Identification of Candidate Driver Genes in Common Focal Chromosomal Aberrations of Microsatellite Stable Colorectal Cancer

Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. Chromosomal instability (CIN) is a major driving force of microsatellite stable (MSS) sporadic CRC. CIN tumours are characterised by a large number of somatic chromosomal copy number aberrations (SCNA) that frequently affect oncogenes and tumour suppressor genes. The main aim of this work was to identify novel candidate CRC driver genes affected by recurrent and focal SCNA. High resolution genome-wide comparative genome hybridisation (CGH) arrays were used to compare tumour and normal DNA for 53 sporadic CRC cases. Context corrected common aberration (COCA) analysis and custom algorithms identified 64 deletions and 32 gains of focal minimal common regions (FMCR) at high frequency (>10%). Comparison of these FMCR with published genomic profiles from CRC revealed common overlap (42.2% of deletions and 34.4% of copy gains). Pathway analysis showed that apoptosis and p53 signalling pathways were commonly affected by deleted FMCR, and MAPK and potassium channel pathways by gains of FMCR. Candidate tumour suppressor genes in deleted FMCR included RASSF3, IFNAR1, IFNAR2 and NFKBIA and candidate oncogenes in gained FMCR included PRDM16, TNS1, RPA3 and KCNMA1. In conclusion, this study confirms some previously identified aberrations in MSS CRC and provides in silico evidence for some novel candidate driver genes.

结直肠癌（Colorectal cancer, CRC）是全球范围内主要的癌症致死病因之一。染色体不稳定性（Chromosomal instability, CIN）是微卫星稳定（microsatellite stable, MSS）型散发性结直肠癌的主要驱动因素。携带CIN的肿瘤以大量体细胞染色体拷贝数变异（somatic chromosomal copy number aberrations, SCNA）为特征，这类变异常靶向累及癌基因与抑癌基因。本研究的核心目标为鉴定受频发且局灶性SCNA影响的新型结直肠癌候选驱动基因。本研究采用高分辨率全基因组比较基因组杂交（comparative genome hybridisation, CGH）芯片，对53例散发性结直肠癌患者的肿瘤组织与正常组织DNA进行配对比对分析。通过背景校正常见异常（Context corrected common aberration, COCA）分析与自定义生物信息学算法，鉴定出64个高频（>10%）出现的局灶性最小共同区域（focal minimal common regions, FMCR）缺失事件与32个高频扩增事件。将上述FMCR与已发表的结直肠癌基因组图谱进行比对，发现二者存在显著重叠：缺失事件的重叠率为42.2%，拷贝数扩增事件的重叠率为34.4%。通路富集分析结果显示，细胞凋亡（apoptosis）与p53信号通路常受FMCR缺失事件调控，而丝裂原活化蛋白激酶（Mitogen-Activated Protein Kinase, MAPK）与钾离子通道通路（potassium channel pathways）则常受FMCR扩增事件影响。位于缺失型FMCR中的候选抑癌基因包括RASSF3、IFNAR1、IFNAR2与NFKBIA，而位于扩增型FMCR中的候选癌基因则包括PRDM16、TNS1、RPA3与KCNMA1。综上，本研究验证了此前已报道的MSS型结直肠癌中的部分染色体异常，并为若干新型结直肠癌候选驱动基因提供了计算机模拟证据。