Dataset Information

CNV Detection from Circulating Tumor DNA in Late Stage Non-Small Cell Lung Cancer Patients.

ABSTRACT: While methods for detecting SNVs and indels in circulating tumor DNA (ctDNA) with hybridization capture-based next-generation sequencing (NGS) have been available, copy number variations (CNVs) detection is more challenging. Here, we present a method enabling CNV detection from a 150-gene panel using a very low amount of ctDNA. First, a read depth-based CNV estimation method without a paired blood sample was developed and cfDNA sequencing data from healthy people were used to build a panel of normal (PoN) model. Then, in silico and in vitro simulations were performed to define the limit of detection (LOD) for EGFR, ERBB2, and MET. Compared to the WES results of the 48 samples, the concordance rate for EGFR, ERBB2, and MET CNVs was 78%, 89.6%, and 92.4%, respectively. In another cohort profiled with the 150-gene panel from 5980 lung cancer ctDNA samples, we detected the three genes' amplification with comparable population frequency with other cohorts. One lung adenocarcinoma patient with MET amplification detected by our method reached partial response to crizotinib. These findings show that our ctDNA CNV detection pipeline can detect CNVs with high specificity and concordance, which enables CNV calling in a non-invasive way for cancer patients when tissues are not available.

SUBMITTER: Peng H

PROVIDER: S-EPMC6895974 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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CNV Detection from Circulating Tumor DNA in Late Stage Non-Small Cell Lung Cancer Patients.

Peng Hao H Lu Lan L Zhou Zisong Z Liu Jian J Zhang Dadong D Nan Kejun K Zhao Xiaochen X Li Fugen F Tian Lei L Dong Hua H Yao Yu Y

Genes 20191114 11

While methods for detecting SNVs and indels in circulating tumor DNA (ctDNA) with hybridization capture-based next-generation sequencing (NGS) have been available, copy number variations (CNVs) detection is more challenging. Here, we present a method enabling CNV detection from a 150-gene panel using a very low amount of ctDNA. First, a read depth-based CNV estimation method without a paired blood sample was developed and cfDNA sequencing data from healthy people were used to build a panel of no ...[more]

PMID: 31739500

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Project description:BackgroundMonitoring circulating tumor cells (CTC) has been shown to be prognostic in most solid malignancies. There is no CTC assay in clinical use for lung cancer therapy monitoring due to inconclusive clinical utility data. Limited data has been published outside of the standard CTC enumerations, regarding clinical significance of phenotypic heterogeneity of CTCs in late stage NSCLC and its ability to correlate with treatment outcomes.MethodsIn 81 patients with stage IV NSCLC, multiple timepoints for CTC analysis were collected after initiation of treatment across 139 lines of therapy using single cell high definition diagnostic pathology imaging of all nucleated cells from 362 peripheral blood samples as a liquid biopsy.ResultsWe analyzed the subset of 25 patients with complete time series data, totaling 117 blood samples, to determine the significance of HD-CTC kinetics during the initiation of treatment. These kinetics follow three distinct patterns: an increase in HD-CTCs with therapy (mean + 118.40 HD-CTCs/mL), unchanged HD-CTCs numbers (stable; mean 0.54 HD-CTCs/mL), and a decrease in HD-CTCs numbers (mean - 81.40 HD-CTCs/mL). Patients with an increasing CTC count during the first 3 months post initiation of new treatment had a better PFS and OS compared to the other groups. There was weak correlation between the absolute number of HD-CTCs at a single time point of therapy and patient outcomes (OS p value = 0.0754). In the whole cohort of 81 patients, HD-CTCs were detected in 51 (63%) patients at initiation of therapy with a median of 2.20 (range 0-509.20) and a mean of 26.21 HD-CTCs/mL (± 15.64).ConclusionsCTCs are identifiable in most patients with stage IV NSCLC. While absolute HD-CTC counts do not correlate with prognosis, the changes in CTC counts were predictive of survival in patients with metastatic lung cancer receiving chemotherapy. The level and dynamics of CTCs indicate very different biological and pharmacological phenomena at different stages of disease and timepoints of treatment, highlighting the complex role of CTCs in cancer research and clinical management.

Project description:Background: There was rare studies on prognosis of pulmonary venous CTC and early or advanced NSCLC patients. We want to investigate whether CTCs and the subtype of it can predict the prognosis of NSCLC patients. Patients and Methods: One hundred and fourteen patients with stage I-III NSCLC were included CanPatrol™ CTC analysis. PD-L1 expression level were detected in CTC of pulmonary vein. PD-L1, number of CTC in pulmonary, CTC's subtype, clinical characteristics, prognosis of patients were analyzed. Results: 110/114 (96.5%) patients could be found CTCs in pulmonary vein, 58/114 (50.9%) patients had CTC?15/ml in pulmonary vein, 53/110 patients (48.2%) were defined as having MCTC subtype and 56/110 patient were found have PD-L1 (+) CTC in pulmonary vein. Multivariate analyses showed that PVCTC, MCTC, and stage were independent factors of DFS (P < 0.05). No OS difference was found between number of CTC (P = 0.33) and other CTC factors (P > 0.05), only stage was independent factor of OS (P = 0.019). There were decreases of CTC number and MCTC number in EGFR mutant subgroup (P = 0.0009 and P = 0.007). There were increases of CTC (P = 0.0217), MCTC (P = 0.0041), and PD-L1 (+) CTC (P = 0.0002) number in KRAS mutant subgroup. There was increase of MCTC (P =0.0323) number in BRAF mutant. There were fewer CTCs in pulmonary vein for patients with EGFR mutant than in patients with full wild-type gene (P = 0.0346). There were more PD-L1 positive CTCs in pulmonary vein for patients with ALK rearrangement, KRAS mutant, BRAF mutant, or ROS1 mutant than in patients with full wild-type gene (P = 0.0610, P = 0.0003, P = 0.032, and P = 0.0237). There were more mesenchymal CTCs in pulmonary vein for patients with KRAS mutant and BRAF mutant than in patients with full wild-type gene (P = 0.073 and P = 0.0381). There were fewer mesenchymal CTCs in pulmonary vein for patients with EGFR mutant than in patients with full wild-type gene (P = 0.0898). Conclusions: The patients with high number of CTCs, MCTCs, or PD-L1 (+) CTCs in pulmonary vein experienced poor prognosis of DFS. There are obvious correlations between the CTC subtype of NSCLC and the gene subgroups of tumor tissue.

Dataset Information

CNV Detection from Circulating Tumor DNA in Late Stage Non-Small Cell Lung Cancer Patients.

Publications

CNV Detection from Circulating Tumor DNA in Late Stage Non-Small Cell Lung Cancer Patients.

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