1.5.17 Tumor Mutational Burden Definition

Tumor Mutational Burden Definition is the description of a quantitative measure representing the total number of somatic mutations found within a defined unit of coding DNA sequence in a tumor's genome, most commonly expressed as the number of mutations per megabase of sequence examined. Tumor mutational burden provides a single summary value that reflects how heavily a tumor's genome has been altered by mutagenic processes over the course of its development, independent of which specific genes carry those mutations, and it serves as a genome-wide indicator of the overall mutation load carried by a tumor's cells.

Conceptual Basis of Tumor Mutational Burden

A Genome-Wide Rather Than Gene-Specific Measure

Tumor mutational burden differs from analyses that focus on alterations within specific individual genes. Rather than asking whether a particular gene carries a mutation, tumor mutational burden aggregates mutations across the entire sequenced coding region, or a defined portion of the genome, to produce a count that reflects the cumulative mutation load of the tumor as a whole.

Normalization to Sequence Length

Because the amount of DNA sequence examined can vary between different sequencing approaches and different studies, the raw count of mutations is normalized to the size of the sequenced region, most typically expressed per megabase of DNA, allowing tumors assessed with different sequencing panels or platforms to be compared on a common scale.

Contributors to Tumor Mutational Burden

Cumulative Effect of Mutagenic Exposure

Tumor mutational burden reflects the cumulative effect of all mutagenic processes that have acted upon a tumor's cells over time, including exposure to external mutagenic agents and the ongoing activity of endogenous mutational processes, such that tumors arising in tissues subject to heavy mutagenic exposure tend to display substantially higher mutational burden than tumors arising in tissues with minimal such exposure.

Contribution of DNA Repair Deficiency

Tumors that have lost the function of pathways responsible for correcting DNA replication errors or repairing DNA damage tend to accumulate mutations at an accelerated rate, since errors and damage that would ordinarily be corrected instead persist and become fixed as permanent mutations, producing a markedly elevated tumor mutational burden relative to tumors with intact repair function.

Measurement of Tumor Mutational Burden

Whole Exome and Whole Genome Approaches

Tumor mutational burden can be measured by sequencing the entire protein-coding exome or the entire genome of a tumor and counting the somatic mutations identified across that sequenced region, providing a comprehensive but resource-intensive assessment of mutation load.

Targeted Panel Approaches

Tumor mutational burden can also be estimated using a smaller, targeted panel of genes, in which the mutation count observed within the panel is used to extrapolate an estimate of the mutational burden across the broader genome, offering a more practical approach when comprehensive sequencing is not feasible.

Distinguishing Somatic Mutations From Germline Variation

Accurate measurement of tumor mutational burden requires distinguishing mutations that arose specifically within the tumor, referred to as somatic mutations, from genetic variation that was already present in the individual's inherited germline genome, since only the tumor-specific somatic mutations should be counted toward the burden.

Significance of Tumor Mutational Burden Within Cancer Cell Biology

Reflection of Genomic Instability

A high tumor mutational burden reflects substantial underlying genomic instability, indicating that the tumor's cells have been subject to extensive mutagenic exposure, defective repair capacity, or both, over the course of the tumor's development.

Relationship to Neoantigen Formation

Because each additional somatic mutation carries some probability of altering the sequence of an expressed protein, tumors with a higher mutational burden tend to produce a greater number of novel, abnormal protein fragments capable of being recognized as foreign, linking tumor mutational burden to the broader immunological context of the tumor's cellular environment.