Increased HIF1α in SDH and FH deficient tumors does not cause microsatellite instability

Heli J. Lehtonen, Markus J. Mäkinen, Maija Ht Kiuru, Päivi Laiho, Riitta Herva, Ivonne Van Minderhout, Pancras C.W. Hogendoorn, Cees Cornelisse, Peter Devilee, Virpi Launonen, Lauri A. Aaltonen

Research output: Contribution to journalArticle

16 Scopus citations

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 1α (HIF1α). According to recent studies, HIF1α 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 HIF1α 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 HIF1α 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 HIF1α 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 HIF1α stabilization and functional MMR deficiency, in TCAC deficient tumors.

Original languageEnglish (US)
Pages (from-to)1386-1389
Number of pages4
JournalInternational Journal of Cancer
Volume121
Issue number6
DOIs
StatePublished - Sep 15 2007
Externally publishedYes

Keywords

  • Fumarate hydratase
  • HIF1
  • Microsatellite instability
  • MSH2
  • Succinate dehydrogenase

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Increased HIF1α in SDH and FH deficient tumors does not cause microsatellite instability'. Together they form a unique fingerprint.

Cite this