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Mutational profiling of colorectal cancers with microsatellite instability.
- Source :
-
Oncotarget [Oncotarget] 2015 Dec 08; Vol. 6 (39), pp. 42334-44. - Publication Year :
- 2015
-
Abstract
- 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.
- Subjects :
- Adenomatous Polyposis Coli Protein genetics
Class I Phosphatidylinositol 3-Kinases
Gene Frequency
Humans
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
Colorectal Neoplasms genetics
DNA Mutational Analysis methods
High-Throughput Nucleotide Sequencing methods
Microsatellite Instability
Mutation
Subjects
Details
- Language :
- English
- ISSN :
- 1949-2553
- Volume :
- 6
- Issue :
- 39
- Database :
- MEDLINE
- Journal :
- Oncotarget
- Publication Type :
- Academic Journal
- Accession number :
- 26517354
- Full Text :
- https://doi.org/10.18632/oncotarget.5997