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Mutation profiling of mismatch repair-deficient colorectal cncers using an in silico genome scan to identify coding
Jane Park1, Doron Betel, Robert Gryfe
1Centre for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, and Department of Laboratory Medicine University of Toronto, Toronto, Ontario, Canada M5G 1X5.
Abstract:
Human colorectal, endometrial, and gastric cancers with defective DNA mismatch repair (MMR) have microsatellite instability, a unique molecular alteration characterized by widespread frameshift mutations of repetitive DNA sequences. We developed "Kangaroo," a bioinformatics program for searches in nucleotide and protein sequence databases, and performed an in silico genome scan for DNA coding microsatellites that may have novel mutations in MMR-deficient cancers. Examination of 29 previously untested coding polyadenines revealed widespread mutations in MMR-deficient colorectal cancers, with the highest frequencies in ERCC5, CASP8AP2, p72, RAD50, CDC25, RECQL1, CBF2, RACK7, GRK4, and DNAPK (range, 10-33%). This algorithm allows comprehensive mutation profiling of MMR-deficient cancers, an important step in understanding the pathogenesis of these neoplasms.
Insights
Researchers identified widespread mutations in DNA coding microsatellites within MMR-deficient colorectal cancers using the "Kangaroo" bioinformatics tool. This finding aids in understanding cancer pathogenesis.
Area of Science:
- Oncology
- Bioinformatics
- Genetics
Background:
- Defective DNA mismatch repair (MMR) leads to microsatellite instability (MSI) in cancers like colorectal, endometrial, and gastric types.
- MSI is characterized by widespread frameshift mutations in repetitive DNA sequences.
Purpose of the Study:
- To develop a bioinformatics program, "Kangaroo," for identifying novel mutations in coding microsatellites within MMR-deficient cancers.
- To perform an in silico genome scan to detect these mutations.
Main Methods:
- Development of the "Kangaroo" bioinformatics program for sequence database searches.
- In silico genome scan of DNA coding microsatellites in MMR-deficient cancer models.
- Analysis of 29 previously untested coding polyadenines for mutations.
Main Results:
- Widespread mutations were observed in MMR-deficient colorectal cancers.
- The highest mutation frequencies (10-33%) were found in ERCC5, CASP8AP2, p72, RAD50, CDC25, RECQL1, CBF2, RACK7, GRK4, and DNAPK.
- The "Kangaroo" algorithm enabled comprehensive mutation profiling.
Conclusions:
- The "Kangaroo" algorithm is effective for comprehensive mutation profiling of MMR-deficient cancers.
- Identification of novel mutations contributes to understanding the pathogenesis of these neoplasms.