Whole-Exome Sequencing on Circulating Tumor Cells Explores Platinum-Drug Resistance Mutations in Advanced Non-small Cell Lung Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuanyuan Chang ◽  
Yin Wang ◽  
Boyi Li ◽  
Xingzhong Lu ◽  
Ruiru Wang ◽  
...  

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.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21021-e21021
Author(s):  
Rong Li ◽  
Shuangxiu Wu ◽  
Yuanyuan Chang ◽  
Yin Wang ◽  
Boyi Li

e21021 Background: Circulating tumour cells (CTCs) have important applications in clinical practice on early tumour diagnosis, prognostic prediction and treatment evaluation. Platinum-based chemotherapy is the first-line treatment for non-small cell lung cancer (NSCLC) patients without targeted drugs. But most patients progressed after a period of treatment. Therefore, to dissect the genetic information contributing to drug resistance and tumour progression in CTCs is valuable for guidance of treatment adjustment. Methods: In this study, we enrolled 9 NSCLC patients treated with platinum-based chemotherapy. For each patient, 10 CTCs were isolated after progression to perform a single cell-level whole-exome sequencing (WES). Meanwhile the patients’ paired primary-diagnosed FFPE sample and progressive biopsy specimens were also performed WES. Results: Comparisons of WES data between primary and progressive specimens, as well as CTCs revealed that more than half patients’ tumour mutation burden (TMB) increased after progression. Dozes to hundreds of single-nucleotide variants (SNVs) and insertions or deletions (Indels) were detected in the CTCs. Slightly more proportion of SNVs/Indels in CTCs shared with paired primary tumours (1.2%-23.1%) than with progressive samples (0.6%-11.7%). Conclusions: Functional annotation on SNVs/Indels showed that CTCs not only harboured cancer driver gene mutations, such as EGFR and TP53, shared with primary and/or progressive tumours, but also harboured chemotherapy-resistance and stem cell-related gene mutations, including SHKBP1, NUMA1, ZNF143, MUC16, ORC1, PON1, PELP1, etc. which have crucial roles in drug resistance and poor prognosis for NSCLCs. Thus, detection of genetic information in CTCs was necessary for guidance of individual therapy and drug resistance study.


2015 ◽  
Vol 5 (3) ◽  
pp. e1093277 ◽  
Author(s):  
Gerhard Hamilton ◽  
Barbara Rath ◽  
Lukas Klameth ◽  
Maximilan J. Hochmair

2017 ◽  
Vol 123 ◽  
pp. S659
Author(s):  
C. Prieto Prieto ◽  
D. De Miguel

2014 ◽  
Vol 25 ◽  
pp. iv512
Author(s):  
P. Gong ◽  
C. Liu ◽  
Y. Shihezi ◽  
Z. Yang ◽  
J. Li

2018 ◽  
Vol 9 (5) ◽  
pp. 640-645 ◽  
Author(s):  
Bing Tong ◽  
Yan Xu ◽  
Jing Zhao ◽  
Minjiang Chen ◽  
Wei Zhong ◽  
...  

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. e22029-e22029
Author(s):  
Robert Lewin Metcalf ◽  
Emma Halkyard ◽  
Lynsey Priest ◽  
Vikki Codlin ◽  
Karen Morris ◽  
...  

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. 7595-7595 ◽  
Author(s):  
Ying Cheng ◽  
Yun Fan ◽  
Xiaoqing Liu ◽  
Yunpeng Liu ◽  
Jiwei Liu ◽  
...  

2013 ◽  
Vol 31 (18) ◽  
pp. 2273-2281 ◽  
Author(s):  
Emma Pailler ◽  
Julien Adam ◽  
Amélie Barthélémy ◽  
Marianne Oulhen ◽  
Nathalie Auger ◽  
...  

Purpose The diagnostic test for ALK rearrangement in non–small-cell lung cancer (NSCLC) for crizotinib treatment is currently done on tumor biopsies or fine-needle aspirations. We evaluated whether ALK rearrangement diagnosis could be performed by using circulating tumor cells (CTCs). Patients and Methods The presence of an ALK rearrangement was examined in CTCs of 18 ALK-positive and 14 ALK-negative patients by using a filtration enrichment technique and filter-adapted fluorescent in situ hybridization (FA-FISH), a FISH method optimized for filters. ALK-rearrangement patterns were determined in CTCs and compared with those present in tumor biopsies. ALK-rearranged CTCs and tumor specimens were characterized for epithelial (cytokeratins, E-cadherin) and mesenchymal (vimentin, N-cadherin) marker expression. ALK-rearranged CTCs were monitored in five patients treated with crizotinib. Results All ALK-positive patients had four or more ALK-rearranged CTCs per 1 mL of blood (median, nine CTCs per 1 mL; range, four to 34 CTCs per 1 mL). No or only one ALK-rearranged CTC (median, one per 1 mL; range, zero to one per 1 mL) was detected in ALK-negative patients. ALK-rearranged CTCs harbored a unique (3′5′) split pattern, and heterogeneous patterns (3′5′, only 3′) of splits were present in tumors. ALK-rearranged CTCs expressed a mesenchymal phenotype contrasting with heterogeneous epithelial and mesenchymal marker expressions in tumors. Variations in ALK-rearranged CTC levels were detected in patients being treated with crizotinib. Conclusion ALK rearrangement can be detected in CTCs of patients with ALK-positive NSCLC by using a filtration technique and FA-FISH, enabling both diagnostic testing and monitoring of crizotinib treatment. Our results suggest that CTCs harboring a unique ALK rearrangement and mesenchymal phenotype may arise from clonal selection of tumor cells that have acquired the potential to drive metastatic progression of ALK-positive NSCLC.


PLoS ONE ◽  
2017 ◽  
Vol 12 (7) ◽  
pp. e0181211 ◽  
Author(s):  
Ippokratis Messaritakis ◽  
Eleni Politaki ◽  
Athanasios Kotsakis ◽  
Eleftheria-Kleio Dermitzaki ◽  
Filippos Koinis ◽  
...  

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. e22020-e22020
Author(s):  
Milena Tariki ◽  
Juliana Valim Romero ◽  
Emne Ali Abdallah ◽  
Luciana Menezes Mendonca Ocea ◽  
Natalia Breve Mingues ◽  
...  

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