Mechanisms underlying mutational signatures in human cancers

• Published in: Nature reviews. Genetics Vol. 15; no. 9; pp. 585 - 598
• Main Authors: Helleday, Thomas, Eshtad, Saeed, Nik-Zainal, Serena
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2014; Nature Publishing Group
• Subjects: 631/208/69; 631/208/737; 631/337/1427; 631/337/151; Agriculture; Analysis; Animal Genetics and Genomics; Biomarkers; Biomedicine; Cancer; Cancer Research; Care and treatment; DNA Damage; DNA Mutational Analysis; DNA Repair; DNA, Neoplasm - genetics; Gene Function; Gene mutations; Genetic aspects; Genome, Human - genetics; Genomes; Human Genetics; Humans; Identification and classification; Medicin och hälsovetenskap; Mutation; Neoplasms - genetics; review-article; Sequence Analysis, DNA; United Kingdom > UK
• ISSN: 1471-0056; 1471-0064; 1471-0064
• DOI: 10.1038/nrg3729

Key Points Cancers bear many thousands of mutations that are the product of the biological perturbations or mutational processes that have occurred throughout the development of the disease. Each mutational process leaves its own characteristic mark of mutations, which is referred to as the mutational signature, on the cancer genome. Mutational signatures are identifiable and quantifiable using mathematical models. Detailed analyses of mutational signatures can determine the DNA damaging components as well as the DNA repair and replicative pathways that have been operative in cancer or that have gone awry. Historical mutational processes give insights into the aetiology of a cancer, whereas ongoing mutational processes might act as biomarkers or targets for treatment. Mutagenic processes leave characteristic imprints on the cancer genome that can help to identify the underlying DNA damaging components as well as DNA repair and replicative pathways that are active or disrupted. This Review discusses these mutational signatures according to different classes of mutations and summarizes how different components contribute mechanistically to produce each signature type. The collective somatic mutations observed in a cancer are the outcome of multiple mutagenic processes that have been operative over the lifetime of a patient. Each process leaves a characteristic imprint — a mutational signature — on the cancer genome, which is defined by the type of DNA damage and DNA repair processes that result in base substitutions, insertions and deletions or structural variations. With the advent of whole-genome sequencing, researchers are identifying an increasing array of these signatures. Mutational signatures can be used as a physiological readout of the biological history of a cancer and also have potential use for discerning ongoing mutational processes from historical ones, thus possibly revealing new targets for anticancer therapies.