Whole exome sequencing reveals intertumor heterogeneity and distinct genetic origins of sporadic synchronous colorectal cancer
Whole exome sequencing reveals intertumor heterogeneity and distinct genetic origins of sporadic synchronous colorectal cancer
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全外显子组测序揭示了散发性同步结直肠癌的肿瘤间异质性和独特的遗传起源
DOI：
10.1002/ijc.31140
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发表时间：
2018-03-01
影响因子：
6.4
通讯作者：
Su, Xiangqian
中科院分区：
文献类型：
--
作者：
Di, Jiabo;Yang, Hong;Su, Xiangqian
散发性同步性结直肠癌（CRC）是指在首次诊断时在单个患者中检测到多于一种原发性肿瘤，而没有癌症发展的倾向。由于它们产生相同的遗传和微环境，散发性同步性CRC是研究CRC肿瘤发生的独特模型。我们对15例散发性同步性结直肠癌患者的32个新鲜冷冻肿瘤病灶进行了全外显子组测序，以比较其遗传学改变。该方法在单个患者中分别在非高度突变肿瘤和高度突变肿瘤中鉴定出0.34%至4.22%和0.8%至7.0%范围内的普遍突变基因。我们发现，来自同一患者不同肿瘤的普遍突变基因和候选癌症基因在不同位点突变。一致地，在大多数非高突变肿瘤病变患者中发现体细胞拷贝数变异（SCNV）的明显差异，其普遍存在的拷贝数扩增率范围为0%至8.8%，普遍存在的拷贝数缺失率范围为0%至8.2%。高突变病变几乎为二倍体，常见拷贝数畸变率为0%至18.8%。因此，克隆结构，改变的信号通路和药物基因在一个单一的患者同步CRC显着变化。总之，不同的SCNV和突变在同步CRC支持肿瘤发生的场效应理论。此外，同步CRC的肿瘤间异质性意味着，分析来自同一患者的所有肿瘤病变对于适当的临床治疗决策是必要的。
Sporadic synchronous colorectal cancer (CRC) refers to more than one primary tumor detected in a single patient at the time of the first diagnosis without predisposition of cancer development. Given the same genetic and microenvironment they raise, sporadic synchronous CRC is a unique model to study CRC tumorigenesis. We performed whole exome sequencing in 32 fresh frozen tumor lesions from 15 patients with sporadic synchronous CRC to compare their genetic alterations. This approach identified ubiquitously mutated genes in the range from 0.34% to 4.22% and from 0.8% to 7.0% in non‐hypermutated tumors and hypermutated tumors, respectively, in a single patient. We show that both ubiquitously mutated genes and candidate cancer genes from different tumors in the same patient mutated at different sites. Consistently, obvious differences in somatic copy number variations (SCNV) were found in most patients with non‐hypermutated tumor lesions, which had ubiquitous copy number amplification rates ranging from 0% to 8.8% and ubiquitous copy number deletion rates ranging from 0% to 8.2%. Hypermutated lesions were nearly diploid with 0% to 18.8% common copy number aberrations. Accordingly, clonal structures, altered signaling pathways and druggable genes in a single patient with synchronous CRC varied significantly. Taken together, the disparate SCNVs and mutations in synchronous CRC supported the field effect theory of tumorigenesis. Moreover, the intertumor heterogeneity of synchronous CRCs implies that analysis of all tumor lesions from the same patient is necessary for appropriate clinical treatment decisions.