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Environmental Factor, September 2015

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NIEHS sheds light on main cause of mutations in certain cancers

By Robin Arnette

Headshot of Gordenin

"If cancer samples have a strong APOBEC mutagenesis signature, it’s coming from APOBEC3A," Gordenin said. "If APOBEC mutagenesis is low in a particular cancer sample, it’s being caused by APOBEC3B." (Photo courtesy of Steve McCaw)

Headshot of chan

"Our work reaffirms that basic science knowledge can explain what’s observed in human cancers, which in turn can be used to inform decision-making for personalized medicine," Chan noted. (Photo courtesy of Steve McCaw)

Headshot of fargo

Fargo’s group promotes and develops bioinformatics tools and resources that support in-house research endeavors at NIEHS. (Photo courtesy of Steve McCaw)

New research published Aug. 10 in the journal Nature Genetics found that a mutation-causing enzyme, known as APOBEC3A (A3A), is most likely the main cause of mutations in certain cancers. Previous work implicated another APOBEC enzyme, known as APOBEC3B (A3B).

Dmitry Gordenin, Ph.D., head of the NIEHS Mechanisms of Genome Dynamics Group and co-author, led the team of scientists from several institutions that made the discovery. Gordenin said the results not only have far-reaching implications for diagnosis and personalized treatment of cancer, but also help scientists better understand the genome instability of the disease.

"Until our work, this specific APOBEC enzyme had not been identified as a cause of the DNA mutations that cause cancer," Gordenin said. "We hope that the thousands of cancer researchers around the world will use the information to further the field."

Searching for the source

Gordenin explained that APOBEC proteins perform an important function in the immune system by restricting the spread of viruses within the body. A few years ago, he and his group were surprised when they found these same proteins could generate clusters of mutations in some cancers. He published those results in a 2012 issue of the journal Molecular Cell. A year later, he determined that APOBEC enzymes were responsible for a large number of mutations in 80-90 percent of bladder and cervical cancers, and 20-30 percent of head and neck, breast, and lung cancers.

Other researchers also saw APOBEC-induced damage in cancer, but many of them reported A3B was responsible, rather than A3A. To determine which protein was the culprit, team members engineered two varieties of yeast. One strain produced A3A and the other produced A3B. Once Gordenin and colleagues identified the DNA sequences that each APOBEC protein preferentially mutated in yeast, they used the findings to mine data from The Cancer Genome Atlas, a cancer database funded and managed by the National Cancer Institute and the National Human Genome Research Institute.

Their study concluded that A3A caused 10 times more DNA sequence changes than A3B in cancer samples with a high number of APOBEC-induced mutations. In samples with small numbers of APOBEC mutations, A3B was responsible.

Bioinformatics makes sense of the data

The discoveries were made, in part, using an analytical package developed by the NIEHS Integrative Bioinformatics Support Group led by David Fargo, Ph.D. Gordenin said the software was key in determining which APOBEC protein was causing the most damage. It was so important that collaborators at the Broad Institute of the Massachusetts Institute of Technology and Harvard incorporated the software into its Firehose analytical package. Fargo noted one of the best things about the software, designed by a contractor working in his group, is its versatility.

"Flexible analytical tools, primarily developed by Dr. Les Klimczak, can be configured to highlight and evaluate mutation patterns, presenting exciting translational science opportunities," Fargo said.

According to Gordenin, the success of the study was also dependent on the dedication, creativity, and talent of Kin, Chan, Ph.D., lead author and research fellow in the Gordenin group. Chan was a recipient of a prestigious National Institutes of Health Pathway to Independence Award.

Gordenin summed up the importance of the paper by saying it combined results from basic science studies with the statistical exploration of big data cancer genomics.

Citation: Chan K, Roberts SA, Klimczak LJ, Sterling JF, Saini N, Malc EP, Kim J, Kwiatkowski DJ, Fargo DC, Mieczkowski PA, Getz G, Gordenin DA. 2015. An APOBEC3A hypermutation signature is distinguishable from the signature of background mutagenesis by APOBEC3B in human cancers. Nat Genet; doi:10.1038/ng.3378 [Online 10 August 2015].

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