Abstract
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.
Highlights
Lung cancer is the most common malignancy with the highest incidence and mortality both in China and worldwide (Siegel et al, 2021)
For the whole-exome sequencing (WES) of primary and progressive tumor or malignant pleural effusion specimens of each patient, at least 93% effective reads were mapped to the reference human genome sequence, and 20× depth reads covered more than 98.3% of the whole exome regions (Supplementary Table 2)
Single nucleotide variations/insertions and deletions (Indels) called in Circulating tumor cells (CTCs) were filtered by those detected in 10 white blood cells (WBCs) and bulk WBCs; only single nucleotide variations (SNVs)/Indels that were detected in primary or progressive specimens or hydrothorax samples were involved for further bioinformatics analysis (Supplementary Table 3) as described in the method section
Summary
Lung cancer is the most common malignancy with the highest incidence and mortality both in China and worldwide (Siegel et al, 2021). With the development of detection techniques and targeted therapies, the diagnosis and treatment of NSCLC have made great progress and increased patients’ 5-year survival rate in recent years (Carlisle et al, 2020; Siegel et al, 2021). A great proportion of NSCLC patients still progress to latestage disease because of development of drug resistance after treatment. It is important to reveal the genetic features of such drug resistance and adjust subsequent treatment to meet precision medicine targets
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