Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.
Nat Genet. 2022 Nov;54(11):1599-1608. doi: 10.1038/s41588-022-01196-8. Epub 2022 Oct 24.
Mutational signatures associated with apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC)3 cytosine deaminase activity have been found in over half of cancer types, including some therapy-resistant and metastatic tumors. Driver mutations can occur in APOBEC3-favored sequence contexts, suggesting that mutagenesis by APOBEC3 enzymes may drive cancer evolution. The APOBEC3-mediated signatures are often detected in subclonal branches of tumor phylogenies and are acquired in cancer cell lines over long periods of time, indicating that APOBEC3 mutagenesis can be ongoing in cancer. Collectively, these and other observations have led to the proposal that APOBEC3 mutagenesis represents a disease-modifying process that could be inhibited to limit tumor heterogeneity, metastasis and drug resistance. However, critical aspects of APOBEC3 biology in cancer and in healthy tissues have not been clearly defined, limiting well-grounded predictions regarding the benefits of inhibiting APOBEC3 mutagenesis in different settings in cancer. We discuss the relevant mechanistic gaps and strategies to address them to investigate whether inhibiting APOBEC3 mutagenesis may confer clinical benefits in cancer.
与载脂蛋白 B mRNA 编辑酶催化多肽样 (APOBEC)3 胞嘧啶脱氨酶活性相关的突变特征已在超过一半的癌症类型中发现，包括一些耐药性和转移性肿瘤。驱动突变可发生在 APOBEC3 偏好的序列环境中，提示 APOBEC3 酶的突变可能驱动癌症进化。APOBEC3 介导的特征通常在肿瘤系统发育的亚克隆分支中检测到，并在癌细胞系中经过长时间获得，表明 APOBEC3 突变可在癌症中持续发生。综上所述，这些和其他观察结果表明，APOBEC3 突变代表一种疾病修饰过程，可通过抑制该过程来限制肿瘤异质性、转移和耐药性。然而，APOBEC3 在癌症和健康组织中的生物学的一些关键方面尚未明确界定，限制了在癌症的不同环境中抑制 APOBEC3 突变的好处的合理预测。我们讨论了相关的机制差距和解决这些差距的策略，以研究抑制 APOBEC3 突变是否可能为癌症带来临床益处。
