Journal Article

Intratumor heterogeneity comparison among different subtypes of non-small-cell lung cancer through multi-region tissue and matched ctDNA sequencing

Pan, Hui, Chen, Xi, Fang, Wenfeng, Zheng, Qiufan, Wang, Xin, Wen, Zhesheng, Zhan, Jianhua, Huang, Yan, Zhao, Shen, Zhao, Yuanyuan, Zhou, Ting, Hou, Xue, Zhao, Hongyun, Chen, Gang, Xia, Xuefeng, Zhang, Lanjun, Guan, Yanfang, Yang, Yunpeng, Yang, Hong, Ma, Yuxiang, Chang, Lianpeng, Zhang, Li, Hong, Shaodong, Yi, Xin, Yang, Haoxian, Zhang, Yaxiong, Zhang, Zhonghan, Long, Hao, Zhou, Ningning, Wu, Aiwei, Zhou, Huaqiang, Wang, Junye

2019

Overview

Understanding of intratumor heterogeneity (ITH) among different non-small cell lung cancer (NSCLC) subtypes is necessary. Whether circulating tumor DNA (ctDNA) profile could represent these ITH is still an open question. We performed 181 multi-region tumor tissues sequencing and matched ctDNA sequencing from 32 operative NSCLC to compare ITH among different NSCLC subtypes, including EGFR-mutant lung adenocarcinoma (LUAD), KRAS-mutant LUAD, EGFR&KRAS-wild-type LUAD, and lung squamous cell carcinoma (LUSC), and examine potential value of ctDNA for ITH analysis. ITH is evaluated by ITH index (ITHi). If the somatic genetic alteration is shared by all the tissue regions, it is defined as trunk mutation. Otherwise, it is called branch mutation. The ITHi will be higher, if the tumor has less trunk mutations. We found EGFR-mutant LUAD showed significantly higher ITHi than KRAS-mutant LUAD/wild-type LUAD ( P  = 0.03) and numerically higher ITH than LUSC. For trunk mutations, driver mutations were identified at a higher proportion than passenger mutations (60% vs. 40%, P  = 0.0023) in overall, especially in EGFR-mutant LUAD (86% vs. 14%, P  = 0.0004), while it was opposite in KRAS-mutant LUAD (40% vs. 60%, P  = 0.18). For branch mutations, the proportions of driver mutations and passenger mutations were similar for each NSCLC subtype. ctDNA analysis showed unsatisfactory detections of tumor-derived trunk and branch mutations (43% vs. 23%, P  = 4.53e-6) among all NSCLC subtypes. In summary, EGFR-mutant LUAD has the highest ITH than other NSCLC subtypes, offering further understanding of tumorigenesis mechanisms among different NSCLC subtypes. Besides, ctDNA maybe not an appropriate method to reflect ITH.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adenocarcinoma / Adenocarcinoma of Lung - genetics / Adenocarcinoma of Lung - pathology / Analysis / Biomedical and Life Sciences / Biomedicine / Cancer Research / Carcinoma / Carcinoma, Non-Small-Cell Lung - genetics / Carcinoma, Non-Small-Cell Lung - pathology / Carcinoma, Squamous Cell - genetics / Carcinoma, Squamous Cell - pathology / Circulating Tumor DNA - genetics / Collaboration / ctDNA / Deoxyribonucleic acid / DNA / DNA, Neoplasm - genetics / Drug resistance / Epidermal growth factor receptors / Evolution / Genes / Genetic research / Genomes / High-Throughput Nucleotide Sequencing - methods / Humans / Intratumor heterogeneity / ITH / Kinases / Laboratories / Letter to the Editor / Lung cancer / Lung carcinoma / Lung Neoplasms - genetics / Lung Neoplasms - pathology / Metastasis / Multi-region sequencing / Mutation / Non-small cell lung cancer / Non-small cell lung carcinoma / NSCLC / Oncology / Patients / Phylogenetics / Small cell lung cancer / Small cell lung carcinoma / Squamous cell carcinoma / Thoracic surgery / Trees / Tumorigenesis / Tumors