Mutational profiling of colorectal cancers with microsatellite instability

Oncotarget. 2015 Dec 8;6(39):42334-44. doi: 10.18632/oncotarget.5997.


Microsatellite instability (MSI) is caused by defective mismatch repair in 15-20% of colorectal cancers (CRCs). Higher mutation loads in tumors with mismatch repair deficiency can predict response to pembrolizumab, an anti-programmed death 1 (PD-1) immune checkpoint inhibitor. We analyzed the mutations in 113 CRCs without MSI (MSS) and 29 CRCs with MSI-High (MSI-H) using the 50-gene AmpliSeq cancer panel. Overall, MSI-H CRCs showed significantly higher mutations than MSS CRCs, including insertion/deletion mutations at repeat regions. MSI-H CRCs showed higher incidences of mutations in the BRAF, PIK3CA, and PTEN genes as well as mutations in the receptor tyrosine kinase families. While the increased mutations in BRAF and PTEN in MSI-H CRCs are well accepted, we also support findings of mutations in the mTOR pathway and receptor tyrosine kinase family genes. MSS CRCs showed higher incidences of mutations in the APC, KRAS and TP53 genes, confirming previous findings. NGS assays may be designed to detect driver mutations for targeted therapeutics and to identify tumors with high mutation loads for potential treatment with immune checkpoint blockade therapies. Further studies may be warranted to elucidate potential targeted therapeutics against mutations in the mTOR pathway and the receptor tyrosine kinase family in MSI-H CRCs as well as the benefit of anti-PD-1 immunotherapy in hypermutated MSS CRCs or other cancers.

Keywords: PTEN; colorectal cancer; mTOR pathway; microsatellite instability; mutation profiling.

MeSH terms

  • Adenomatous Polyposis Coli Protein / genetics
  • Class I Phosphatidylinositol 3-Kinases
  • Colorectal Neoplasms / genetics*
  • DNA Mutational Analysis / methods*
  • Gene Frequency
  • High-Throughput Nucleotide Sequencing / methods*
  • Humans
  • Microsatellite Instability*
  • Mutation*
  • PTEN Phosphohydrolase / genetics
  • Phosphatidylinositol 3-Kinases / genetics
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Signal Transduction / genetics
  • TOR Serine-Threonine Kinases / genetics
  • Tumor Suppressor Protein p53 / genetics


  • APC protein, human
  • Adenomatous Polyposis Coli Protein
  • KRAS protein, human
  • Tumor Suppressor Protein p53
  • MTOR protein, human
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • Proto-Oncogene Proteins B-raf
  • TOR Serine-Threonine Kinases
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Proto-Oncogene Proteins p21(ras)