Molecular mechanism and clinical impact of APOBEC3B-catalyzed mutagenesis in breast cancer.
Molecular mechanism and clinical impact of APOBEC3B-catalyzed mutagenesis in breast cancer.
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DOI：
10.1186/s13058-014-0498-3
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发表时间：
2015-01-21
期刊：
影响因子：
--
通讯作者：
Harris RS
中科院分区：
文献类型：
--
作者：
Harris RS
癌症基因组DNA序列能够识别所有突变，并为精确医学提供靶标。突变本身的身份和模式也为推断原始DNA损伤剂、因果分子机制和额外的治疗靶点提供了关键信息。一个典型的例子是紫外光，它会使相邻的嘧啶类化合物发生交联，并导致C-T转变。一个新的例子是DNA胞嘧啶脱氨酶APOBEC3B，它最近被发现是乳腺癌、头/颈、宫颈、膀胱癌、肺癌、卵巢癌的DNA损伤和突变的来源，在较小程度上还会导致其他癌症类型。这种酶通常是病毒感染的先天免疫反应中的效应蛋白，但在这些癌症类型中上调会导致基因组C-U脱氨事件水平的升高，在不同的DNA三核苷酸环境中表现为C-T转换和C-G转换(优先是5‘-TCA和5’-TCG)。在相同的三核苷酸环境中，基因组C-到-U脱氨基事件也会导致胞嘧啶突变簇(Kataegi)，并可能导致可见的染色体异常，如易位。临床研究表明，对于雌激素受体阳性的乳腺癌患者，APOBEC3B上调与较差的预后相关，包括较短的无病生存期和术后总生存期。因此，APOBEC3B可能同时具有诊断和预测预后的潜力。APOBEC3B也可能是治疗靶向的候选者，因为抑制这种非必需的酶被预测可以降低肿瘤突变率，并减少不良突变依赖结果的可能性，如复发、转移和耐药肿瘤的发展。
Cancer genomic DNA sequences enable identification of all mutations and suggest targets for precision medicine. The identities and patterns of the mutations themselves also provide critical information for deducing the originating DNA damaging agents, causal molecular mechanisms, and thus additional therapeutic targets. A classic example is ultraviolet light, which crosslinks adjacent pyrimidines and leads to C-to-T transitions. A new example is the DNA cytosine deaminase APOBEC3B, which was identified recently as a source of DNA damage and mutagenesis in breast, head/neck, cervix, bladder, lung, ovary, and to lesser extents additional cancer types. This enzyme is normally an effector protein in the innate immune response to virus infection but upregulation in these cancer types causes elevated levels of genomic C-to-U deamination events, which manifest as C-to-T transitions and C-to-G transversions within distinct DNA trinucleotide contexts (preferentially 5’-TCA and 5’-TCG). Genomic C-to-U deamination events within the same trinucleotide contexts also lead to cytosine mutation clusters (kataegis), and may precipitate visible chromosomal aberrations such as translocations. Clinical studies indicate that APOBEC3B upregulation correlates with poorer outcomes for estrogen receptor-positive breast cancer patients, including shorter durations of disease-free survival and overall survival after surgery. APOBEC3B may therefore have both diagnostic and prognostic potential. APOBEC3B may also be a candidate for therapeutic targeting because inhibition of this non-essential enzyme is predicted to decrease tumor mutation rates and diminish the likelihood of undesirable mutation-dependent outcomes such as recurrence, metastasis, and the development of therapy resistant tumors.
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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：
2.7
作者：
Jia P;Pao W;Zhao Z
通讯作者：
Zhao Z
影响因子：
16
作者：
Harris, RS;Petersen-Mahrt, SK;Neuberger, MS
通讯作者：
Neuberger, MS
DOI：
10.1126/science.1251827
发表时间：
2014-03-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Couch FJ;Nathanson KL;Offit K
通讯作者：
Offit K
影响因子：
4
作者：
EHRLICH, M;NORRIS, KF;GEHRKE, CW
通讯作者：
GEHRKE, CW