1.5.16 Mutational Signature Definition

Mutational Signature Definition is the description of a characteristic pattern of mutation types, and of the sequence context surrounding those mutations, that arises across a genome as the cumulative result of a specific mutagenic process, such that the pattern can be recognized and attributed to its causative process when observed in the genome of a cell or tumor. A mutational signature is not a single mutation but rather a statistical distribution describing the relative frequency of different mutation categories, most commonly single base substitutions classified according to the identity of the mutated base and the identity of the immediately flanking bases, and this distribution serves as a molecular record of the biological or chemical process that generated the mutations.

Conceptual Basis of Mutational Signatures

Mutations as a Record of Process

Every mutagenic process, whether it originates from an external chemical or physical exposure or from an internal cellular mechanism, tends to damage or miscopy DNA in a manner that is not entirely random. Instead, each process exhibits characteristic preferences, favoring certain base changes, certain flanking sequence contexts, or certain genomic regions over others. Because these preferences are consistent each time the process acts, the accumulated mutations left behind by a given process form a recognizable pattern rather than an unstructured collection of changes.

Composition of a Mutational Signature

A mutational signature is typically defined using a base substitution classification scheme that records, for each single base substitution, the type of nucleotide change together with the nucleotide located immediately before and immediately after the mutated position. This scheme produces a defined set of possible mutation categories, and a mutational signature is expressed as the relative proportion of mutations falling into each of these categories, forming a distinctive profile that can be compared across samples.

Categories of Mutational Signature Origin

Endogenous Cellular Processes

Certain mutational signatures arise from mutagenic processes that occur naturally within cells, independent of any external exposure. These include the spontaneous chemical instability of certain modified bases, error-prone activity of specific DNA-editing enzyme families, and imperfect proofreading during DNA replication. Each of these endogenous sources produces a characteristic and reproducible mutational pattern.

Exogenous Environmental Exposures

Other mutational signatures result from exposure to external mutagenic agents, such as components of tobacco smoke, ultraviolet radiation, or other environmental chemical carcinogens. Each such external agent tends to damage DNA through a distinct chemical mechanism, producing a signature that differs from those generated by endogenous processes and often differs from the signatures of other external agents.

DNA Repair Deficiency-Associated Signatures

A further category of mutational signature arises not from a mutagen itself but from the failure of a DNA repair pathway that would ordinarily correct naturally occurring DNA damage or replication errors. When a specific repair pathway is impaired, the types of damage or errors that pathway would normally correct instead persist and become fixed as mutations, producing a signature that reflects the particular repair function that has been lost.

Identification and Extraction of Mutational Signatures

Cataloging Mutations Across a Genome

Identification of mutational signatures begins with cataloging all detected mutations across a sequenced genome, recording each mutation's type and its surrounding sequence context, to build a comprehensive tally of how frequently each mutation category occurs within that particular genome.

Decomposition Into Component Signatures

Because a single tumor genome commonly reflects the combined activity of more than one mutagenic process operating over its history, the overall mutation catalog is mathematically decomposed into a combination of individual component signatures, each contributing a certain proportion of the total mutations observed, allowing the distinct processes that shaped the genome to be inferred even though their effects are superimposed on one another.

Significance of Mutational Signatures Within Cancer Cell Biology

Reconstructing the Mutagenic History of a Tumor

Mutational signatures allow the mutagenic history of a tumor to be reconstructed, revealing which endogenous processes, environmental exposures, or repair deficiencies contributed to the accumulation of genetic alteration over the course of that tumor's development, even when the exposures themselves occurred long before the tumor was detected.

Association With Underlying Molecular Defects

Certain mutational signatures are strongly associated with specific underlying molecular defects, such as the loss of function of a particular DNA repair pathway, and the presence of such a signature within a tumor's mutation catalog can therefore serve as indirect evidence that the corresponding molecular defect is present in that tumor.