多区域测序和亚克隆分析揭示食管鳞癌肿瘤内异质性。

Multiregion sequencing and subclonal analysis reveal intratumoral heterogeneity in esophageal squamous cell carcinoma.

机构信息

Department of Clinical Medicine, Cheeloo College of Medicine, Shandong University; Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China.

Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong; Department of Radiation Oncology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China.

出版信息

J Cancer Res Ther. 2021 Jul;17(3):756-763. doi: 10.4103/jcrt.jcrt_270_21.

DOI:10.4103/jcrt.jcrt_270_21

PMID:34269310

Abstract

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.

摘要

目的

本研究旨在探讨食管鳞癌（ESCC）肿瘤内基因组异质性和亚克隆结构。

材料与方法

对 2019 年采集的 5 例未经治疗的 ESCC 患者的 24 个手术获得的肿瘤样本进行了多区域全外显子组测序，以确定肿瘤内突变景观的异质性。采用系统发育分析和突变过程分析来探讨突变谱的分布和动态变化，并进行亚克隆分析以探讨 ESCC 的亚克隆组成和空间结构。

结果

平均有 60.2%的突变呈异质性。TP53 和 NOTCH1 突变被证实为早期事件，不同肿瘤区域特有的突变呈现出分支进化的模式。很大一部分突变与载脂蛋白 B mRNA 编辑酶、催化多肽样（APOBEC）家族的异常活性有关，主干和分支变异体之间的突变类型存在显著差异。亚克隆结构表现出空间对应性和空间局限性，并且近克隆和远克隆之间具有不同的基因组特征。