Immunological Features with DNA Microsatellite Alterations in Patients with Colorectal Cancer.

Maide Ö Raeker ,John M Carethers

doi:10.33696/cancerimmunol.2.024

Maide Ö Raeker , John M Carethers

Open Access

https://doi.org/10.33696/cancerimmunol.2.024

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Abstract

Competent human DNA mismatch repair (MMR) corrects DNA polymerase mistakes made during cell replication to maintain complete DNA fidelity in daughter cells; faulty DNA MMR occurs in the setting of inflammation and neoplasia, creating base substitutions (e.g. point mutations) and frameshift mutations at DNA microsatellite sequences in progeny cells. Frameshift mutations at DNA microsatellite sequences are a detected biomarker termed microsatellite instability (MSI) for human disease, as this marker can prognosticate and determine therapeutic approaches for patients with cancer. There are two types of MSI: MSI-High (MSI-H), defined by frameshifts at mono- and di-nucleotide microsatellite sequences, and elevated microsatellite alterations at selected tetranucleotide repeats or EMAST, defined by frameshifts in di- and tetranucleotide microsatellite sequences but not mononucleotide sequences. Patients with colorectal cancers (CRCs) manifesting MSI-H demonstrate improved survival over patients without an MSI-H tumor, driven by the generation of immunogenic neoantigens caused by novel truncated proteins from genes whose sequences contain coding microsatellites; these patients' tumors contain hundreds of somatic mutations, and show responsiveness to treatment with immune checkpoint inhibitors. Patients with CRCs manifesting EMAST demonstrate poor survival over patients without an EMAST tumor, and may be driven by a more dominant defect in double strand break repair attributed to the MMR protein MSH3 over its frameshift correcting function; these patients' tumors often have a component of inflammation (and are also termed inflammation-associated microsatellite alterations) and show less somatic mutations and lack coding mononucleotide frameshift mutations that seem to generate the neoantigens seen in the majority of MSI-H tumors. Overall, both types of MSI are biomarkers that can prognosticate patients with CRC, can be tested for simultaneously in marker panels, and informs the approach to specific therapy including immunotherapy for their cancers.

Highlights

DNA microsatellites are tandemly repeating short (1-6 base pairs) DNA motifs, such as mononucleotide (A)n, dinucleotide (CA)n, trinucleotide (CAG)n, and tetranucleotide (AAAG)n, with each motif potentially repeating up to 50 times
The vast majority of microsatellite sequences are found in non-coding DNA, with a small proportion of mono, di, and tri-nucleotide repeats occurring within exons that code for proteins
Our results suggest that insertions do occur, but often are converted into deletions through continual reversions that contract the number of tetranucleotide microsatellite units to give a broad diverse mutational spectrum in the absence of mismatch repair (MMR)

Summary

Introduction

DNA microsatellites are tandemly repeating short (1-6 base pairs) DNA motifs, such as mononucleotide (A)n, dinucleotide (CA)n, trinucleotide (CAG)n, and tetranucleotide (AAAG)n, with each motif potentially repeating up to 50 times. There is a fifth MMR-defective condition that does not result in MSI-H and appears not to generate hypermutated CRCs. Elevated microsatellite alterations at selected tetranucleotide repeats or EMAST is defined by frameshifts in di- and tetranucleotide microsatellite sequences but not mononucleotide sequences [14,15].

Results

Conclusion