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Environmental Factor, June 2012

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Cellular damage from normal metabolism potentially causes cancer

By Robin Arnette

Dmitry Gordenin, Ph.D.

Gordenin said that he and his group are working with bioinformatics experts on future studies. They plan to develop tools that will dissect the history and mutation mechanisms operating in specific cancers by extracting the information from published sequence data and from cancer sequence databases. (Photo courtesy of Steve McCaw)

Steven Roberts, Ph.D.

The research team is the first to report the existence of mutation clusters in yeast and cancers, and the first to determine that the mutations happen simultaneously. As first author on the paper, Roberts played a major role in the discovery. (Photo courtesy of Steve McCaw)

Michael Resnick, Ph.D.

Resnick’s research group uses budding yeast and human cell models to study genome maintenance and natural environmental challenges to chromosome stability. (Photo courtesy of Steve McCaw)

Individual mutations, or changes to an organism’s DNA, are thought to be rare events that occur randomly, but new research from a team led by NIEHS scientists has identified DNA regions in yeast and in some cancers that have a disproportionately high number of mutations. These mutation clusters arose simultaneously, and are produced by exposure to environmental toxins and through typical biochemical processes that occur in living cells. The findings represent an exception to the traditional view that mutations accumulate over time and may explain one of the mechanisms behind cancer development.

Investigators from NIEHS, The Broad Institute of MIT and Harvard, and the Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill published the work online May 17 in the journal Molecular Cell. The journal also selected the paper as the featured article.

Discovery in a yeast model

Dmitry Gordenin, Ph.D., a senior associate scientist in the NIEHS Laboratory of Molecular Genetics (LMG) and corresponding author on the paper, said the discovery resulted from work in a yeast model system designed to investigate mutations caused by environmental damage. Team members subjected yeast to continuous damage, by growing them in media that contained the carcinogen methyl methanesulfonate (MMS). After sequencing the genomes, or total DNA, of approximately 70 yeast cells that emerged after MMS treatment, they found that the number, distribution, and pattern of mutations far exceeded expectations.

“Normally, mutations occur haphazardly throughout the genome, and there is no rule by which [nucleotide] bases are changed, but we found that certain patches, i.e., clusters, contained more mutations than the rest of the genome,” Gordenin said. “These clusters also exhibited a very unusual pattern, suggesting they were formed at the same time in stretches of abnormally long single-stranded DNA.”

Mutation clusters in human tumors

Gordenin and his team wondered if they could use the same principle to see if a similar phenomenon occurred in human cancers. At the time, hundreds of thousands of cancer mutations were being published in the scientific literature, so the team developed bioinformatics tools to look for mutation clusters in 32 human tumors. The tumors belonged to three different cancer types — head and neck, prostate, and multiple myeloma, which is cancer of the antibody-producing white blood cells. The scientists were surprised to find a little over half of the cancers also had mutation clusters.

“We found that in cancer, the cause of the mutation clusters wasn’t environmental damage like we saw in yeast,” explained Steven Roberts, Ph.D., an NIEHS postdoctoral fellow and first author on the paper. “The DNA sequence surrounding clustered mutations suggested that specific proteins called APOBEC cytosine deaminases that contribute to our natural defenses against viruses somehow damage our DNA. APOBEC proteins are stimulated via Toll-like receptors and interferons to inactivate viruses attacking our body. Our work suggests that they are also mutating our chromosomal DNA. Thus, damage is coming from our normal physiology.”

Michael Resnick, Ph.D., is a co-author on the study and leads the LMG Chromosome Stability Group at NIEHS. He said, “Researchers have always considered that mutagenic lesions in the DNA of an organism could be caused by normal metabolism and that these lesions could contribute to genetic damage observed in the cancer genome. Now, we see a clear example supporting this hypothesis.”

Importantly, the NIEHS-led study was published online the same day as a Cell paper from a Wellcome Trust Sanger Institute team in the United Kingdom. The Sanger team studied 21 breast cancer samples and made similar conclusions about mutation clusters and the involvement of APOBEC enzymes.

Utilizing NextGen sequencing

Gordenin said that the results of both teams were only possible due to the advancements of Next Generation (NextGen) sequencing that happened in recent years. He hopes the technology and accumulating information stored in other NextGen databases, such as The Cancer Genome Atlas (TCGA), a major cancer database managed by the National Cancer Institute and the National Human Genome Research Institute, will allow him to hunt for mutation clusters in sequences from thousands of additional tumors and normal human tissue. The work may provide an understanding of the role of clustered mutagenesis in human disease and highlight exposures that damage the human genome. The immediate implication from the current study is that several antiviral drugs capable of stimulating APOBEC genes, such as interferon-containing or interferon-stimulating drugs, should be looked at for potential long-term effects connected with enhanced mutagenesis.

Gordenin said, “Looking at clusters is a productive way to explore the mechanisms that were acting when the cancer was emerging and developing. Our work shows the value of re-analyzing sequenced cancers to find things that no one has paid attention to before.”

Citation: Roberts SA, Sterling J, Thompson C, Harris S, Mav D, Shah R, Klimczak LJ, Kryukov GV, Malc E, Mieczkowski PA, Resnick MA, Gordenin DA. 2012. Clustered mutations in yeast and in human cancers can arise from damaged long single-strand DNA regions. Mol Cell; doi:10.1016/j.molcel.2012.03.030 [Online 17 May 2012].

The mutation clusters phenomenon as demonstrated in yeast and in human cancers.

The mutation clusters phenomenon as demonstrated in yeast and in human cancers. The DNA sequence surrounding clustered mutations in cancers suggested that specific proteins called APOBEC cytosine deaminases, which contribute to our natural defenses against viruses, somehow damage our DNA. (Photo courtesy of Dmitry Gordenin)

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