A research team led by the University of California, Irvine has discovered the key role that the APOBEC3A and APOBEC3B enzymes play in driving cancer mutations by modifying the DNA in tumour genomes, offering potential new targets for intervention strategies.

The study, published today online in the journal Nature Communications, describes how the researchers identified the process by which APOBEC3A and APOBEC3B detect specific DNA structures, resulting in mutations at distinct positions within the tumour genome.

“It’s critical to understand how cancer cells accumulate mutations leading to hot spots that contribute to disease progression, drug resistance and metastasis,” said corresponding author Rémi Buisson, UCI assistant professor of biological chemistry.

“Both APOBEC3A and APOBEC3B were known to generate mutations in many kinds of tumours, but until now we did not know how to identify the specific type caused by each. This finding will allow us to develop novel therapies to suppress mutation formation by directly targeting each enzyme accordingly.”

In this study, graduate student Ambrocio Sanchez and postdoctoral fellow Pedro Ortega, both in Buisson’s laboratory at the UCI School of Medicine, developed a new method to characterise the particular kind of DNA modified by APOBEC3A and APOBEC3B.

It revealed that the two enzymes do not recognise the same DNA sequences and structures within the genomes of cancer cells.

Based on this observation, an innovative approach utilising these unique target preferences was employed to classify cancer patients who had accumulated mutations caused by each enzyme.

“The next steps are to investigate whether mutations caused by these enzymes lead to various types of therapy resistance.

It’s also critical to identify molecules that inhibit APOBEC3A and APOBEC3B to prevent mutations from forming.

Our findings could, in the future, help to assess patient risk before treatment and suppress tumour evolution using the appropriate drug therapy,” Buisson said.

Source: University of California - Irvine