UK
10 Biomedical Magnetic Resonance Research Group, Department of Basic Medical Sciences, St Georges Hospital, London SW17 ORE, UK
11 Department of Histopathology, St Georges Hospital, London SW17 ORE, UK
12 St John's Institute of Dermatology, The Guy's, King's and St Thomas' Medical School, St Thomas' Hospital, London, UK
13 Department of Otolaryngology, Guy's Hospital, London, SE1 9RT, UK
14 Department of Clinical Genetics, St Georges Hospital, London SW17 ORE, UK
I. P.M. Tomlinson, E-mail: ian.tomlinson{at}cancer.org.uk
Abstract 
?(HIF1), activation of HIF1?targets (such as vascular endothelial growth factor (VEGF)) and high microvessel density. We found no evidence of increased reactive oxygen species in our cells. Our data provide in vivo evidence to support the hypothesis that increased succinate and/or fumarate cause stabilisation of HIF1; a plausible mechanism, inhibition of HIF prolyl hydroxylases, has previously been suggested by in vitro studies. The basic mechanism of tumorigenesis in HPGL and HLRCC is likely to be pseudo-hypoxic drive, just as it is in von Hippel-Lindau syndrome.
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