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

Nat Commun
Authors
Keywords
Abstract

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.

Year of Publication
2018
Journal
Nat Commun
Volume
9
Issue
1
Pages
1746
Date Published
2018 05 01
ISSN
2041-1723
DOI
10.1038/s41467-018-04002-4
PubMed ID
29717118
PubMed Central ID
PMC5931517
Links
Grant list
K08 CA219504 / CA / NCI NIH HHS / United States
U24 CA143845 / CA / NCI NIH HHS / United States
UL1 TR001102 / TR / NCATS NIH HHS / United States