Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
Cell. 2012 May 25;149(5):979-93. doi: 10.1016/j.cell.2012.04.024. Epub 2012 May 17.
All cancers carry somatic mutations. The patterns of mutation in cancer genomes reflect the DNA damage and repair processes to which cancer cells and their precursors have been exposed. To explore these mechanisms further, we generated catalogs of somatic mutation from 21 breast cancers and applied mathematical methods to extract mutational signatures of the underlying processes. Multiple distinct single- and double-nucleotide substitution signatures were discernible. Cancers with BRCA1 or BRCA2 mutations exhibited a characteristic combination of substitution mutation signatures and a distinctive profile of deletions. Complex relationships between somatic mutation prevalence and transcription were detected. A remarkable phenomenon of localized hypermutation, termed "kataegis," was observed. Regions of kataegis differed between cancers but usually colocalized with somatic rearrangements. Base substitutions in these regions were almost exclusively of cytosine at TpC dinucleotides. The mechanisms underlying most of these mutational signatures are unknown. However, a role for the APOBEC family of cytidine deaminases is proposed.
所有癌症都携带体细胞突变。癌细胞及其前体细胞所经历的 DNA 损伤和修复过程反映在癌症基因组的突变模式中。为了进一步探索这些机制，我们从 21 例乳腺癌中生成了体细胞突变目录，并应用数学方法提取了潜在过程的突变特征。可识别出多种不同的单核苷酸和双核苷酸取代特征。具有 BRCA1 或 BRCA2 突变的癌症表现出特征性的取代突变特征组合和独特的缺失特征。检测到体细胞突变流行率和转录之间的复杂关系。观察到一种称为“kataegis”的局部超突变的显著现象。kataegis 区域在癌症之间存在差异，但通常与体细胞重排共定位。这些区域中的碱基替换几乎完全是 TpC 二核苷酸上的胞嘧啶。这些突变特征的大多数机制尚不清楚。然而，提出了 APOBEC 家族的胞嘧啶脱氨酶的作用。
