Prospects & Overviews
Clustered and genome-wide transient mutagenesis in human cancers: Hypermutation without permanent mutators or loss of fitness
Article first published online: 26 FEB 2014
Published 2014. This article is a U.S. Government work and is in the public domain in the USA. Bioessays published by WILEY Periodicals, Inc.
Volume 36, Issue 4, pages 382–393, April 2014
How to Cite
Roberts, S. A. and Gordenin, D. A. (2014), Clustered and genome-wide transient mutagenesis in human cancers: Hypermutation without permanent mutators or loss of fitness. Bioessays, 36: 382–393. doi: 10.1002/bies.201300140
- Issue published online: 5 MAR 2014
- Article first published online: 26 FEB 2014
- NIH, National Institute of Environmental Health Sciences. Grant Number: ES065073
- NIH Pathway to Independence Award. Grant Number: K99ES022633-01
- DNA damage;
- DNA repair;
- mutation cluster
The gain of a selective advantage in cancer as well as the establishment of complex traits during evolution require multiple genetic alterations, but how these mutations accumulate over time is currently unclear. There is increasing evidence that a mutator phenotype perpetuates the development of many human cancers. While in some cases the increased mutation rate is the result of a genetic disruption of DNA repair and replication or environmental exposures, other evidence suggests that endogenous DNA damage induced by AID/APOBEC cytidine deaminases can result in transient localized hypermutation generating simultaneous, closely spaced (i.e. “clustered”) multiple mutations. Here, we discuss mechanisms that lead to mutation cluster formation, the biological consequences of their formation in cancer and evidence suggesting that APOBEC mutagenesis can also occur genome-wide. This raises the possibility that dysregulation of these enzymes may enable rapid malignant transformation by increasing mutation rates without the loss of fitness associated with permanent mutators.