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How a family of enzymes meant to fend off viruses can lead to ‘cyclones’ that drive cancer

A family of enzymes tasked with squashing viruses as part of the body’s immune response is typically associated with doing good. But as we know from the Good Place, doing good isn’t always what it seems. Researchers now say that in cancer cells, the enzymes might pose danger. 

The family, dubbed APOBEC3, is usually involved in the cell’s internal immune response, helping bar viruses from entering. But in cancer cells, the family might wreak havoc. The enzymes seem to mistake a popular cancer driver, known as circular rings of extrachromosomal DNA, or ecDNA, for foreign viruses. APOBEC3, true to its purpose, wants to bar entry to the rings of ecDNA and destroy them. 

That then leads to clusters of mutations, which in turn can trigger drug resistance, according to a new study published this month in Nature. The University of California, San Diego researchers said the findings could lead to new therapies that either restrict the family’s activity or target the ecDNA. They also designated a name for the clustered mutations: kyklonas, or cyclones in Greek.

Researchers previously pinpointed one member of the APOBEC3 family, specifically 3B, as a major source of genetic mutations in multiple cancers of the bladder, lung, head, neck, cervix and other tissues. The researchers said they could selectively inhibit 3B using chemically modified DNA molecules, but “more powerful inhibitors” would be needed to go further, a team at Massey University reported in October 2019. 

RELATED: Blocking tumor evolution to halt cancer drug resistance

The APOBEC3 family is not the only potential culprit causing clustered somatic mutations, or non-inherited mutations that group up in a specific area of the cell’s genome. The UC San Diego team highlighted UV radiation, alcohol consumption and tobacco smoking as other bad actors.

The clustered somatic mutations have been mostly ignored because they account for a limited share of all mutations, said Erik Bergstrom, paper author and bioengineering PhD student, in a statement

“We typically see somatic mutations occurring randomly across the genome. But when we looked closer at some of these mutations, we saw that they were occurring in these hotspots. It’s like throwing balls on the floor and then suddenly seeing them cluster in a single space,” said Ludmil Alexandrov, professor of bioengineering and cellular and molecular medicine at UC San Diego, in a statement.

By mapping all the clustered and non-clustered mutations across the genomes of more than 2,500 patients, which encompassed 30 different cancer types, the team found that the mutations contributed to the evolution of about 10% of cancers. 

The team also found that clustered mutations in the BRAF gene, deemed the main driver gene in melanoma, led to better overall patient survival when compared to patients who don’t have the clustered mutations. Whereas in the EGFR gene, central to the development of lung cancer, clustered mutations are associated with decreased survival.

With the insights on this “simple and precise biomarker,” in hand, the researchers said clinicians have “commonly used” platforms at the ready to understand a patient’s chance of survival.

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