Association of germline variants in the APOBEC3 region with cancer risk and enrichment with APOBEC-signature mutations in tumors.
Association of germline variants in the APOBEC3 region with cancer risk and enrichment with APOBEC-signature mutations in tumors.
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DOI：
10.1038/ng.3670
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发表时间：
2016-11
期刊：
影响因子：
30.8
通讯作者：
Prokunina-Olsson L
中科院分区：
文献类型：
--
作者：
Middlebrooks CD;Banday AR;Matsuda K;Udquim KI;Onabajo OO;Paquin A;Figueroa JD;Zhu B;Koutros S;Kubo M;Shuin T;Freedman ND;Kogevinas M;Malats N;Chanock SJ;Garcia-Closas M;Silverman DT;Rothman N;Prokunina-Olsson L
在许多肿瘤中发现了高比率的APOBEC签名突变，但影响这种突变模式的因素还不清楚。在这里，我们探索了APOBEC 3区域中两种常见种系变异的贡献。单核苷酸多态性rs 1014971与膀胱癌风险、APOBEC 3B表达增加以及膀胱肿瘤中APOBEC特征突变富集相关。相比之下，消除APOBEC 3B并产生APOBEC 3AB嵌合体的30 Kb缺失在膀胱癌中并不重要，而与乳腺癌风险和乳腺肿瘤中APOBEC-signature突变的富集相关。在体外，APOBEC 3B主要通过在膀胱癌细胞系中用DNA损伤药物处理来诱导，而APOBEC 3A作为抗病毒干扰素刺激应答的一部分在乳腺癌细胞系中被诱导。这些发现表明环境致癌触发物的组织特异性作用，特别是在具有生殖系APOBEC 3风险变体的个体中。
High rates of APOBEC-signature mutations are found in many tumors, but factors affecting this mutation pattern are not well understood. Here, we explored the contribution of two common germline variants in the APOBEC3 region. A single nucleotide polymorphism, rs1014971, was associated with bladder cancer risk, increased APOBEC3B expression, and enrichment with APOBEC-signature mutations in bladder tumors. In contrast, a 30 Kb deletion that eliminates APOBEC3B and creates APOBEC3AB chimera, was not important in bladder cancer, while being associated with breast cancer risk and enrichment with APOBEC-signature mutations in breast tumors. In vitro, APOBEC3B was predominantly induced by treatment with a DNA-damaging drug in bladder cancer cell lines and APOBEC3A was induced as part of antiviral interferon-stimulated response in breast cancer cell lines. These findings suggest a tissue-specific role of environmental oncogenic triggers, particularly in individuals with germline APOBEC3 risk variants.
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影响因子：
30.8
作者：
Burns, Michael B.;Temiz, Nuri A.;Harris, Reuben S.
通讯作者：
Harris, Reuben S.
影响因子：
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作者：
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Harris RS
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4.6
作者：
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Bellmunt J
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30.8
作者：
Mifsud, Borbala;Tavares-Cadete, Filipe;Osborne, Cameron S.
通讯作者：
Osborne, Cameron S.
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30.8
作者：
Chan K;Roberts SA;Klimczak LJ;Sterling JF;Saini N;Malc EP;Kim J;Kwiatkowski DJ;Fargo DC;Mieczkowski PA;Getz G;Gordenin DA
通讯作者：
Gordenin DA