Researchers find that proteins involved in immunity potentially cause cancer

This is Dmitry Gordenin, Ph.D., and Steven Roberts, Ph.D., NIEHS. Credit: Steve McCaw, 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 the National Institutes of Health. 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 -like (APOBEC) cytidine deaminases. The investigators found that APOBEC can outnumber all other mutations in some cancers, accounting for over two-thirds in some bladder, cervical, breast, head and neck, and .

The scientists published their findings online July 14 in the journal Nature Genetics. Dmitry Gordenin, Ph.D., is corresponding author of the paper and a senior associate scientist at the National Institute of Environmental Health Sciences (NIEHS), part of NIH. He said scientists knew the main functions of APOBEC cytosine deaminases were to inactivate viruses that attack the body and prevent ancient viruses present in the 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 study is a follow-up to one Gordenin and his group published in Molecular Cell in 2012, after they discovered APOBECs could generate clusters of mutations in some cancers.

This video is not supported by your browser at this time.
Dmitry Gordenin, Ph.D., NIEHS, discusses results of research published July 14, 2013 in Nature Genetics. Credit: John Maruca, NIEHS

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

Gordenin's team at NIEHS, comprised of scientists from the Chromosome Stability Group, headed by Michael Resnick, Ph.D., and the Integrative Bioinformatics Group, headed by David Fargo, Ph.D., took the 2012 research one step further by applying a modern data science approach.

The group collaborated with co-corresponding author Gad Getz, Ph.D., and other colleagues from the Broad Institute of MIT and Harvard, Cambridge, Mass. They looked for signs of genome-wide APOBEC mutagenesis in cancers listed in The Cancer Genome Atlas, a database funded and managed by the National Cancer Institute and the National Human Genome Research Institute, both part of NIH.

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.

Steven Roberts, Ph.D., a postdoctoral fellow who works with Gordenin, is first author on both studies. He 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," Roberts said.

In upcoming work, he and Gordenin plan to address why APOBEC mutagenesis appears in some cancer types and not others.

More information: An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers, DOI: 10.1038/ng.2702

Related Stories

Researchers discover enzyme behind breast cancer mutations

Feb 06, 2013

Researchers at the University of Minnesota have uncovered a human enzyme responsible for causing DNA mutations found in the majority of breast cancers. The discovery of this enzyme – called APOBEC3B – may change the way ...

New mutations driving malignant melanoma discovered

Jan 24, 2013

Two new mutations that collectively occur in 71 percent of malignant melanoma tumors have been discovered in what scientists call the "dark matter" of the cancer genome, where cancer-related mutations haven't ...

Recommended for you

DNA signature found in ice storm babies

Sep 29, 2014

The number of days an expectant mother was deprived of electricity during Quebec's Ice Storm (1998) predicts the epigenetic profile of her child, a new study finds.

User comments

Adjust slider to filter visible comments by rank

Display comments: newest first

JVK
1 / 5 (3) Jul 14, 2013
Which mutations lead to Mutation-driven evolution? http://www.amazon...99661731

Is there a model for that?
Nyloc
not rated yet Jul 16, 2013
I read a recent study that suggested that the introduction of Neanderthal DNA into our genome enhanced our immune systems. Is it possible that the proteins in this a article were introduced into human DNA through the Neanderthal influence?

Is it possible that we gain a short-term benefit to our immune system but then loose long-term survival through an increased risk of cancer? This would explain how these proteins have been passed through the generations, particularly if our ancestors had short lifespans anyway.
JVK
1 / 5 (2) Jul 16, 2013
It's more likely that natural selection for nutrients introduced plant DNA into our genomes that enhanced the thermodynamic control of intracellular signaling, which led to increased organism-level thermoregulatory capacity via changes to our immune system. That's how natural selection leads to sexual selection for phenotypic expression of traits associated with organism-level immune system function (i.e., self / non-self differences) and the thermodynamics of organism-level thermoregulation in my model. Simply put, we are what we eat and signal who and what we are via the metabolism of nutrients to pheromones, which control reproduction in species from microbes to man.