Newly Discovered Mutation Fog Triggers Cancer

Scientists have discovered that a hypermutation phenomenon that triggers cancer cell development is related to a normal DNA process. A research team from the IRB Barcelona Genome Data Science lab has identified a new genetic phenomenon of hypermutation—called mutation fog—which can develop multiple mutations in many cells. 

The hypermutation described occurs through a genetic repair reaction, as the APOBEC enzyme is typically coupled and used by human cells to defend themselves from pathogens. Their results—published in Nature Genetics— show that in some cases if APOBEC enzymes and the DNA repair process become activated at the same time, APOBEC hijacks the DNA repair, generating the mutation fog. These mutations are distributed widely but can accumulate in the most important parts of the genome.  

"We think that this APOBEC-driven mutation fog has a mutagenic potential that matches or even exceeds that of well-known strong carcinogens, such as tobacco smoke or ultraviolet radiation," study leader Fran Supek explains. Recent literature suggests that the pathways appear to be more active in late-stage metastatic cancers: it helps cancer evolve, enabling it to become resistant to treatment.  "This finding makes APOBEC an attractive target for treating cancer, removing its ability to evolve and to become more aggressive," Supek adds.

Through analysis of more than 6,000 cancer genomes—including breast, lung, melanoma and other cancer types—led to the finding that the mutation fog is a common phenomenon  "More than half of all APOBEC mutations in some lung or breast cancers are generated by the hypermutation mechanism that we have found," says David Mas-Ponte, first author of the study. 

While other types of cancers are known to be caused by viruses, their study found that mutations caused by the APOBEC system can be found in all tumors. "Understanding APOBEC better could have broad implications for cancer treatment," Mas-Ponte concludes. The statistical method created and used has been shared as open-source software in a Github repository.