No evidence for dual role of loss of heterozygosity in hereditary non-polyposis colorectal cancer

Sari Tuupanen, Auli Karhu, Heikki J Järvinen, Jukka-Pekka Mecklin, Virpi Launonen, Lauri A Aaltonen

    Research output: Contribution to journalArticleScientificpeer-review

    Abstract

    Hereditary non-polyposis colorectal cancer (HNPCC) is caused by germline mutations in mismatch repair (MMR) genes, mostly MLH1 and MSH2. Somatic inactivation of the wild-type allele of the respective MMR gene is required for tumor development. Unexpectedly, a recent study utilizing DNA from paraffin-embedded tissue material detected frequent loss of the mutant MMR gene allele in HNPCC tumors. Dual role for loss of heterozygosity (LOH) was proposed. If somatic loss of the wild-type MMR gene allele had occurred through point mutation or promoter hypermethylation, frequent somatic deletions at the region of the MMR gene locus, perhaps targeting other relevant cancer genes, could quite commonly lead to loss of the mutant allele. To test this hypothesis, we studied a population-based series of 25 fresh-frozen HNPCC tumors with a germline mutation in MLH1 or MSH2 for LOH. Fourteen of the 25 tumors (56%) showed LOH at the respective locus, and all 14 losses targeted the wild-type allele (P=0.00006). These results strongly support the traditional two-hit model of HNPCC gene inactivation.
    Original languageEnglish
    JournalOncogene
    Volume26
    Issue number17
    Pages (from-to)2513-2517
    Number of pages5
    ISSN0950-9232
    DOIs
    Publication statusPublished - 2007
    MoE publication typeA1 Journal article-refereed

    Fields of Science

    • 311 Basic medicine

    Cite this

    @article{87dd290a5a034947a11e2ed8161ec4d6,
    title = "No evidence for dual role of loss of heterozygosity in hereditary non-polyposis colorectal cancer",
    abstract = "Hereditary non-polyposis colorectal cancer (HNPCC) is caused by germline mutations in mismatch repair (MMR) genes, mostly MLH1 and MSH2. Somatic inactivation of the wild-type allele of the respective MMR gene is required for tumor development. Unexpectedly, a recent study utilizing DNA from paraffin-embedded tissue material detected frequent loss of the mutant MMR gene allele in HNPCC tumors. Dual role for loss of heterozygosity (LOH) was proposed. If somatic loss of the wild-type MMR gene allele had occurred through point mutation or promoter hypermethylation, frequent somatic deletions at the region of the MMR gene locus, perhaps targeting other relevant cancer genes, could quite commonly lead to loss of the mutant allele. To test this hypothesis, we studied a population-based series of 25 fresh-frozen HNPCC tumors with a germline mutation in MLH1 or MSH2 for LOH. Fourteen of the 25 tumors (56{\%}) showed LOH at the respective locus, and all 14 losses targeted the wild-type allele (P=0.00006). These results strongly support the traditional two-hit model of HNPCC gene inactivation.",
    keywords = "311 Basic medicine",
    author = "Sari Tuupanen and Auli Karhu and J{\"a}rvinen, {Heikki J} and Jukka-Pekka Mecklin and Virpi Launonen and Aaltonen, {Lauri A}",
    year = "2007",
    doi = "10.1038/sj.onc.1210038",
    language = "English",
    volume = "26",
    pages = "2513--2517",
    journal = "Oncogene",
    issn = "0950-9232",
    publisher = "Nature Publishing Group",
    number = "17",

    }

    No evidence for dual role of loss of heterozygosity in hereditary non-polyposis colorectal cancer. / Tuupanen, Sari; Karhu, Auli; Järvinen, Heikki J; Mecklin, Jukka-Pekka; Launonen, Virpi; Aaltonen, Lauri A.

    In: Oncogene, Vol. 26, No. 17, 2007, p. 2513-2517.

    Research output: Contribution to journalArticleScientificpeer-review

    TY - JOUR

    T1 - No evidence for dual role of loss of heterozygosity in hereditary non-polyposis colorectal cancer

    AU - Tuupanen, Sari

    AU - Karhu, Auli

    AU - Järvinen, Heikki J

    AU - Mecklin, Jukka-Pekka

    AU - Launonen, Virpi

    AU - Aaltonen, Lauri A

    PY - 2007

    Y1 - 2007

    N2 - Hereditary non-polyposis colorectal cancer (HNPCC) is caused by germline mutations in mismatch repair (MMR) genes, mostly MLH1 and MSH2. Somatic inactivation of the wild-type allele of the respective MMR gene is required for tumor development. Unexpectedly, a recent study utilizing DNA from paraffin-embedded tissue material detected frequent loss of the mutant MMR gene allele in HNPCC tumors. Dual role for loss of heterozygosity (LOH) was proposed. If somatic loss of the wild-type MMR gene allele had occurred through point mutation or promoter hypermethylation, frequent somatic deletions at the region of the MMR gene locus, perhaps targeting other relevant cancer genes, could quite commonly lead to loss of the mutant allele. To test this hypothesis, we studied a population-based series of 25 fresh-frozen HNPCC tumors with a germline mutation in MLH1 or MSH2 for LOH. Fourteen of the 25 tumors (56%) showed LOH at the respective locus, and all 14 losses targeted the wild-type allele (P=0.00006). These results strongly support the traditional two-hit model of HNPCC gene inactivation.

    AB - Hereditary non-polyposis colorectal cancer (HNPCC) is caused by germline mutations in mismatch repair (MMR) genes, mostly MLH1 and MSH2. Somatic inactivation of the wild-type allele of the respective MMR gene is required for tumor development. Unexpectedly, a recent study utilizing DNA from paraffin-embedded tissue material detected frequent loss of the mutant MMR gene allele in HNPCC tumors. Dual role for loss of heterozygosity (LOH) was proposed. If somatic loss of the wild-type MMR gene allele had occurred through point mutation or promoter hypermethylation, frequent somatic deletions at the region of the MMR gene locus, perhaps targeting other relevant cancer genes, could quite commonly lead to loss of the mutant allele. To test this hypothesis, we studied a population-based series of 25 fresh-frozen HNPCC tumors with a germline mutation in MLH1 or MSH2 for LOH. Fourteen of the 25 tumors (56%) showed LOH at the respective locus, and all 14 losses targeted the wild-type allele (P=0.00006). These results strongly support the traditional two-hit model of HNPCC gene inactivation.

    KW - 311 Basic medicine

    U2 - 10.1038/sj.onc.1210038

    DO - 10.1038/sj.onc.1210038

    M3 - Article

    VL - 26

    SP - 2513

    EP - 2517

    JO - Oncogene

    JF - Oncogene

    SN - 0950-9232

    IS - 17

    ER -