Monthly Scientific Update – May 2023

APOBEC3-Mediated Mutagenesis in Cholangiocarcinoma

Many enzymes are involved in the immune response to viruses and APOBEC3s are a class of those enzymes. APOBEC3s are expressed in cells as soon as a virus enters the body and they help eliminate it by damaging its genome. However, APOBEC3s can also act on host cell DNA, leaving it susceptible to mutation.

APOBEC3s leave specific molecular footprints in human DNA known as mutational signatures 2 and 13. These mutations play a big role in human cancer, and APOBEC3s are expressed in many tumor types. A recent review article explored the causes, consequences, and therapeutic potential of APOBEC3-mediated mutagenesis in cancers—including cholangiocarcinoma.

In explaining the prevalence of the APOBEC3 overexpression in cancer, the article noted that APOBEC3A and APOBEC3B are both overexpressed in cholangiocarcinoma. Certain mutations suggest that APOBEC3A may be a significant mutagenic driver in this tumor type. Which of the seven APOBEC3s are the most significant mutators is an active research area and may vary across tumor types.

The article next reviewed the many factors that can trigger aberrant APOBEC3 expression in cancer. Certain genotoxic drug exposures have been shown to induce APOBEC3s in other tumor types, and inflammation—specifically the pro-inflammatory factors IL-6 and TNF-α—have been shown to increase APOBEC3B expression in cholangiocarcinoma. Other factors such as replication stress, retrotransposon activity, and certain mutations and germline variants were also noted as factors able to induce APOBEC3s in cancer. For cholangiocarcinoma specifically, the article discussed two germline genetic variants that affect APOBEC3 expression and cancer risk.

The review also summarized studies on the immune-modulating effects of APOBEC3s, although no data were available for cholangiocarcinoma. Studies on the prognostic significance of APOEBC3s in cholangiocarcinoma were similarly unavailable but could pave the road for the use of APOBEC3s as clinical biomarkers. APOBEC3s may be especially useful biomarkers for cisplatin chemotherapy.

The article also discussed multiple emerging APOEBC3-based treatment options for cancer. Specifically, the article discussed how APOBEC3 activity could be either inhibited to slow tumor growth or enhanced to sensitize tumors to cisplatin or immunotherapy. The ideal APOBEC3 targeting strategy depends on the tumor type and treatment context, so further research on the role and prognostic impact of APOBEC3s in cholangiocarcinoma is essential and could pave the road for new treatment options.

Reference: Butler, K., Banday, A.R. APOBEC3-mediated mutagenesis in cancer: causes, clinical significance and therapeutic potential. J Hematol Oncol 16, 31 (2023).

Kelly Butler

Kelly Butler is an NIH Postbac Research Fellow and the Founding Director of SAFE