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Updated: Nov 19, 2025
Evaluation of Colorectal Cancer Risk and Prevalence by Stool DNA Integrity Detection
Published on: June 8, 2020
No evidence of EMAST in whole genome sequencing data from 248 colorectal cancers
Johanna Kondelin1,2, Samantha Martin1,2, Riku Katainen1,2
1Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.
Abstract:
Microsatellite instability (MSI) is caused by defective DNA mismatch repair (MMR), and manifests as accumulation of small insertions and deletions (indels) in short tandem repeats of the genome. Another form of repeat instability, elevated microsatellite alterations at selected tetranucleotide repeats (EMAST), has been suggested to occur in 50% to 60% of colorectal cancer (CRC), of which approximately one quarter are accounted for by MSI. Unlike for MSI, the criteria for defining EMAST is not consensual. EMAST CRCs have been suggested to form a distinct subset of CRCs that has been linked to a higher tumor stage, chronic inflammation, and poor prognosis. EMAST CRCs not exhibiting MSI have been proposed to show instability of di- and trinucleotide repeats in addition to tetranucleotide repeats, but lack instability of mononucleotide repeats. However, previous studies on EMAST have been based on targeted analysis of small sets of marker repeats, often in relatively few samples. To gain insight into tetranucleotide instability on a genome-wide level, we utilized whole genome sequencing data from 227 microsatellite stable (MSS) CRCs, 18 MSI CRCs, 3 POLE-mutated CRCs, and their corresponding normal samples. As expected, we observed tetranucleotide instability in all MSI CRCs, accompanied by instability of mono-, di-, and trinucleotide repeats. Among MSS CRCs, some tumors displayed more microsatellite mutations than others as a continuum, and no distinct subset of tumors with the previously proposed molecular characters of EMAST could be observed. Our results suggest that tetranucleotide repeat mutations in non-MSI CRCs represent stochastic mutation events rather than define a distinct CRC subclass.
Insights
Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) may not define a distinct colorectal cancer (CRC) subtype. Tetranucleotide repeat mutations in microsatellite-stable CRCs appear to be stochastic events, not indicative of a specific cancer subclass.
Area of Science:
- Genomics
- Cancer Biology
- Molecular Oncology
Background:
- Microsatellite instability (MSI) arises from DNA mismatch repair defects, causing insertions/deletions in genomic repeats.
- Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) is proposed in 50-60% of colorectal cancers (CRCs), but its definition and characteristics are debated.
- EMAST CRCs are hypothesized to represent a distinct subset linked to advanced stage, inflammation, and poor prognosis.
Purpose of the Study:
- To investigate tetranucleotide repeat instability genome-wide in colorectal cancer.
- To determine if EMAST represents a distinct molecular subclass of microsatellite-stable (MSS) colorectal cancer.
Main Methods:
- Whole genome sequencing data from 227 MSS CRCs, 18 MSI CRCs, and 3 POLE-mutated CRCs were analyzed.
- Analysis focused on identifying tetranucleotide repeat instability across the genome.
- Comparison of mutation patterns between MSI and MSS CRC cohorts.
Main Results:
- Tetranucleotide instability was observed in all MSI CRCs, along with instability in other repeat types (mono-, di-, tri-nucleotide).
- In MSS CRCs, microsatellite mutations occurred on a continuum, without a distinct subset matching proposed EMAST criteria.
- No evidence supported EMAST as a distinct CRC subclass separate from MSI.
Conclusions:
- Tetranucleotide repeat mutations in non-MSI CRCs are likely stochastic events.
- EMAST does not appear to define a distinct colorectal cancer subclass based on genome-wide analysis.
- Further research is needed to understand the implications of tetranucleotide repeat instability in MSS CRCs.
