title: Increased HIF1 alpha in SDH and FH deficient tumors does not cause microsatellite instability.
abstract: Germline mutations in nuclear genes encoding mitochondrial enzymes fumarate hydratase (FH) and succinate dehydrogenase (subunits SDHB/C/D) have been implicated in the development of tumor syndromes referred to as hereditary leiomyomatosis and renal cell cancer (HLRCC) and hereditary paragangliomatosis (HPGL), respectively. FH and SDH are operating in the tricarboxylic acid cycle (the TCA cycle, the Krebs cycle). In the FH and SDH deficient tumors, accumulation of the substrates, fumarate and succinate, has been shown to cause stabilization of hypoxia inducible factor 1 alpha (HIF1 alpha). According to recent studies, HIF1 alpha could contribute to the hypoxia induced genomic instability seen in many cancers, through repression of mismatch repair (MMR) protein MSH2. In this study, in agreement with previous works, we found HIF1 alpha to be moderately or highly stabilized in 67% (16/24) and 77% (48/62) of HLRCC tumors and SDHB/C/D paragangliomas (PGL) and pheochromocytomas (PHEO), respectively. In addition, a set of 54 other familial and nonfamilial PGLs/PHEOs were studied. Moderately or highly stabilized HIF1 alpha was present in 68% (26/38) of the PGLs but in PHEOs (n = 16) no such pattern was observed. We then analyzed the suggested link between HIF1 alpha stabilization and MSH2 repression, in HLRCC and HPGL tumor material. No microsatellite instability (MSI) or lack of MSH2 expression was, however, observed. Thus we failed to provide in vivo evidence for the proposed link between HIF1 alpha stabilization and functional MMR deficiency, in TCAC deficient tumors.
authors.affiliation: Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: Heli J
authors.initials: HJ
authors.lastname: Lehtonen
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Mäkinen
authors.forename: Maija
authors.initials: M
authors.lastname: Kiuru
authors.forename: Päivi
authors.initials: P
authors.lastname: Laiho
authors.forename: Riitta
authors.initials: R
authors.lastname: Herva
authors.forename: Ivonne
authors.initials: I
authors.lastname: van Minderhout
authors.forename: Pancras C W
authors.initials: PC
authors.lastname: Hogendoorn
authors.forename: Cees
authors.initials: C
authors.lastname: Cornelisse
authors.forename: Peter
authors.initials: P
authors.lastname: Devilee
authors.forename: Virpi
authors.initials: V
authors.lastname: Launonen
authors.forename: Lauri A
authors.initials: LA
authors.lastname: Aaltonen
mesh_terms: D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism; D002952:Citric Acid Cycle / Q000502:physiology; D005649:Fumarate Hydratase / Q000172:deficiency* / Q000235:genetics; D018095:Germ-Line Mutation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism; D018231:Leiomyomatosis / Q000235:genetics / Q000378:metabolism; D053842:Microsatellite Instability; D051718:MutS Homolog 2 Protein / Q000378:metabolism; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics* / Q000378:metabolism; D010235:Paraganglioma / Q000235:genetics / Q000378:metabolism; D010673:Pheochromocytoma / Q000235:genetics / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000172:deficiency* / Q000235:genetics; D046888:Tissue Array Analysis
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D013385:Succinate Dehydrogenase; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein; D005649:Fumarate Hydratase