Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), FI-00014, Helsinki, Finland.
Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), FI-00014, Helsinki, Finland.
Nat Commun. 2018 Sep 10;9(1):3664. doi: 10.1038/s41467-018-06132-1.
Point mutations in cancer have been extensively studied but chromosomal gains and losses have been more challenging to interpret due to their unspecific nature. Here we examine high-resolution allelic imbalance (AI) landscape in 1699 colorectal cancers, 256 of which have been whole-genome sequenced (WGSed). The imbalances pinpoint 38 genes as plausible AI targets based on previous knowledge. Unbiased CRISPR-Cas9 knockout and activation screens identified in total 79 genes within AI peaks regulating cell growth. Genetic and functional data implicate loss of TP53 as a sufficient driver of AI. The WGS highlights an influence of copy number aberrations on the rate of detected somatic point mutations. Importantly, the data reveal several associations between AI target genes, suggesting a role for a network of lineage-determining transcription factors in colorectal tumorigenesis. Overall, the results unravel the contribution of AI in colorectal cancer and provide a plausible explanation why so few genes are commonly affected by point mutations in cancers.
癌症中的点突变已得到广泛研究，但由于其非特异性，染色体的增益和缺失更具挑战性。在这里，我们检查了 1699 例结直肠癌中的高分辨率等位基因失衡（AI）图谱，其中 256 例已进行全基因组测序（WGSed）。这些失衡根据以往的知识将 38 个基因确定为可能的 AI 靶标。在 AI 峰中总共鉴定了 79 个基因的无偏 CRISPR-Cas9 敲除和激活筛选，这些基因调节细胞生长。遗传和功能数据表明，TP53 的缺失是 AI 的充分驱动因素。WGS 强调了拷贝数异常对检测到的体细胞点突变率的影响。重要的是，这些数据揭示了 AI 靶基因之间的几种关联，提示谱系决定转录因子网络在结直肠肿瘤发生中的作用。总的来说，这些结果揭示了 AI 在结直肠癌中的贡献，并提供了一个合理的解释，说明为什么在癌症中很少有基因受到点突变的共同影响。
