PerspectiveCANCER

Mutation hotspots may not be drug targets

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Science  28 Jun 2019:
Vol. 364, Issue 6447, pp. 1228-1229
DOI: 10.1126/science.aax9108

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Summary

Landmark studies of tumor genomes have revealed considerable intertumoral genomic heterogeneity, characterized by acquired (somatic) mutations and chromosomal aberrations (1, 2). The majority of somatic mutations in tumor genomes are thought to be randomly occurring passenger mutations that do not drive tumorigenesis. However, some are driver mutations, affecting a limited number of genes and pathways that are important for oncogenesis (1, 2). Because random mutations are unlikely to affect the same genomic position, recurrent mutations or “hotspots” are assumed to indicate positive selection for mutations that confer a fitness advantage (3). Genes harboring mutational hotspots are often prioritized for drug development and clinical investigation. On page 1251 of this issue, Buisson et al. (4) show that inappropriate activation of APOBEC3A (apolipoprotein B mRNA editing enzyme catalytic subunit 3A), an enzyme that deaminates cytidine DNA bases and thereby causes mutations, can create mutational hotspots that are independent of tumor cell fitness.

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