Comprehensive evaluation of coding region point mutations in microsatellite-unstable colorectal cancer.
Gylfe, Alexandra E
Taipale, Anssi Jussi Nikolai
Dermitzakis, Emmanouil T
EMBO molecular medicine
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Kondelin, J., Salokas, K., Saarinen, L., Ovaska, K., Rauanheimo, H., Plaketti, R., Hamberg, J., et al. (2018). Comprehensive evaluation of coding region point mutations in microsatellite-unstable colorectal cancer.. EMBO molecular medicine, 10 (9)https://doi.org/10.15252/emmm.201708552
Microsatellite instability (MSI) leads to accumulation of an excessive number of mutations in the genome, mostly small insertions and deletions. MSI colorectal cancers (CRCs), however, also contain more point mutations than microsatellite-stable (MSS) tumors, yet they have not been as comprehensively studied. To identify candidate driver genes affected by point mutations in MSI CRC, we ranked genes based on mutation significance while correcting for replication timing and gene expression utilizing an algorithm, MutSigCV Somatic point mutation data from the exome kit-targeted area from 24 exome-sequenced sporadic MSI CRCs and respective normals, and 12 whole-genome-sequenced sporadic MSI CRCs and respective normals were utilized. The top 73 genes were validated in 93 additional MSI CRCs. The MutSigCV ranking identified several well-established MSI CRC driver genes and provided additional evidence for previously proposed CRC candidate genes as well as shortlisted genes that have to our knowledge not been linked to CRC before. Two genes, SMARCB1 and STK38L, were also functionally scrutinized, providing evidence of a tumorigenic role, for SMARCB1 mutations in particular.
Humans, Colorectal Neoplasms, Sequence Analysis, DNA, Point Mutation, Microsatellite Instability, Gene Regulatory Networks, Molecular Sequence Annotation
Wellcome Trust (091310/Z/10/Z)
External DOI: https://doi.org/10.15252/emmm.201708552
This record's URL: https://www.repository.cam.ac.uk/handle/1810/293417
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/