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

ABSTRACT: 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.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC6325778 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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

Zhang Yaxiong Y Chang Lianpeng L Yang Yunpeng Y Fang Wenfeng W Guan Yanfang Y Wu Aiwei A Hong Shaodong S Zhou Huaqiang H Chen Gang G Chen Xi X Zhao Shen S Zheng Qiufan Q Pan Hui H Zhang Lanjun L Long Hao H Yang Haoxian H Wang Xin X Wen Zhesheng Z Wang Junye J Yang Hong H Xia Xuefeng X Zhao Yuanyuan Y Hou Xue X Ma Yuxiang Y Zhou Ting T Zhang Zhonghan Z Zhan Jianhua J Huang Yan Y Zhao Hongyun H Zhou Ningning N Yi Xin X Zhang Li L

Molecular cancer 20190109 1

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 carcino ...[more]

PMID: 30626401

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Project description:BackgroundScreening for epidermal growth factor receptor (EGFR) mutations is the key to select suitable patients with non-small cell lung cancer (NSCLC) for EGFR-TKI therapy in clinical practice. Nevertheless, tumor tissue that needed for mutation analysis is frequently unavailable, especially for patients with recurrence after operation. Therefore, detection of EGFR from circulating tumor DNA (ctDNA) in patients with NSCLC is a sensitive and convenient method to direct patient sequential treatment strategy.MethodsOne hundred and seventy-nine NSCLC patients with both tumor tissue samples and paired plasma samples were recruited. EGFR mutations were detected in 68 tumor tissue samples and 179 plasma samples using Anlongen Locked Nucleic Acid-Amplification Refractory Mutation System (LNA-ARMS) EGFR Mutation Detection Kit. The remaining 111 tumor tissue samples were detected with the use of multiplex PCR-Based NGS sequence. We calculated the sensitivity, specificity, positive prediction value (PPV) and negative prediction value (NPV) of LAN-ARMS PCR. The objective response rate (ORR) of patients received TKIs therapy was calculated.ResultsOf the 179 patients, EGFR mutations were detected in 77 of the 179 tumor tissue samples, with a positive rate of 43.01% (77/179). In addition, EGFR mutations were detected in 42 of the 179 plasma samples. The sensitivity and specificity of LAN-ARMS in detecting EGFR mutations were 57.18% and 98.04% respectively compared to tissue results. The PPV was 95.24%, and NPV was 72.99%. Of the 179 pair of samples, EGFR mutations were inconsistent in 39 pairs of tissue and plasma. The overall agreement of EGFR mutation detection was 78.21% (140/179). The ORR was higher in patients with both tissue and plasma EGFR mutations compared with that in patients with only tissue EGFR mutations (73.33% vs. 68.29%), but the difference was not significant. It was suggested that tissue detection combined with plasma detection could improve the mutation rate.ConclusionIn plasma samples, Anlongen LAN-ARMS EGFR Mutation Detection Kit had a high sensitivity and specificity for the detection of EGFR mutations. Anlongen LAN-ARMS EGFR Mutation Detection Kit had the advantages of easy-to-operate and high sensitivity in clinical application.

Dataset Information

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

Publications

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

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