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Human Molecular Genetics Advance Access originally published online on June 29, 2005
Human Molecular Genetics 2005 14(15):2231-2239; doi:10.1093/hmg/ddi227
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Accumulation of Krebs cycle intermediates and over-expression of HIF1{alpha} in tumours which result from germline FH and SDH mutations

P.J. Pollard1, J.J. Brière4, N.A. Alam1,5, J. Barwell6, E. Barclay1, N.C. Wortham1, T. Hunt2, M. Mitchell3, S. Olpin8, S.J. Moat9, I.P. Hargreaves10, S.J. Heales10, Y.L. Chung12, J.R. Griffiths12, A. Dalgleish13, J.A. McGrath5, M.J. Gleeson7, S.V. Hodgson11, R. Poulsom2, P. Rustin4 and I.P.M. Tomlinson1,*

1Molecular and Population Genetics Laboratory, 2Histopathology Unit and In Situ Hybridisation Service and 3Computational Genome Analysis Laboratory, London Research Institute, Cancer Research UK, 44, Lincoln's Inn Fields, London WC2A 3PX, UK, 4INSERM U676, Hopital Robert Debre, 48 Bd Serurier, 75019 Paris, France, 5St John's Institute of Dermatology, The Guy's, King's and St Thomas' Medical School, St Thomas' Hospital, London, UK, 6Department of Clinical Genetics and 7Department of Otolaryngology, Guy's Hospital, London SE1 9RT, UK, 8Neonatal Screening and Chemical Pathology, Sheffield Children's Hospital, Sheffield S10 2TH, UK, 9Department of Medical Biochemistry and Immunology, University Hospital of Wales, Heath Park, Cardiff CF14 4XW, UK, 10Neurometabolic Unit, National Hospital, Queen Square, London WC1 N 3BG, UK, 11Department of Clinical Genetics, 12Biomedical Magnetic Resonance Research Group, Department of Basic Medical Sciences and 13Department of Histopathology, St Georges Hospital, London SW17 ORE, UK

* To whom correspondence should be addressed. Tel: +44 2072692884; Fax: +44 2072693093; Email: ian.tomlinson{at}cancer.org.uk

Received May 13, 2005; Revised June 3, 2005; Accepted June 23, 2005

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{alpha} (HIF1{alpha}), activation of HIF1{alpha}targets (such as vascular endothelial growth factor) 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 causes stabilization of HIF1{alpha} 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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