Background mutation frequency in microsatellite-unstable colorectal cancer

Heli Sammalkorpi, Pia Alhopuro, Rainer Lehtonen, Jarno Tuimala, Jukka-Pekka Mecklin, Heikki J Järvinen, Josef Jiricny, Auli Karhu, Lauri A Aaltonen

    Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

    Sammanfattning

    Microsatellite instability (MSI) is observed in similar to 12% of colorectal cancers. Genes containing a mommucleotide microsatellite in the coding sequence are particularly prone to inactivation in MSI tumorigenesis, and much work has been conducted to identify genes with high repetitive tract mutation rates in these tumors. Much less attention has been paid to background mutation frequencies, and no work has focused on nontranscribed regions. Here, we studied 114 nontranscribed intergenic A/T and C/G repeats 6 to 10 bp in length, located distant from known genes, to examine background mutation frequencies in MSI colorectal cancers. A strong correlation with tract length was observed, and mutation frequencies of up to 87% were observed in 8 to 10 lip tracts. Subsequently, to compare the background mutation rate in transcribed and nontranscribed noncoding repeats, we screened nine randomly selected intronic C/G8 repeats. In addition, the coding repeats of seven suggested MSI target genes, and nine previously published intronic A8 and G8 repeats were analyzed. Intronic repeats seemed to mutate less frequently than nontranscribed intergenic repeats. Our results show that strand slippage mutations in mismatch repairdeficient cells are as abundant in short intergenic repeats as in many proposed MSI target genes. However, under mismatch repair deficiency, strand slippage mutations in transcribed sequences seem to be repaired more efficiently than in intergenic nontranscribed sequences. The mechanisms causing these differences are not yet understood and should be a subject for further studies. For MSI target gene identification, repeats in transcribed sequences seem to be the most appropriate reference group for coding region repeat mutations.
    Originalspråkengelska
    TidskriftCancer Research
    Volym67
    Utgåva12
    Sidor (från-till)5691-5698
    Antal sidor8
    ISSN0008-5472
    DOI
    StatusPublicerad - 2007
    MoE-publikationstypA1 Tidskriftsartikel-refererad

    Vetenskapsgrenar

    • 311 Basmedicin

    Citera det här

    Sammalkorpi, Heli ; Alhopuro, Pia ; Lehtonen, Rainer ; Tuimala, Jarno ; Mecklin, Jukka-Pekka ; Järvinen, Heikki J ; Jiricny, Josef ; Karhu, Auli ; Aaltonen, Lauri A. / Background mutation frequency in microsatellite-unstable colorectal cancer. I: Cancer Research. 2007 ; Vol. 67, Nr. 12. s. 5691-5698.
    @article{14da777ae1e7476e9155636ed6da8507,
    title = "Background mutation frequency in microsatellite-unstable colorectal cancer",
    abstract = "Microsatellite instability (MSI) is observed in similar to 12{\%} of colorectal cancers. Genes containing a mommucleotide microsatellite in the coding sequence are particularly prone to inactivation in MSI tumorigenesis, and much work has been conducted to identify genes with high repetitive tract mutation rates in these tumors. Much less attention has been paid to background mutation frequencies, and no work has focused on nontranscribed regions. Here, we studied 114 nontranscribed intergenic A/T and C/G repeats 6 to 10 bp in length, located distant from known genes, to examine background mutation frequencies in MSI colorectal cancers. A strong correlation with tract length was observed, and mutation frequencies of up to 87{\%} were observed in 8 to 10 lip tracts. Subsequently, to compare the background mutation rate in transcribed and nontranscribed noncoding repeats, we screened nine randomly selected intronic C/G8 repeats. In addition, the coding repeats of seven suggested MSI target genes, and nine previously published intronic A8 and G8 repeats were analyzed. Intronic repeats seemed to mutate less frequently than nontranscribed intergenic repeats. Our results show that strand slippage mutations in mismatch repairdeficient cells are as abundant in short intergenic repeats as in many proposed MSI target genes. However, under mismatch repair deficiency, strand slippage mutations in transcribed sequences seem to be repaired more efficiently than in intergenic nontranscribed sequences. The mechanisms causing these differences are not yet understood and should be a subject for further studies. For MSI target gene identification, repeats in transcribed sequences seem to be the most appropriate reference group for coding region repeat mutations.",
    keywords = "311 Basic medicine",
    author = "Heli Sammalkorpi and Pia Alhopuro and Rainer Lehtonen and Jarno Tuimala and Jukka-Pekka Mecklin and J{\"a}rvinen, {Heikki J} and Josef Jiricny and Auli Karhu and Aaltonen, {Lauri A}",
    year = "2007",
    doi = "10.1158/0008-5472.CAN-06-4314",
    language = "English",
    volume = "67",
    pages = "5691--5698",
    journal = "Cancer Research",
    issn = "0008-5472",
    publisher = "American Association for Cancer Research",
    number = "12",

    }

    Background mutation frequency in microsatellite-unstable colorectal cancer. / Sammalkorpi, Heli; Alhopuro, Pia; Lehtonen, Rainer; Tuimala, Jarno; Mecklin, Jukka-Pekka; Järvinen, Heikki J; Jiricny, Josef; Karhu, Auli; Aaltonen, Lauri A.

    I: Cancer Research, Vol. 67, Nr. 12, 2007, s. 5691-5698.

    Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

    TY - JOUR

    T1 - Background mutation frequency in microsatellite-unstable colorectal cancer

    AU - Sammalkorpi, Heli

    AU - Alhopuro, Pia

    AU - Lehtonen, Rainer

    AU - Tuimala, Jarno

    AU - Mecklin, Jukka-Pekka

    AU - Järvinen, Heikki J

    AU - Jiricny, Josef

    AU - Karhu, Auli

    AU - Aaltonen, Lauri A

    PY - 2007

    Y1 - 2007

    N2 - Microsatellite instability (MSI) is observed in similar to 12% of colorectal cancers. Genes containing a mommucleotide microsatellite in the coding sequence are particularly prone to inactivation in MSI tumorigenesis, and much work has been conducted to identify genes with high repetitive tract mutation rates in these tumors. Much less attention has been paid to background mutation frequencies, and no work has focused on nontranscribed regions. Here, we studied 114 nontranscribed intergenic A/T and C/G repeats 6 to 10 bp in length, located distant from known genes, to examine background mutation frequencies in MSI colorectal cancers. A strong correlation with tract length was observed, and mutation frequencies of up to 87% were observed in 8 to 10 lip tracts. Subsequently, to compare the background mutation rate in transcribed and nontranscribed noncoding repeats, we screened nine randomly selected intronic C/G8 repeats. In addition, the coding repeats of seven suggested MSI target genes, and nine previously published intronic A8 and G8 repeats were analyzed. Intronic repeats seemed to mutate less frequently than nontranscribed intergenic repeats. Our results show that strand slippage mutations in mismatch repairdeficient cells are as abundant in short intergenic repeats as in many proposed MSI target genes. However, under mismatch repair deficiency, strand slippage mutations in transcribed sequences seem to be repaired more efficiently than in intergenic nontranscribed sequences. The mechanisms causing these differences are not yet understood and should be a subject for further studies. For MSI target gene identification, repeats in transcribed sequences seem to be the most appropriate reference group for coding region repeat mutations.

    AB - Microsatellite instability (MSI) is observed in similar to 12% of colorectal cancers. Genes containing a mommucleotide microsatellite in the coding sequence are particularly prone to inactivation in MSI tumorigenesis, and much work has been conducted to identify genes with high repetitive tract mutation rates in these tumors. Much less attention has been paid to background mutation frequencies, and no work has focused on nontranscribed regions. Here, we studied 114 nontranscribed intergenic A/T and C/G repeats 6 to 10 bp in length, located distant from known genes, to examine background mutation frequencies in MSI colorectal cancers. A strong correlation with tract length was observed, and mutation frequencies of up to 87% were observed in 8 to 10 lip tracts. Subsequently, to compare the background mutation rate in transcribed and nontranscribed noncoding repeats, we screened nine randomly selected intronic C/G8 repeats. In addition, the coding repeats of seven suggested MSI target genes, and nine previously published intronic A8 and G8 repeats were analyzed. Intronic repeats seemed to mutate less frequently than nontranscribed intergenic repeats. Our results show that strand slippage mutations in mismatch repairdeficient cells are as abundant in short intergenic repeats as in many proposed MSI target genes. However, under mismatch repair deficiency, strand slippage mutations in transcribed sequences seem to be repaired more efficiently than in intergenic nontranscribed sequences. The mechanisms causing these differences are not yet understood and should be a subject for further studies. For MSI target gene identification, repeats in transcribed sequences seem to be the most appropriate reference group for coding region repeat mutations.

    KW - 311 Basic medicine

    U2 - 10.1158/0008-5472.CAN-06-4314

    DO - 10.1158/0008-5472.CAN-06-4314

    M3 - Article

    VL - 67

    SP - 5691

    EP - 5698

    JO - Cancer Research

    JF - Cancer Research

    SN - 0008-5472

    IS - 12

    ER -