Mutations in two short noncoding mononucleotide repeats in most microsatellite-unstable colorectal cancers

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Deficient Pms2, ERCC1, Ku86, CcOI in Field Defects During Progression to Colon Cancer
28:15

Deficient Pms2, ERCC1, Ku86, CcOI in Field Defects During Progression to Colon Cancer

Published on: July 28, 2010

Tuija Hienonen1, Heli Sammalkorpi, Susa Enholm

  • 1Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, Finland.

Cancer Research
|June 3, 2005
PubMed

Insights

Microsatellite instability (MSI) in DNA mismatch repair (MMR)-deficient tumors frequently mutates noncoding DNA repeats. High mutation frequencies were observed in intronic and intergenic T9 repeats, suggesting broader instability in these sequences.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • DNA mismatch repair (MMR) deficiency leads to microsatellite instability (MSI), characterized by mutations in repetitive DNA sequences.
  • MSI is a hallmark of certain cancers, promoting malignant transformation through mutations in critical genes.
  • Previous research focused on coding regions, but intronic repeat mutations also warrant investigation in MSI tumorigenesis.

Purpose of the Study:

  • To investigate mutation frequencies in noncoding repetitive DNA sequences within MMR-deficient colorectal cancers.
  • To assess the impact of intronic T9 repeat mutations in the semenogelin I (SEMG1) gene.
  • To evaluate the general mutation frequency of short repetitive sequences in the noncoding regions of MSI colorectal cancers.

Main Methods:

  • Analysis of an intronic T9 repeat in the semenogelin I (SEMG1) gene in MMR-deficient colorectal cancers and cell lines.
  • Assessment of SEMG1 mutation effects using RNA and protein level analyses.
  • Screening for intergenic T9 repeat alterations in a cohort of MSI colorectal cancers.

Main Results:

  • High mutation frequencies (51% in primary tumors, 62% in cell lines) were observed in the intronic T9 repeat of SEMG1.
  • No significant differences in SEMG1 RNA or protein levels were detected between cell lines with varying SEMG1 mutation status.
  • One of ten examined intergenic T9 repeats showed high mutation frequency (70%) in MSI colorectal cancers.
  • Observed mutation frequencies in noncoding repeats were higher than previously reported for short repeats (<10 bp) in MMR-deficient tumors.

Conclusions:

  • MMR-deficient tumors exhibit substantial mutation frequencies in noncoding repeat tracts, potentially exceeding those in known target genes.
  • These findings suggest that neutral short repetitive sequences can accumulate mutations at high rates in MSI tumors, irrespective of selection pressure.
  • A comprehensive, large-scale evaluation of mutation frequencies in these neutral sequences is crucial for understanding MSI tumorigenesis.

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