Whole-Exome Sequencing on Circulating Tumor Cells Explores Platinum-Drug Resistance Mutations in Advanced Non-small Cell Lung Cancer.
Whole-Exome Sequencing on Circulating Tumor Cells Explores Platinum-Drug Resistance Mutations in Advanced Non-small Cell Lung Cancer.
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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类耐药突变
DOI：
10.3389/fgene.2021.722078
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发表时间：
2021
影响因子：
3.7
通讯作者：
Li R
中科院分区：
文献类型：
--
作者：
Chang Y;Wang Y;Li B;Lu X;Wang R;Li H;Yan B;Gu A;Wang W;Huang A;Wu S;Li R
循环肿瘤细胞(CTCs)在肿瘤早期诊断、预后预测、疗效评价等方面具有重要的临床应用价值。以铂为基础的化疗是非小细胞肺癌(NSCLC)患者的基本治疗方法，这些患者不适合进行靶向药物治疗。然而，大多数患者在一段时间的治疗后进展。因此，揭示CTCs耐药和肿瘤转移的遗传信息对治疗调整具有重要意义。在这项研究中，我们招募了9名铂类化疗耐药的非小细胞肺癌患者。对于每个患者，在疾病进展发生时分离10个CTC进行单细胞水平的全外显子测序(WES)。同时，还选择患者的初诊福尔马林固定石蜡包埋标本和进展性活检标本进行WES。比较原发标本和进展期标本以及CTC的不同突变特征，反映了CTC与淋巴结转移的不同进化机制，表现在进展性肺肿瘤和胸腔积液标本中CTC的突变比例(4.4-33.3%)高于进展性淋巴结标本(0.6-11.8%)。功能注释显示，CTCs不仅含有致癌基因突变，包括与原发和/或进展期肿瘤共有的常见的EGFR和TP53突变，还特别含有细胞周期调控或干细胞相关的基因突变，包括SHKBP1、NUMA1、ZNF143、MUC16、ORC1、PON1、PELP1等，这些突变大多来自原发肿瘤样本，在NSCLC的化疗耐药和转移中发挥关键作用。因此，在没有进展性肿瘤标本的情况下，检测CTCs中的遗传信息对于研究耐药性和发现新的药物靶点是一种可行的策略。
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.
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癌症基因组地图集中的致癌信号通路。
影响因子：
64.5
作者：
Sanchez-Vega F;Mina M;Armenia J;Chatila WK;Luna A;La KC;Dimitriadoy S;Liu DL;Kantheti HS;Saghafinia S;Chakravarty D;Daian F;Gao Q;Bailey MH;Liang WW;Foltz SM;Shmulevich I;Ding L;Heins Z;Ochoa A;Gross B;Gao J;Zhang H;Kundra R;Kandoth C;Bahceci I;Dervishi L;Dogrusoz U;Zhou W;Shen H;Laird PW;Way GP;Greene CS;Liang H;Xiao Y;Wang C;Iavarone A;Berger AH;Bivona TG;Lazar AJ;Hammer GD;Giordano T;Kwong LN;McArthur G;Huang C;Tward AD;Frederick MJ;McCormick F;Meyerson M;Cancer Genome Atlas Research Network;Van Allen EM;Cherniack AD;Ciriello G;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
64.8
作者：
Relling MV;Evans WE
通讯作者：
Evans WE
影响因子：
2.9
作者：
Mao CG;Jiang SS;Shen C;Long T;Jin H;Tan QY;Deng B
通讯作者：
Deng B
影响因子：
6.1
作者：
Qin WS;Wu J;Chen Y;Cui FC;Zhang FM;Lyu GT;Zhang HM
通讯作者：
Zhang HM
影响因子：
28.2
作者：
Girotti, Maria Romina;Gremel, Gabriela;Marais, Richard
通讯作者：
Marais, Richard