Molecular mechanism and clinical impact of APOBEC3B-catalyzed mutagenesis in breast cancer

被引:75
作者
Harris, Reuben S. [1 ,2 ]
机构
[1] Univ Minnesota, Masonic Canc Ctr, Inst Mol Virol, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA
[2] Ctr Genome Engn, Minneapolis, MN 55455 USA
来源
BREAST CANCER RESEARCH | 2015年 / 17卷
基金
美国国家卫生研究院;
关键词
DNA CYTOSINE DEAMINASE; EDITING ENZYME APOBEC1; MUTATIONAL PROCESSES; SOMATIC MUTATIONS; FOREIGN DNA; NUCLEAR-DNA; DELETION; PATTERNS; REPAIR; RETROTRANSPOSITION;
D O I
10.1186/s13058-014-0498-3
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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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页数:10
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