Contribution Of Allelic Imbalance To Colorectal Cancer

<strong>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, and unbiased CRISPR-Cas9 knockout and activation screens identified altogether 79 genes within AI peaks regulating cell growth. Genetic and functional data implicates 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.</strong>癌症中的点突变已得到广泛研究，但由于染色体增益与缺失的非特异性特征，其相关机制的阐释难度更高。本研究针对1699例结直肠癌样本开展高分辨率等位基因不平衡（allelic imbalance, AI）图谱分析，其中256例已完成全基因组测序（WGS）。基于既往研究认知，本次AI分析精准定位出38个潜在AI靶点基因；同时通过无偏CRISPR-Cas9敲除与激活筛选，在AI峰区域内共鉴定出79个调控细胞生长的基因。遗传与功能实验数据证实，TP53缺失可作为AI发生的充分驱动因素。全基因组测序数据揭示，拷贝数畸变对体细胞点突变的检出率存在影响。尤为重要的是，本研究数据揭示了AI靶点基因间的多种关联，提示谱系决定性转录因子网络在结直肠癌发生过程中发挥重要作用。综上，本研究结果阐明了AI在结直肠癌发生发展中的作用，并为癌症中仅少量基因常受点突变影响这一现象提供了合理的解释。