Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Nuevo Leon, México.
Mol Genet Genomic Med. 2019 Aug;7(8):e810. doi: 10.1002/mgg3.810. Epub 2019 Jul 11.
The observed mutations in cancer are the result of ~30 mutational processes, which stamp particular mutational signatures (MS). Nevertheless, it is still not clear which genomic alterations correlate to several MS. Here, a method to analyze associations of genomic data with MS is presented and applied to The Cancer Genome Atlas breast cancer data revealing promising associations.
The MS were discretized into clusters whose extremes were statistically associated with mutations, copy number, and gene expression data.
Known associations for apolipoprotein B editing complex (APOBEC) and for BRCA1 and BRCA2 support the proposal. For BRCA1/2, mutations in ARAP3, three focal deletions, and one amplification were detected. Around 50 mutated genes for the two APOBEC signatures were identified including three kinesins (KIF13A, KIF1B, KIF4A), three ubiquitins (USP45, UBR4, UBR1), and two demethylases (KDM5B, KDM5C) among other genes also connected to DNA damage pathways. The results suggest novel roles for other genes currently not involved in DNA repair. The altered expression program was very high for the BRCA1/2 signature, high for APOBEC signature 13 clearly associated to immune response, and low for APOBEC signature 2. The remaining signatures show scarce associations.
Specific genetic alterations can be associated with particular MS.
在癌症中观察到的突变是大约 30 种突变过程的结果，这些过程会产生特定的突变特征（MS）。然而，目前仍不清楚哪些基因组改变与多个 MS 相关。在这里，提出了一种分析基因组数据与 MS 相关性的方法，并应用于癌症基因组图谱乳腺癌数据，揭示了有希望的相关性。
将 MS 离散化为簇，其极端与突变、拷贝数和基因表达数据存在统计学关联。
载脂蛋白 B 编辑复合物（APOBEC）和 BRCA1 和 BRCA2 的已知关联支持该提议。在 BRCA1/2 中，检测到 ARAP3、三个焦点缺失和一个扩增的突变。确定了两个 APOBEC 特征的大约 50 个突变基因，包括三个驱动蛋白（KIF13A、KIF1B、KIF4A）、三个泛素（USP45、UBR4、UBR1）和两个去甲基酶（KDM5B、KDM5C）以及其他与 DNA 损伤途径相关的基因。结果表明，其他目前不参与 DNA 修复的基因可能具有新的作用。BRCA1/2 特征的表达程序改变非常高，与免疫反应明显相关的 APOBEC 特征 13 高，APOBEC 特征 2 低。其余特征显示出很少的关联。
特定的遗传改变可以与特定的 MS 相关联。
