An enzyme that protects human cells against viruses can help drive cancer evolution towards greater malignancy by causing myriad mutations in cancer cells, a new study has shown.
According to a study led by investigators at Weill Cornell Medicine in the US, the enzyme called "APOBEC3G" may be a potential target for future cancer treatments.
The researchers investigated the role of the enzyme in promoting bladder cancer using a preclinical model and discovered that it significantly increased the number of mutations in tumour cells, increasing the genetic diversity of bladder tumours and hastening mortality.
"Our findings suggest that APOBEC3G is a big contributor to bladder cancer evolution and should be considered as a target for future treatment strategies," said study's senior author Dr Bishoy M. Faltas, assistant professor at Weill Cornell Medicine.
The APOBEC3 family of enzymes is capable of mutating RNA or DNA — by chemically modifying a cytosine nucleotide, according to the study.
The normal roles of these enzymes, including APOBEC3G, are to fight retroviruses like HIV by attempting to stymie viral replication by mutating the cytosines in the viral genome.
Such findings point to the possibility that cancers generally harness APOBEC3s to mutate their genomes, said the study.
As APOBEC3G is a human enzyme not found in mice, the researchers replaced the gene for the sole APOBEC3-type enzyme in mice with the gene for human APOBEC3G.
Identifying the specific mutational signature of APOBEC3G and mapping it in the tumour genomes, the team discovered ample evidence that the enzyme caused a higher mutational burden and genomic diversity in the tumours, likely accounting for the increased malignancy and mortality in the APOBEC3G mice.
"We saw a distinct mutational signature caused by APOBEC3G in these tumours that is different from signatures caused by other members of the APOBEC3 family," said first author Dr Weisi Liu, a postdoctoral research associate.
Finally, the researchers looked for APOBEC3G's mutational signature in The Cancer Genome Atlas, a widely used human tumour DNA database, and discovered that these mutations appear to be common in bladder cancers and are associated with poorer outcomes, the study added.
"These findings will inform future efforts to restrict or steer tumour evolution by targeting APOBEC3 enzymes with drugs," said Dr Faltas.20221229-175401