Heterogeneous contributions of APOBEC3 deaminases to substitution and indel mutagenesis in lung adenocarcinoma.

In lung adenocarcinoma, APOBEC3 mutagenesis in 197 long-term propagated single-cell clones shows three distinct patterns, driven predominantly by APOBEC3A, by APOBEC3A+APOBEC3B, or minimal despite detectable expression.

• Why it matters: APOBEC3 enzymes are major sources of cancer mutations and are linked to tumor evolution and therapy resistance, but LUAD-specific paralog contributions remain unclear for targeting.
• What they did: Using CRISPR-Cas9 knockouts and whole-genome sequencing of 197 long-term propagated single-cell clones, the study tested whether mRNA/protein levels and in vitro deaminase activity predict APOBEC3A/B contributions.
• The result: Surrogate measures do not predict paralog contributions, and endogenous APOBEC3A is causally shown to generate the indel signature InD9a via uracil excision after cytosine deamination, enabling biomarker-guided therapeutic targeting.