Analysis of the human APC mutation spectrum in a Saccharomyces cerevisiae strain with a mismatch repair defect

Kazunori Otsuka, Takao Suzuki, Hiroyuki Shibata, Satoshi Kato, Masato Sakayori, Hideki Shimodaira, Ryunosuke Kanamaru, Chikashi Ishioka

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Somatic APC mutations in colorectal tumors with an RER phenotype reflect excessive frameshift mutations, especially in simple repetition tracts within the coding sequence. Because this type of mutation is characteristic of cells with a deficient DNA MMR system, the APC mutation signature of RER tumors may be attributable to a defect in the MMR system. However, there is little experimental evidence to prove that the spectrum of mutations and the APC gene distribution are directly influenced by MMR system defects. We therefore examined the mutation spectrum of the MCR of the APC gene after transfection into both MMR-proficient and MMR-deficient yeast strains and compared it with a previously reported human APC mutation database. Small insertions or deletions in mono- or dinucleotide repeats were more common in the MMR-deficient than in the MMR-proficient strain (91.2% vs. 38.1%, Fisher's exact test p < 0.0001). Furthermore, the 2 mutation hot spots, 4385-4394(AG)5 and 4661-4666(A)6, found in the yeast system corresponded with those in human tumors. Combining our data with those from human tumors, there appears to be hypermutable mutations in specific simple repetitive sequences within the MCR, which are more prevalent in MMR-deficient cells and RER tumors than in MMR-proficient cells and non-RER tumors. We therefore consider that the differences in the spectra of RER and non-RER tumors are attributable at least in part to the MMR system of the host cells.

Original languageEnglish
Pages (from-to)624-630
Number of pages7
JournalInternational Journal of Cancer
Volume103
Issue number5
DOIs
Publication statusPublished - 2003 Feb 20

Keywords

  • APC gene
  • Colorectal tumorigenesis
  • Mismatch repair
  • Replication error
  • Yeast

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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