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

    Research output: Contribution to journalArticleScientificpeer-review

    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.
    Original languageEnglish
    JournalCancer Research
    Volume67
    Issue number12
    Pages (from-to)5691-5698
    Number of pages8
    ISSN0008-5472
    DOIs
    Publication statusPublished - 2007
    MoE publication typeA1 Journal article-refereed

    Fields of Science

    • 311 Basic medicine

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