Dataset Information

Circulating tumor cell characterization of lung cancer brain metastases in the cerebrospinal fluid through single-cell transcriptome analysis.

ABSTRACT:

Background

Brain metastases explain the majority of mortality associated with lung cancer, which is the leading cause of cancer death. Cytology analysis of the cerebrospinal fluid (CSF) remains the diagnostic gold standard, however, the circulating tumor cells (CTCs) in CSF (CSF-CTCs) are not well defined at the molecular and transcriptome levels.

Methods

We established an effective CSF-CTCs collection procedure and isolated individual CSF cells from five lung adenocarcinoma leptomeningeal metastases (LUAD-LM) patients and three controls. Three thousand seven hundred ninety-two single-cell transcriptomes were sequenced, and single-cell RNA sequencing (scRNA-seq) gene expression analysis was used to perform a comprehensive characterization of CSF cells.

Results

Through clustering and expression analysis, we defined CSF-CTCs at the transcriptome level based on epithelial markers, proliferation markers, and genes with lung origin. The metastatic-CTC signature genes are enriched for metabolic pathway and cell adhesion molecule categories, which are crucial for the survival and metastases of tumor cells. We discovered substantial heterogeneity in patient CSF-CTCs. We quantified the degree of heterogeneity and found significantly greater among-patient heterogeneity compared to among-cell heterogeneity within a patient. This observation could be explained by spatial heterogeneity of metastatic sites, cell-cycle gene, and cancer-testis antigen (CTA) expression profiles as well as the proportion of CTCs displaying mesenchymal and cancer stem cell properties. In addition, our CSF-CTCs transcriptome profiling allowed us to determine the biomarkers during the progression of an LM patient with cancer of unknown primary site (CUP).

Conclusions

Our results will provide candidate genes for an RNA-based digital detection of CSF-CTCs from LUAD-LM and CUP-LM cases, and shed light on the therapy and mechanism of LUAD-LM.

SUBMITTER: Ruan H

PROVIDER: S-EPMC7737787 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Publications

Circulating tumor cell characterization of lung cancer brain metastases in the cerebrospinal fluid through single-cell transcriptome analysis.

Ruan Haoyu H Zhou Yihang Y Shen Jie J Zhai Yue Y Xu Ying Y Pi Linyu L Huang Ruofan R Chen Kun K Li Xiangyu X Ma Weizhe W Wu Zhiyuan Z Deng Xuan X Wang Xu X Zhang Chao C Guan Ming M Guan Ming M

Clinical and translational medicine 20201201 8

<h4>Background</h4>Brain metastases explain the majority of mortality associated with lung cancer, which is the leading cause of cancer death. Cytology analysis of the cerebrospinal fluid (CSF) remains the diagnostic gold standard, however, the circulating tumor cells (CTCs) in CSF (CSF-CTCs) are not well defined at the molecular and transcriptome levels.<h4>Methods</h4>We established an effective CSF-CTCs collection procedure and isolated individual CSF cells from five lung adenocarcinoma lepto ...[more]

PMID: 33377642

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Project description:Importance:Owing to the improvement of systemic therapies for lung cancer, patients live longer, but the incidence of central nervous system (CNS) metastases also increases. Cerebrospinal fluid (CSF) has been proven better than plasma to reveal unique genetic profiling of intracranial metastases. How genetic alterations in CSF are associated with the prognosis of this heterogeneous patient group remains elusive. Objective:To examine the association of molecular alterations in CSF with the survival of patients with a diagnosis of lung adenocarcinoma and CNS metastases. Design, Setting, and Participants:This retrospective cohort analysis of 94 patients with advanced lung adenocarcinoma and CNS metastases was conducted from July 1, 2016, to July 31, 2018. Patients' CSF samples were collected, and next-generation sequencing of CSF circulating tumor DNA was performed. Main Outcome and Measures:The main outcome was survival after diagnosis with CNS metastases. Genotyping of CSF circulating tumor DNA was studied to examine its association with the clinical outcomes of patients with CNS metastases. Results:Of the 94 patients (49 male; mean [SD] age, 53 [1] years) with lung adenocarcinoma and CNS metastases evaluated, 79 harbored an EGFR variant. The most common genes seen in CSF were EGFR (79 [84.0%]), TP53 (57 [60.6%]), MET (23 [24.5%]), CDKN2A (22 [23.4%]), MYC (20 [21.3%]), NTRK1 (19 [20.2%]), and CDK6 (15 [16.0%]). Cluster analysis identified 5 molecular subtypes of CNS metastases. Patients in cluster I had the shortest median survival after diagnosis of CNS metastases compared with each of the other clusters (cluster I, 7.5 months; cluster II, 55.7 months; cluster III, 17.9 months; cluster IV, 27.9 months; cluster V, 21.0 months) and significantly increased risk of death compared with patients in the other clusters (cluster II: hazard ratio [HR], 4.95; 95% CI, 1.50-16.41; P?=?.009; cluster III: HR, 4.75; 95% CI, 1.49-15.12; P?=?.008; cluster IV: HR, 6.38; 95% CI, 1.76-23.09; P?=?.005; cluster V: HR, 5.42; 95% CI, 1.63-17.98; P?=?.006). The genetic profiles of cluster I were characterized by a high detection rate of CDK4 (9 of 9 [100%]), TP53 (8 of 9 [88.9%]), MET (7 of 9 [77.8%]), and CDKN2A (7 of 9 [77.8%]). For those with EGFR variants, coalterations with CDK4 (HR, 2.02; 95% CI, 1.03-3.96; P?=?.04), CDK6 (HR, 2.52; 95% CI, 1.32-4.83; P?=?.005), and MYC (HR, 2.24; 95% CI, 1.21-4.15; P?=?.01) were associated with poor outcomes. Conclusions and Relevance:Patients with a diagnosis of lung adenocarcinoma and CNS metastases experienced heterogeneous survival outcomes based on genetic profiling in CSF. These data suggest that CSF might facilitate risk stratifying CNS metastases into appropriate outcomes and provide reference for further clinical study.

Dataset Information

Circulating tumor cell characterization of lung cancer brain metastases in the cerebrospinal fluid through single-cell transcriptome analysis.

Background

Methods

Results

Conclusions

Publications

Circulating tumor cell characterization of lung cancer brain metastases in the cerebrospinal fluid through single-cell transcriptome analysis.

Similar Datasets

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