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.
Highlights
Fidelity of DNA replication is maintained using polymerase proofreading and the mismatch repair pathway
Experimental microsatellite instability (MSI) status (MSI-high [MSI-H], MSI-low [MSI-L], or microsatellite stable (MSS)) was available for 410 tumors[11], and we identified 15 samples classified as MSI-H that harbored a somatic point mutation in the polymerase epsilon (POLE) exonuclease domain, as well as eight MSI-H samples with no POLE proofreading mutation but instead possessing a POLD1 exonuclease domain mutation
The majority (7/8) of POLE and all (3/3) POLD1-mutated tumors classified as MSI-H but lacking MLH1 silencing had either a truncating/frame shift mutation or deletion of one of the four major mismatch repair pathway (MMR) pathway genes (MLH1, MSH2, MSH6, or PMS2), due to the high mutation rate of POLE, many tumors may have such mutations in MMR genes by chance
Summary
Fidelity of DNA replication is maintained using polymerase proofreading and the mismatch repair pathway. DNA replication fidelity is frequently compromised in cancer, leading to accumulation of somatic mutations throughout the evolution of the tumor. These mutations serve as a footprint of the tumor’s underlying DNA damage and repair landscape[1,2]. Specific mutational signatures have been identified in tumors with mutations in the exonuclease (proofreading) domain of polymerase epsilon (POLE), as well as tumors with mutations or epigenetic silencing of genes in the mismatch repair pathway (MMR)[3,4]. A study of more than 500 endometrial tumors revealed that nearly half (12/ 30) of the tumors with a POLE exonuclease domain mutation displayed microsatellite instability (MSI)[10], the characteristic patterns of insertions and deletions associated with loss of MMR function. We identify mutational signatures associated with concurrent POLE or POLD1 exonuclease mutations (POLE-exo* or POLD1-exo*) and MMR loss that are distinct from the signatures associated with either event in isolation
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