



The development of an advanced immune system to fight off microbial pathogens is a considerable part of the evolutionary success of multicellular organisms. Yet, like most success stories there is always a flip side. New evidence from investigators at the University of Colorado (CU) Cancer Center shows how the action of various immunity-based enzymes can spill over onto the host genome when trying to fight off various viral pathogens—ultimately leading to cancer-causing DNA mutations. Findings from the new study were published recently in Viruses, in an article entitled “Roles of APOBEC3A and APOBEC3B in Human Papillomavirus Infection and Disease Progression.”

Infection with human papillomavirus (HPV) is the primary cause of cervical cancer as well as a subset of head and neck cancers worldwide. In the current study, the researchers found that a family of enzymes, called APOBEC3, may be the link between viral infection and cancer. Typically, the APOBEC3 enzymes respond to viral infection by attacking viral DNA, causing debilitating mutations. The CU researchers found that this facet of the immune system, designed to scramble viral DNA, can scramble human DNA as well, sometimes in ways that cause cancer.

“We know that the majority of cancers are caused by genetic mutations,” explained senior study investigator Dohun Pyeon, Ph.D., associate professor in the department of immunology and microbiology at the CU School of Medicine. “And we know some of the mechanisms that cause these mutations; for example, ultraviolet (UV) radiation can cause mutations that lead to skin cancer and smoking can cause mutations that lead to lung cancer. But there are many more cancers in which we don't know the source of the mutations. The APOBEC3 family can explain how some of these mutations are created. In fact, APOBEC3A can be activated in many ways—not just with HPV infection—and its action may drive a percentage of oncogenic mutations across many cancer types.”

Utilizing data from the Cancer Genome Atlas, the investigators were able to show signatures of APOBEC3-mediated mutations in the PIK3CA gene of about 40% of HPV-positive head and neck cancers, but only about 10% of HPV-negative head and neck cancers. Additionally, the expression of APOBEC3A was much higher in HPV-positive cancers—providing additional evidence to the hypothesis of APOBEC3A-mediated oncogenesis.

“About four years ago, cancer genomics researchers found interesting mutation signatures in the DNA of cancer cells, showing that these mutations were caused by APOBEC3 enzymes,” Dr. Pyeon noted. “Our study shows that a significant fraction of mutations in HPV-positive cancers are potentially caused by one of these APOBEC3 enzymes.”

Interestingly, this system that so heavily risks damaging host DNA doesn't work so well against its intended target—APOBEC3A does not successfully eliminate the HPV virus, which remains as a chronic infection.

“We have another paper from 2015 showing that HPV has revised its genome against this APOBEC3 enzyme, altering and reducing the target sequences in its own DNA,” Dr. Pyeon remarked. If APOBEC3 fails to recognize its target sequence, it does not interrupt the DNA. “In this, we can see the complex race of evolution—the host evolves the APOBEC3 system to target viruses, but then the viruses evolve their DNA to evade APOBEC3. We are not at any endpoint of evolution—what we may be seeing is our body's attempt to use this APOBEC3 system to help it evolve more quickly in response to the virus.”

The researchers also noted that because APOBEC3A is an enzyme, it would likely be susceptible to drug development aimed at stopping its action. However, the enzyme isn't something that acts once, as it is chronically elevated along with HPV infection, leading to years or decades of higher mutation rates. However, while this mechanism describes the beginnings of carcinogenesis, inhibiting APOBEC3A would be akin to “locking the barn door after the horse has bolted.”

“This would have to be a cancer prevention strategy,” Dr. Pyeon concluded. “Perhaps if you are infected with HPV or have especially high APOBEC3A levels, you could have a drug to prevent any significant mutations. [Alternatively,] now that we can recognize cells altered by APOBEC3, we could teach tumor neoantigen-based immunotherapies to recognize these cells as well.”



























