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Nat Commun DOI:10.1038/s41467-018-04002-4

Distinct mutational signatures characterize concurrent loss of polymerase proofreading and mismatch repair.

Publication TypeJournal Article
Year of Publication2018
AuthorsHaradhvala, NJ, Kim, J, Maruvka, YE, Polak, P, Rosebrock, D, Livitz, D, Hess, JM, Leshchiner, I, Kamburov, A, Mouw, KW, Lawrence, MS, Getz, G
JournalNat Commun
Date Published2018 05 01
KeywordsCohort Studies, Databases, Genetic, DNA Mismatch Repair, DNA Polymerase II, DNA Polymerase III, DNA Replication, Endometrial Neoplasms, Female, Genome, Human, Humans, Mutation

Fidelity of DNA replication is maintained using polymerase proofreading and the mismatch repair pathway. Tumors with loss of function of either mechanism have elevated mutation rates with characteristic mutational signatures. Here we report that tumors with concurrent loss of both polymerase proofreading and mismatch repair function have mutational patterns that are not a simple sum of the signatures of the individual alterations, but correspond to distinct, previously unexplained signatures: COSMIC database signatures 14 and 20. We then demonstrate that in all five cases in which the chronological order of events could be determined, polymerase epsilon proofreading alterations precede the defect in mismatch repair. Overall, we illustrate that multiple distinct mutational signatures can result from different combinations of a smaller number of mutational processes (of either damage or repair), which can influence the interpretation and discovery of mutational signatures.


Alternate JournalNat Commun
PubMed ID29717118
PubMed Central IDPMC5931517
Grant ListK08 CA219504 / CA / NCI NIH HHS / United States
U24 CA143845 / CA / NCI NIH HHS / United States
UL1 TR001102 / TR / NCATS NIH HHS / United States