Edinburgh Research Explorer Association of germline variants in the APOBEC3 region with cancer risk and enrichment with APOBEC-signature mutations in tumors
Edinburgh Research Explorer Association of germline variants in the APOBEC3 region with cancer risk and enrichment with APOBEC-signature mutations in tumors
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许多肿瘤中都存在高比例的 APOBEC 特征突变，但影响这 47 种突变模式的因素尚不清楚。在这里，我们探讨了 APOBEC3 区域中两个常见的 48 个种系变异的贡献。单核苷酸多态性 rs1014971 49 与膀胱癌风险、APOBEC3B ( A3B ) 表达增加以及膀胱肿瘤中 APOBEC 特征突变富集 50 相关。相比之下，51 消除 A3B 并产生 A3AB 嵌合体的 30 Kb 缺失在膀胱癌中并不重要，而 52 与乳腺癌风险和乳腺癌肿瘤中 APOBEC 特征突变的富集相关。在体外，A3B 主要是通过在 54 种膀胱癌细胞系中使用 DNA 损伤药物处理来诱导的，而 A3A 则是作为抗病毒干扰素刺激反应的一部分在乳腺癌细胞系中诱导的 55 。这些发现表明环境 56 种致癌触发因素具有组织特异性作用，特别是在具有种系 APOBEC3 风险变异的个体中。 57
High rates of APOBEC-signature mutations are found in many tumors, but factors affecting this 47 mutation pattern are not well understood. Here, we explored the contribution of two common 48 germline variants in the APOBEC3 region. A single nucleotide polymorphism, rs1014971, was 49 associated with bladder cancer risk, increased APOBEC3B ( A3B ) expression, and enrichment 50 with APOBEC-signature mutations in bladder tumors. In contrast, a 30 Kb deletion that 51 eliminates A3B and creates A3AB chimera, was not important in bladder cancer, while being 52 associated with breast cancer risk and enrichment with APOBEC-signature mutations in breast 53 tumors. In vitro, A3B was predominantly induced by treatment with a DNA-damaging drug in 54 bladder cancer cell lines and A3A was induced as part of antiviral interferon-stimulated response 55 in breast cancer cell lines. These findings suggest a tissue-specific role of environmental 56 oncogenic triggers, particularly in individuals with germline APOBEC3 risk variants. 57