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Whole-Exome Sequencing on Circulating Tumor Cells Explores Platinum-Drug Resistance Mutations in Advanced Non-small Cell Lung Cancer
Frontiers in Genetics ( IF 3.7 ) Pub Date : 2021-09-20 , DOI: 10.3389/fgene.2021.722078
Yuanyuan Chang 1, 2 , Yin Wang 3 , Boyi Li 3 , Xingzhong Lu 3 , Ruiru Wang 3 , Hui Li 3 , Bo Yan 1, 2 , Aiqin Gu 1 , Weimin Wang 1 , Aimi Huang 1 , Shuangxiu Wu 3 , Rong Li 1, 2
Affiliation  

Circulating tumor cells (CTCs) have important applications in clinical practice on early tumor diagnosis, prognostic prediction, and treatment evaluation. Platinum-based chemotherapy is a fundamental treatment for non-small cell lung cancer (NSCLC) patients who are not suitable for targeted drug therapies. However, most patients progressed after a period of treatment. Therefore, revealing the genetic information contributing to drug resistance and tumor metastasis in CTCs is valuable for treatment adjustment. In this study, we enrolled nine NSCLC patients with platinum-based chemotherapy resistance. For each patient, 10 CTCs were isolated when progression occurred to perform single cell–level whole-exome sequencing (WES). Meanwhile the patients’ paired primary-diagnosed formalin-fixed and paraffin-embedded samples and progressive biopsy specimens were also selected to perform WES. Comparisons of distinct mutation profiles between primary and progressive specimens as well as CTCs reflected different evolutionary mechanisms between CTC and lymph node metastasis, embodied in a higher proportion of mutations in CTCs shared with paired progressive lung tumor and hydrothorax specimens (4.4–33.3%) than with progressive lymphatic node samples (0.6–11.8%). Functional annotation showed that CTCs not only harbored cancer-driver gene mutations, including frequent mutations of EGFR and TP53 shared with primary and/or progressive tumors, but also particularly harbored cell cycle–regulated or stem cell–related gene mutations, including SHKBP1, NUMA1, ZNF143, MUC16, ORC1, PON1, PELP1, etc., most of which derived from primary tumor samples and played crucial roles in chemo-drug resistance and metastasis for NSCLCs. Thus, detection of genetic information in CTCs is a feasible strategy for studying drug resistance and discovering new drug targets when progressive tumor specimens were unavailable.



中文翻译:

循环肿瘤细胞的全外显子组测序探索晚期非小细胞肺癌的铂耐药突变

循环肿瘤细胞 (CTC) 在临床实践中对早期肿瘤诊断、预后预测和治疗评估具有重要应用。铂类化疗是不适合靶向药物治疗的非小细胞肺癌(NSCLC)患者的基本治疗方法。然而,大多数患者在治疗一段时间后病情进展。因此,揭示导致 CTC 耐药和肿瘤转移的遗传信息对于治疗调整具有重要意义。在这项研究中,我们招募了 9 名对铂类化疗耐药的 NSCLC 患者。对于每位患者,在发生进展时分离出 10 个 CTC,以进行单细胞水平全外显子组测序 (WES)。同时,还选择患者配对的初步诊断福尔马林固定石蜡包埋样本和渐进活检标本进行 WES。原发和进展标本以及 CTC 之间不同突变谱的比较反映了 CTC 和淋巴结转移之间不同的进化机制,体现在与配对的进展性肺肿瘤和胸水标本共享的 CTC 突变比例(4.4-33.3%)高于进行性淋巴结样本 (0.6–11.8%)。功能注释显示 CTC 不仅包含癌症驱动基因突变,包括 原发和进展标本以及 CTC 之间不同突变谱的比较反映了 CTC 和淋巴结转移之间不同的进化机制,体现在与配对的进展性肺肿瘤和胸水标本共享的 CTC 突变比例(4.4-33.3%)高于进行性淋巴结样本 (0.6–11.8%)。功能注释显示 CTC 不仅包含癌症驱动基因突变,包括 原发和进展标本以及 CTC 之间不同突变谱的比较反映了 CTC 和淋巴结转移之间不同的进化机制,体现在与配对的进展性肺肿瘤和胸水标本共享的 CTC 突变比例(4.4-33.3%)高于进行性淋巴结样本 (0.6–11.8%)。功能注释显示 CTC 不仅包含癌症驱动基因突变,包括表皮生长因子受体TP53 与原发性和/或进展性肿瘤相同,但也特别含有细胞周期调节或干细胞相关的基因突变,包括 SHKBP1, NUMA1, ZNF143, MUC16, 兽人1, PON1, PELP1等,其中大部分来自原发肿瘤样本,并在 NSCLC 的化疗耐药和转移中起关键作用。因此,在无法获得进展性肿瘤标本时,检测 CTC 中的遗传信息是研究耐药性和发现新药物靶点的可行策略。

更新日期:2021-09-20
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