Abstract
The APOBEC proteins fight off viruses by editing their genomes. A deletion that removes one of the proteins produces large numbers of mutations in the human genome, potentially leading to cancer.
A deletion that eliminates an antiviral gene in the APOBEC family leads to an explosion of mutations throughout the genome, researchers report.
APOBEC proteins combat viruses by editing their nucleic acids. For example, one family member, APOBEC3G, converts cytidines into uridines in HIV's genome. Although APOBEC proteins are generally beneficial, researchers have wondered whether the proteins' actions might also prompt cancer-causing mutations. They've homed in on two distinctive mutation patterns, known as signature 2 and signature 13, that might result from APOBEC activity. These alterations affect three-nucleotide sequences in which the first two bases are T and C—the C is typically altered to either a T or a G.
A team led by Michael Stratton, MD, PhD, of the Wellcome Trust Sanger Institute in Hinxton, UK, found that these changes are prevalent in certain breast tumors and other cancers; some so-called hypermutator tumors can harbor up to 70,000 of the mutations.
In their new study, Stratton and colleagues looked for a link between signatures 2 and 13 and a deletion in one APOBEC gene cluster that has been implicated in breast cancer. Seven APOBEC genes sit next to each other on chromosome 22, and the deletion removes parts of the APOBEC3A and APOBEC3B genes. Next-generation sequencing of more than 900 breast cancer tumors showed a relationship between the deletion and the number of signature 2 and signature 13 mutations in the genome.
“People who have this deletion have a greater likelihood of having breast cancers that are heavily mutated with this specific pattern,” says lead author Serena Nik-Zainal, MD, PhD, also of the Wellcome Trust Sanger Institute.
Multiple signature 2 and signature 13 mutations also showed up in patients with acute lymphoblastic leukemia and bladder cancer who carry the deletion, the researchers reported (Nat Genet 2014;46:487–91).
The team added further evidence that the deletion prompts the characteristic mutations. When APOBEC proteins make sequential edits, they tend to occur on the same DNA strand. In breast cancer tumors with the deletion, these same-strand mutations are unusually common.
Not everyone with the deletion develops a hypermutator tumor, and not everyone with numerous signature 2 and 13 mutations carries the deletion. The deletion is “probably one of multiple contributing factors” that increase the number of mutations, says Nik-Zainal.
What these other factors are isn't clear. The tantalizing mystery is how the deletion leads to so many mutations. It eliminates the coding region for APOBEC3B, so individuals with the deletion lack this protein. However, they produce a functional form of APOBEC3A that's under control of the 3′-UTR regulatory region for APOBEC3B, so “you might be getting a more mutagenic APOBEC3A,” says Nik-Zainal.
Although it might favor cancer, this APOBEC3A variant could be beneficial in some circumstances, Nik-Zainal notes. The deletion is very common in parts of the world—93% of people from Oceania carry it—so it might provide some survival advantage, possibly by increasing disease resistance.
For more news on cancer research, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
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