1] Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK. [2] Department of Medical Genetics, Addenbrooke's Hospital National Health Service (NHS) Trust, Cambridge, UK.
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
Nat Genet. 2014 May;46(5):487-91. doi: 10.1038/ng.2955. Epub 2014 Apr 13.
The somatic mutations in a cancer genome are the aggregate outcome of one or more mutational processes operative through the lifetime of the individual with cancer. Each mutational process leaves a characteristic mutational signature determined by the mechanisms of DNA damage and repair that constitute it. A role was recently proposed for the APOBEC family of cytidine deaminases in generating particular genome-wide mutational signatures and a signature of localized hypermutation called kataegis. A germline copy number polymorphism involving APOBEC3A and APOBEC3B, which effectively deletes APOBEC3B, has been associated with modestly increased risk of breast cancer. Here we show that breast cancers in carriers of the deletion show more mutations of the putative APOBEC-dependent genome-wide signatures than cancers in non-carriers. The results suggest that the APOBEC3A-APOBEC3B germline deletion allele confers cancer susceptibility through increased activity of APOBEC-dependent mutational processes, although the mechanism by which this increase in activity occurs remains unknown.
癌症基因组中的体细胞突变是一个或多个突变过程在癌症个体的一生中作用的综合结果。每个突变过程都会留下一个特征性的突变特征，由构成它的 DNA 损伤和修复机制决定。最近有人提出，APOBEC 家族的胞嘧啶脱氨酶在产生特定的全基因组突变特征和称为 kataegis 的局部超突变特征方面发挥了作用。涉及 APOBEC3A 和 APOBEC3B 的种系拷贝数多态性，有效地删除了 APOBEC3B，与乳腺癌的风险适度增加有关。在这里，我们表明，携带缺失的乳腺癌比非携带者的癌症显示出更多的假定依赖 APOBEC 的全基因组特征的突变。结果表明，APOBEC3A-APOBEC3B 种系缺失等位基因通过增加依赖 APOBEC 的突变过程的活性赋予癌症易感性，尽管这种活性增加的机制尚不清楚。
