Analysis of fumarate hydratase mutations in a population-based series of early onset uterine leiomyosarcoma patients

Sanna Ylisaukko-oja, Maija Kiuru, Heli J Lehtonen, Rainer Lehtonen, Eero Pukkala, Johanna Arola, Virpi Launonen, Lauri A Aaltonen

    Research output: Contribution to journalArticleScientificpeer-review

    Abstract

    "Germline mutations in fumarate hydratase (FH) gene at 1q43 predispose to hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. In HLRCC, the most common clinical features are leiomyomas of the skin and uterus, and in a subset of the families, renal cell cancer (RCC) and uterine leiomyosarcoma (ULMS) occur frequently at young age. This study was conducted to evaluate the possible contribution of FH mutations in a population-based series of early onset (<= 45 years) ULMSs. Eighty-one cases were identified through the national cancer registry, and samples from 67 cases (83%) were available for FH mutation screening and analysis of allelic imbalance (AI) at the FH locus. Seventeen percent of tumors showed AI. In the mutation analysis, a novel missense mutation K424R was found. The mutation was also found from the patient's normal tissue. To study whether this variant has functional consequences, FlH enzyme activity assay was performed in a cell model. The activity of the mutated protein was significantly reduced as compared to wild type (p = 0.009). This study shows that FH germline mutations can occur in seemingly nonsyndromic cases of ULMS (1/67, 1.5%). It appears that on the population level hereditary FH defects do play a role in pathogenesis of sporadic early onset ULMSs, albeit rarely. (c) 2006 Wiley-Liss, Inc."
    Original languageEnglish
    JournalInternational Journal of Cancer
    Volume119
    Issue number2
    Pages (from-to)283-287
    Number of pages5
    ISSN0020-7136
    DOIs
    Publication statusPublished - 2006
    MoE publication typeA1 Journal article-refereed

    Fields of Science

    • 311 Basic medicine

    Cite this

    Ylisaukko-oja, Sanna ; Kiuru, Maija ; Lehtonen, Heli J ; Lehtonen, Rainer ; Pukkala, Eero ; Arola, Johanna ; Launonen, Virpi ; Aaltonen, Lauri A. / Analysis of fumarate hydratase mutations in a population-based series of early onset uterine leiomyosarcoma patients. In: International Journal of Cancer. 2006 ; Vol. 119, No. 2. pp. 283-287.
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    title = "Analysis of fumarate hydratase mutations in a population-based series of early onset uterine leiomyosarcoma patients",
    abstract = "{"}Germline mutations in fumarate hydratase (FH) gene at 1q43 predispose to hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. In HLRCC, the most common clinical features are leiomyomas of the skin and uterus, and in a subset of the families, renal cell cancer (RCC) and uterine leiomyosarcoma (ULMS) occur frequently at young age. This study was conducted to evaluate the possible contribution of FH mutations in a population-based series of early onset (<= 45 years) ULMSs. Eighty-one cases were identified through the national cancer registry, and samples from 67 cases (83{\%}) were available for FH mutation screening and analysis of allelic imbalance (AI) at the FH locus. Seventeen percent of tumors showed AI. In the mutation analysis, a novel missense mutation K424R was found. The mutation was also found from the patient's normal tissue. To study whether this variant has functional consequences, FlH enzyme activity assay was performed in a cell model. The activity of the mutated protein was significantly reduced as compared to wild type (p = 0.009). This study shows that FH germline mutations can occur in seemingly nonsyndromic cases of ULMS (1/67, 1.5{\%}). It appears that on the population level hereditary FH defects do play a role in pathogenesis of sporadic early onset ULMSs, albeit rarely. (c) 2006 Wiley-Liss, Inc.{"}",
    keywords = "311 Basic medicine",
    author = "Sanna Ylisaukko-oja and Maija Kiuru and Lehtonen, {Heli J} and Rainer Lehtonen and Eero Pukkala and Johanna Arola and Virpi Launonen and Aaltonen, {Lauri A}",
    year = "2006",
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    language = "English",
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    Analysis of fumarate hydratase mutations in a population-based series of early onset uterine leiomyosarcoma patients. / Ylisaukko-oja, Sanna; Kiuru, Maija; Lehtonen, Heli J; Lehtonen, Rainer; Pukkala, Eero; Arola, Johanna; Launonen, Virpi; Aaltonen, Lauri A.

    In: International Journal of Cancer, Vol. 119, No. 2, 2006, p. 283-287.

    Research output: Contribution to journalArticleScientificpeer-review

    TY - JOUR

    T1 - Analysis of fumarate hydratase mutations in a population-based series of early onset uterine leiomyosarcoma patients

    AU - Ylisaukko-oja, Sanna

    AU - Kiuru, Maija

    AU - Lehtonen, Heli J

    AU - Lehtonen, Rainer

    AU - Pukkala, Eero

    AU - Arola, Johanna

    AU - Launonen, Virpi

    AU - Aaltonen, Lauri A

    PY - 2006

    Y1 - 2006

    N2 - "Germline mutations in fumarate hydratase (FH) gene at 1q43 predispose to hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. In HLRCC, the most common clinical features are leiomyomas of the skin and uterus, and in a subset of the families, renal cell cancer (RCC) and uterine leiomyosarcoma (ULMS) occur frequently at young age. This study was conducted to evaluate the possible contribution of FH mutations in a population-based series of early onset (<= 45 years) ULMSs. Eighty-one cases were identified through the national cancer registry, and samples from 67 cases (83%) were available for FH mutation screening and analysis of allelic imbalance (AI) at the FH locus. Seventeen percent of tumors showed AI. In the mutation analysis, a novel missense mutation K424R was found. The mutation was also found from the patient's normal tissue. To study whether this variant has functional consequences, FlH enzyme activity assay was performed in a cell model. The activity of the mutated protein was significantly reduced as compared to wild type (p = 0.009). This study shows that FH germline mutations can occur in seemingly nonsyndromic cases of ULMS (1/67, 1.5%). It appears that on the population level hereditary FH defects do play a role in pathogenesis of sporadic early onset ULMSs, albeit rarely. (c) 2006 Wiley-Liss, Inc."

    AB - "Germline mutations in fumarate hydratase (FH) gene at 1q43 predispose to hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. In HLRCC, the most common clinical features are leiomyomas of the skin and uterus, and in a subset of the families, renal cell cancer (RCC) and uterine leiomyosarcoma (ULMS) occur frequently at young age. This study was conducted to evaluate the possible contribution of FH mutations in a population-based series of early onset (<= 45 years) ULMSs. Eighty-one cases were identified through the national cancer registry, and samples from 67 cases (83%) were available for FH mutation screening and analysis of allelic imbalance (AI) at the FH locus. Seventeen percent of tumors showed AI. In the mutation analysis, a novel missense mutation K424R was found. The mutation was also found from the patient's normal tissue. To study whether this variant has functional consequences, FlH enzyme activity assay was performed in a cell model. The activity of the mutated protein was significantly reduced as compared to wild type (p = 0.009). This study shows that FH germline mutations can occur in seemingly nonsyndromic cases of ULMS (1/67, 1.5%). It appears that on the population level hereditary FH defects do play a role in pathogenesis of sporadic early onset ULMSs, albeit rarely. (c) 2006 Wiley-Liss, Inc."

    KW - 311 Basic medicine

    U2 - 10.1002/ijc.21798

    DO - 10.1002/ijc.21798

    M3 - Article

    VL - 119

    SP - 283

    EP - 287

    JO - International Journal of Cancer

    JF - International Journal of Cancer

    SN - 0020-7136

    IS - 2

    ER -