Tumor Mutational Burden and Microsatellite Instability

Tumor mutational burden and microsatellite instability are genome-wide measures that summarize how heavily mutated a tumor is, rather than focusing on any single gene. Tumor mutational burden counts somatic mutations across the analyzed genome, while microsatellite instability reflects a specific failure of DNA mismatch repair that produces a distinctive pattern of length changes at repetitive sequences; both are used to stratify tumors by their underlying mutational processes.

Definition

Tumor mutational burden is the number of somatic mutations per unit of analyzed genome (commonly expressed per megabase); microsatellite instability is the accumulation of insertions and deletions at short tandem-repeat sequences (microsatellites) caused by deficient DNA mismatch repair, producing a measurable hypermutated, often microsatellite-unstable, tumor phenotype.

Scope

This entry covers what tumor mutational burden and microsatellite instability are, the DNA-repair biology behind a hypermutated phenotype, how each is measured, and how they relate to one another. It is a methodological and conceptual reference within tumor molecular profiling and does not provide testing or treatment recommendations.

Core questions

• How are tumor mutational burden and microsatellite instability defined and measured?
• How does deficient mismatch repair produce microsatellite instability and a high mutational burden?
• How do these genome-wide measures relate to one another and to specific gene alterations?
• What analytic factors affect the reliability and comparability of these measures across assays?

Key concepts

• Tumor mutational burden (mutations per megabase)
• Microsatellite instability
• DNA mismatch-repair deficiency
• Hypermutated phenotype
• Microsatellites and repeat tracts
• Genome-wide versus single-gene biomarkers
• PCR, immunohistochemistry, and sequencing-based detection
• Mutational processes and signatures

Mechanisms

The DNA mismatch-repair system corrects base-pairing errors that arise during replication, and it is especially important at microsatellites, where slippage readily introduces insertions and deletions. When mismatch repair is deficient - through gene mutation or epigenetic silencing - these errors go uncorrected, repeat tracts change length, and microsatellite instability results; the same deficiency lets mutations accumulate genome-wide, producing a high tumor mutational burden. Microsatellite instability is therefore one molecular cause of a high mutational burden, though high burden can also arise from other processes such as carcinogen exposure or defects in proofreading. Microsatellite instability is assessed by PCR of marker loci, by immunohistochemistry for mismatch-repair proteins, or from sequencing data, while tumor mutational burden is derived by counting somatic mutations across a panel, exome, or genome, with results sensitive to the region analyzed and the counting rules used.

Clinical relevance

These genome-wide measures are used to stratify tumors by their mutational processes and have been studied as tissue-agnostic biomarkers in the context of immune-checkpoint therapy. This entry explains the underlying biology, measurement, and evidence; it characterizes how these markers are defined and studied and is not a basis for diagnostic or treatment decisions for any individual.

Epidemiology

Sequencing of very large tumor series shows that tumor mutational burden spans several orders of magnitude across and within cancer types, with the highest burdens in cancers linked to mutagen exposure or repair defects. Microsatellite-unstable tumors form a recognizable minority across several cancer types and are characteristically hypermutated, and the two measures are correlated but not interchangeable.

History

Microsatellite instability was characterized in the 1990s in the context of hereditary nonpolyposis colorectal cancer and deficient mismatch repair, and consensus marker panels and testing recommendations were subsequently established. Large-scale sequencing in the 2010s defined the genome-wide landscape of tumor mutational burden across cancers, and studies of immune-checkpoint therapy drew attention to mismatch-repair deficiency and high mutational burden as cross-tumor molecular features, consolidating both as elements of tumor stratification.

Debates

How should tumor mutational burden be measured and thresholds defined?

Estimates of mutational burden depend on the genomic region analyzed, the assay, and the variant-counting rules, so values are not directly comparable across platforms, and the choice of thresholds for defining a high-burden tumor remains an active harmonization problem.

Key figures

• Dung Le
• C. Richard Boland

Seminal works

• chalmers-2017
• le-2015
• umar-2004

Frequently asked questions

Are tumor mutational burden and microsatellite instability the same thing?

No. Microsatellite instability is a specific signature of deficient DNA mismatch repair seen at repetitive sequences, whereas tumor mutational burden is a count of somatic mutations across the genome; mismatch-repair deficiency raises the mutational burden, but high burden can also arise from other causes, so the two are related but distinct.

Why can tumor mutational burden values differ between laboratories?

Because the measure depends on which part of the genome is sequenced, the depth and quality of the assay, and the rules used to count mutations, results from different platforms are not directly comparable, which is why harmonization and threshold standardization are actively discussed.