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.
Highlights
Microsatellites are repetitive elements of 1–6 nucleotides tandemly repeated 10–60 times [1]
In a previous retrospective analysis for quality assessment in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory, we demonstrated the robust performance characteristics of an next-generation sequencing (NGS) assay using the AmpliSeq Cancer Hotspot Panel and Personal Genome Machine to detect a panel of KRAS, NRAS, BRAF, and PIK3CA genes (CRC panel) for prediction of anti-EGFR resistance [30, 31]
Of the 142 samples tested for both the AmpliSeq panel and microsatellite instability (MSI), 113 were MSS and 29 were microsatellite instability-high www.impactjournals.com/oncotarget (MSI-H)
Summary
Microsatellites (or short tandem repeats, STRs) are repetitive elements of 1–6 nucleotides tandemly repeated 10–60 times [1]. When the MMR machinery is defective, these slippage events go unrepaired and this results in microsatellite instability (MSI), defined as deviation in the number of tandem repeats in the tumor when compared to normal [6, 7, 8]. CRCs with defective MMR have a mutation rate that is 100 to 1000 fold greater than that of CRCs with intact MMR [14] These mutations occur in roughly equal numbers of frameshifts and base substitution mutations in the HPRT reporter gene, indicative of the mutations that occur in all genes and thereby creating mutational profiles distinct than those of microsatellite-stable (MSS) CRCs [15, 16, 17]
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