Increased HIF1 alpha in SDH and FH deficient tumors does not cause microsatellite instability

Heli J Lehtonen, Markus J Mäkinen, Maija 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 journalArticleScientificpeer-review

    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. (c) 2007 Wiley-Liss, Inc.
    Original languageEnglish
    JournalInternational Journal of Cancer
    Volume121
    Issue number6
    Pages (from-to)1386-1389
    Number of pages4
    ISSN0020-7136
    DOIs
    Publication statusPublished - 2007
    MoE publication typeA1 Journal article-refereed

    Fields of Science

    • 311 Basic medicine

    Cite this

    Lehtonen, Heli J ; Mäkinen, Markus J ; Kiuru, Maija ; Laiho, Päivi ; Herva, Riitta ; van Minderhout, Ivonne ; Hogendoorn, Pancras C. W ; Cornelisse, Cees ; Devilee, Peter ; Launonen, Virpi ; Aaltonen, Lauri A. / Increased HIF1 alpha in SDH and FH deficient tumors does not cause microsatellite instability. In: International Journal of Cancer. 2007 ; Vol. 121, No. 6. pp. 1386-1389.
    @article{d46c9c543e1d481ab5d044418aa83235,
    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. (c) 2007 Wiley-Liss, Inc.",
    keywords = "311 Basic medicine",
    author = "Lehtonen, {Heli J} and M{\"a}kinen, {Markus J} and Maija Kiuru and P{\"a}ivi Laiho and Riitta Herva and {van Minderhout}, Ivonne and Hogendoorn, {Pancras C. W} and Cees Cornelisse and Peter Devilee and Virpi Launonen and Aaltonen, {Lauri A}",
    year = "2007",
    doi = "10.1002/ijc.22819",
    language = "English",
    volume = "121",
    pages = "1386--1389",
    journal = "International Journal of Cancer",
    issn = "0020-7136",
    publisher = "Wiley",
    number = "6",

    }

    Lehtonen, HJ, Mäkinen, MJ, Kiuru, M, Laiho, P, Herva, R, van Minderhout, I, Hogendoorn, PCW, Cornelisse, C, Devilee, P, Launonen, V & Aaltonen, LA 2007, 'Increased HIF1 alpha in SDH and FH deficient tumors does not cause microsatellite instability', International Journal of Cancer, vol. 121, no. 6, pp. 1386-1389. https://doi.org/10.1002/ijc.22819

    Increased HIF1 alpha in SDH and FH deficient tumors does not cause microsatellite instability. / Lehtonen, Heli J; Mäkinen, Markus J; Kiuru, Maija; Laiho, Päivi; Herva, Riitta; van Minderhout, Ivonne; Hogendoorn, Pancras C. W; Cornelisse, Cees; Devilee, Peter; Launonen, Virpi; Aaltonen, Lauri A.

    In: International Journal of Cancer, Vol. 121, No. 6, 2007, p. 1386-1389.

    Research output: Contribution to journalArticleScientificpeer-review

    TY - JOUR

    T1 - Increased HIF1 alpha in SDH and FH deficient tumors does not cause microsatellite instability

    AU - Lehtonen, Heli J

    AU - Mäkinen, Markus J

    AU - Kiuru, Maija

    AU - Laiho, Päivi

    AU - Herva, Riitta

    AU - van Minderhout, Ivonne

    AU - Hogendoorn, Pancras C. W

    AU - Cornelisse, Cees

    AU - Devilee, Peter

    AU - Launonen, Virpi

    AU - Aaltonen, Lauri A

    PY - 2007

    Y1 - 2007

    N2 - 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. (c) 2007 Wiley-Liss, Inc.

    AB - 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. (c) 2007 Wiley-Liss, Inc.

    KW - 311 Basic medicine

    U2 - 10.1002/ijc.22819

    DO - 10.1002/ijc.22819

    M3 - Article

    VL - 121

    SP - 1386

    EP - 1389

    JO - International Journal of Cancer

    JF - International Journal of Cancer

    SN - 0020-7136

    IS - 6

    ER -