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DNA mutations happening as cancer spreads

Clusters of simultaneous multiple DNA mutations can be a source of rapid change as cancer starts and spreads and also during evolution. Now new research of DNA mutations eventually could lead to new cancer therapies, says a new study, "Break-Induced Replication Is a Source of Mutation Clusters Underlying Kataegis,” published online in the May 29, 2014 issue of the journal Cell Reports. DNA mutations—long known to fuel cancer as well as evolutionary changes in a living organism—had been thought to be rare events that occur randomly throughout the genome. However, recent studies have shown that cancer development frequently involves the formation of multiple mutations that arise simultaneously and in close proximity to each other.

DNA mutations happening as cancer spreads.
Photo by Janette Pellegrini

These groups of clustered mutations are frequently found in regions where chromosomal rearrangements take place. The discovery, published in the journal Cell Reports, may one day lead to new cancer therapies, according to a University of Iowa biologist and her colleagues, and a group of researchers from the National Institute of Environmental Health Sciences led by Senior Associate Scientist Dmitry Gordenin. The formation of clustered mutations may result from the process of DNA repair.

The finding that cancer development often involves multiple mutations arising in clusters and in regions where chromosomal rearrangement takes place may one day lead to new cancer therapies

Anna Malkova, associate professor of biology in the University of Iowa (UI) College of Liberal Arts and Sciences, notes that the DNA repair pathway, known as break-induced replication (BIR), can promote clusters of DNA mutations. “Previously, we have shown that double-strand DNA breaks, which can result from oxidation, ionizing radiation and replication errors, can be repaired by BIR,” says Malkova, according to a July 30, 2014 news release, Biologists describe mechanism promoting multiple DNA mutations. “During BIR, one broken DNA end is paired with an identical DNA sequence on another chromosome and initiates an unusual type of replication, which proceeds as a migrating bubble and is associated with the accumulation of large amounts of single-strand DNA,” she says in the news release.

In the Cell Reports study, researchers subjected yeast cells undergoing BIR to alkylating (cancer cell-killing agents) damage. “We found that the single-stranded DNA regions that accumulate during BIR are susceptible to damage that leads to the formation of mutation clusters,” explains Cynthia Sakofsky, according to the news release. Sakofsky is a postdoctoral fellow at the UI and one of two co-first authors on the paper. “These clusters are similar to those found in human cancer,” she says in the news release.

Importantly, say the researchers, the paper provides a mechanism to potentially explain how genetic changes form in human cancers

So, it will be critical for future research to determine whether BIR can form clustered mutations that lead to cancer in humans. If this turns out to be true, it may lead to the discovery of new targets for developing therapies against human cancers. In addition to Malkova, Gordenin and Sakofsky, co-authors of the paper are: Steven A. Roberts, co-first author, and Michael A. Resnick, both of the National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina; and Ewa Malc and Piotr A. Mieczkowski, both of the Department of Genetics, Lineberger Comprehensive Cancer Center and Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, North Carolina.

Funders of the research are NIH grants R01GM084242 (to A.M.) and 5R01GM052319-17 (to P.A.M.) and by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (project ES065073, to M.A.R). And the NIH Pathway to Independence Award K99ES022633-01 supported S.A.R.