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Mutational signatures are characteristic combinations of mutation types arising from specific mutagenesis processes such as DNA replication infidelity, exogenous and endogenous genotoxin exposures, defective DNA repair pathways, and DNA enzymatic editing.

The term is used for two distinct concepts, often conflated: mutagen signatures and tumor signatures. Its original use, mutagen signature, referred to a pattern of mutations made in the laboratory by a known mutagen and not made by other mutagens – unique to the mutagen as a human signature is unique to the signer. Uniqueness allows the mutagen to be deduced from a cell's mutations Later, the phrase referred to a pattern of mutations characteristic of a tumor type, although usually not unique to the tumor type nor to a mutagen. If a tumor mutational signature matches a unique mutagen mutational signature, it is valid to deduce the carcinogen exposure or mutagenesis process that occurred in the patient's distant past. Increasingly refined tumor signatures are becoming assignable to mutagen signatures.

Ultraviolet radiation (UV)

 * Signature 7 has a predominance of C>T substitutions at sites of adjacent pyrimidines (adjacent C or T), with a particularly diagnostic subset being the CC>TT dinucleotide mutation. This pattern arises because the major UV-induced DNA photoproducts join two adjacent pyrimidines; the photoproduct is typically the cyclobutane pyrimidine dimer (CPD). Specificity for C>T appears to be due to the million-fold acceleration of C deamination when it is part of a CPD, with the resulting uracil acting as T. CPDs are repaired via transcription-coupled nucleotide excision repair, causing a strong bias for C>T substitutions enriched on the untranscribed DNA strand. The regions of a tumor suppressor protein that are mutationally inactivated in sunlight-related skin cancers are the same as in cancers of organs not exposed to sunlight, but the nucleotide mutated is often shifted a few bases to a site where a CPD could form. Ultraviolet radiation exposure is therefore the proposed underlying mutagenic mechanism of this signature. UV also illustrates a subtlety in interpreting a tumor signature as a mutagen signature: only three-quarters of mutations induced by UV in the laboratory are UV signature mutations because UV also triggers cellular oxidative processes. Therefore even if all mutations in a tumor were caused by UV from sunlight, one quarter of the mutations are expected to not be UV signature mutations. A second carcinogen needn't be invoked to explain those mutations, but a second mutational process is required.

History
During the 1990s, Curtis Harris at the US National Cancer Institute and Bert Vogelstein at the Johns Hopkins Oncology Center in Baltimore reviewed data showing that different types of cancer had their own unique suite of mutations in p53, which were likely to have been caused by different agents, such as the chemicals in tobacco smoke or ultraviolet light from the sun.

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The biological mutagenesis mechanisms underlying mutational signatures (e.g. COSMIC Signatures 1 to 30) include, but are not limited to:

Signature 5 has a predominance of T>C substitutions in the ApTpN trinucleotide context with transcriptional strand bias.

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