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Vol. LXV, No. 16
August 2, 2013

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Proteins Involved in Immunity Potentially Cause Cancer, NIH Scientists Say

Drs. Dmitry Gordenin (l) and Steven Roberts of NIEHS and their colleagues found that naturally produced mutations are just as powerful as known cancer-causing agents in producing tumors.

Drs. Dmitry Gordenin (l) and Steven Roberts of NIEHS and their colleagues found that naturally produced mutations are just as powerful as known cancer-causing agents in producing tumors.

Photo: NIEHS

A set of proteins involved in the body’s natural defenses produces a large number of mutations in human DNA, according to a study led by researchers at NIH. The findings suggest that these naturally produced mutations are just as powerful as known cancer-causing agents in producing tumors.

The proteins are part of a group called apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) cytidine deaminases. The investigators found that APOBEC mutations can outnumber all other mutations in some cancers, accounting for over two-thirds in some bladder, cervical, breast, head and neck and lung tumors.

The scientists published their findings online July 14 in Nature Genetics. Dr. Dmitry Gordenin, a senior associate scientist at NIEHS, said scientists knew the main functions of APOBEC cytidine deaminases were to inactivate viruses that attack the body and prevent ancient viruses present in the human genome from moving around and causing disrupting mutations. Because they are so important to normal physiology, he and his collaborators were surprised to find a dark side to them—that of mutating human chromosomal DNA.

“The presence of APOBEC clusters in the genome of tumor cells indicates that APOBEC enzymes could also have caused many mutations across the genome,” Gordenin said.

Gordenin’s team at NIEHS and collaborators at medical centers looked for signs of genome-wide APOBEC mutagenesis in cancers listed in The Cancer Genome Atlas. Using APOBEC’s distinctive DNA mutational signature, they examined approximately 1 million mutations in 2,680 cancer samples and found that, in some tumors, nearly 70 percent of mutations in a given specimen resulted from APOBEC mutagenesis. The mutation pattern, which appeared in clusters and individual mutations, could affect many cancer-associated genes.

Dr. Steven Roberts, a postdoctoral fellow who works with Gordenin, explained that since APOBECs are regulated by the immune system, which is responsive to many environmental factors, he believes there may be a significant environmental component to APOBEC mutagenesis. “We hope that determining the environmental link to these mutations will lead to viable cancer prevention strategies,” he said.

NIH Study Identifies Brain Circuits Involved in Learning, Decision-Making

Research from NIH has identified neural circuits in mice that are involved in the ability to learn and alter behaviors. The findings help explain the brain processes that govern choice and the ability to adapt behavior based on the end results.

Researchers think this might provide insight into patterns of compulsive behavior such as alcoholism and other addictions.

“Much remains to be understood about exactly how the brain strikes the balance between learning a behavioral response that is consistently rewarded, versus retaining the flexibility to switch to a new, better response,” said Dr. Kenneth Warren, acting NIAAA director. “These findings give new insight into the process and how it can go awry.”

The study, published online in Nature Neuroscience, indicates that specific circuits in the forebrain play a critical role in choice and adaptive learning.

NIH Scientists Assess History, Pandemic Potential of H7 Influenza Viruses

The emergence of a novel H7N9 avian influenza virus in humans in China has raised questions about its pandemic potential as well as that of related influenza viruses. In a commentary published online July 9 in mBio, scientists at NIAID address these questions by evaluating past outbreaks of H7 subtype influenza viruses among mammals and birds and comparing H7 viruses with other avian influenza viruses and strains.

In recent decades, the scientists write, avian H7 viruses have caused numerous influenza outbreaks among poultry in Europe and North America. Since at least 1918, none of these poultry-adapted viruses has evolved to widely infect humans or cause a pandemic. However, some of them have stably adapted to infect mammals such as horses, suggesting that these viruses might become adapted to and transmissible among other mammals, including humans. In particular, the novel H7N9 virus shares some genes with the H9N2 influenza virus subtype, which has also infected humans. This genetic relatedness may predispose it to more easily adapt to humans than other H7 viruses.

The possibility that H7N9 or another H7 virus may adapt to easily infect humans highlights a need for more research on how avian influenza strains adapt to mammals, especially humans, and better integration of flu research between human and veterinary public health specialists, study authors conclude.

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