Multiregion sequencing and subclonal analysis reveal intratumoral heterogeneity in esophageal squamous cell carcinoma
Multiregion sequencing and subclonal analysis reveal intratumoral heterogeneity in esophageal squamous cell carcinoma
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多区域测序和亚克隆分析揭示食管鳞状细胞癌瘤内异质性
DOI：
10.4103/jcrt.jcrt_270_21
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发表时间：
2021-07-01
影响因子：
1.3
通讯作者：
Li, Baosheng
中科院分区：
文献类型：
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作者：
Gao, Dongni;Zhang, Zicheng;Li, Baosheng
目的：探讨食管鳞状细胞癌(ESCC)的基因组异质性及其亚克隆结构。材料和方法：对2019年收集的5例未经治疗的食管鳞癌患者的24例手术标本进行多区全外显子组测序，以确定肿瘤内突变格局的异质性。用系统发育分析和突变过程分析探讨突变谱的分布和动态变化，用亚克隆分析探讨ESCC的亚克隆组成和空间结构。结果：平均有60.2%的突变是异源突变。TP53和NOTCH1突变被确认为早期事件，不同肿瘤区域特有的突变显示出分支进化的模式。很大比例的突变与载脂蛋白B mRNA编辑酶催化多肽样(APOBEC)家族的活性异常有关，并且主干和分支突变体的突变类型有显著差异。亚克隆结构表现出空间一致性和空间局限性，近克隆和远克隆具有不同的基因组特征。结论：5例食管癌组织中存在明显的基因组异质性，其亚克隆结构与空间位置有关。
Purpose: The aim of this study was to investigate intratumoral genomic heterogeneity and subclonal structure of esophageal squamous cell carcinoma (ESCC). Materials and Methods: Multiregion whole-exome sequencing was performed on 24 surgically acquired tumor samples from five untreated ESCC patients collected in 2019 to determine the heterogeneity of mutational landscape within tumors. Phylogenetic analysis and mutation process analysis were used to explore the distribution and dynamic changes of mutation spectrum, and subclone analysis was used to explore the subclonal composition and spatial structure of ESCC. Results: An average of 60.2% of mutations were found heterogenous. TP53 and NOTCH1 mutations were confirmed to be early events, and mutations unique in different tumor regions showed a pattern of branching evolution. A large proportion of mutations were associated with abnormal activity of the apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) family, and significant differences in mutation types between trunk and branch variants were found. Subclonal structure exhibited spatial correspondence and spatial limitations, and different genomic features were characterized between close and distant clones. Conclusions: There is significant intratumoral genomic heterogeneity in the five ESCCs, and their subclonal structure is related to spatial locations.