scholarly journals Detection of genes mutations in cerebrospinal fluid circulating tumor DNA from neoplastic meningitis patients using next generation sequencing

2020 ◽  
Author(s):  
Yue Zhao ◽  
JunYing He ◽  
JunZhao Cui ◽  
Zi-Qi Meng ◽  
YueLi Zou ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Next Generation Sequencing ◽  
Signaling Pathway ◽  
Gene Mutations ◽  
Circulating Tumor Dna ◽  
Akt Signaling ◽  
Neoplastic Meningitis ◽  
Akt Signaling Pathway ◽  
Tumor Dna ◽  
Generation Sequencing

Abstract Background: This study profiled the somatic gene mutations and the copy number variations (CNVs) in cerebrospinal fluid (CSF)-circulating tumor DNA (ctDNA) from patients with neoplastic meningitis (NM). Methods: A total of 62 CSF ctDNA samples were collected from 58 NM patients for the next generation sequencing. The data were bioinformatically analyzed by (Database for Annotation, Visualization and Integrated Discovery) DAVID software. Results: The most common mutated gene was TP53 (54/62; 87.10%), followed by EGFR (44/62; 70.97%), PTEN (39/62; 62.90%), CDKN2A (32/62; 51.61%), APC (27/62: 43.55%), TET2 (27/62; 43.55%), GNAQ (18/62; 29.03%), NOTCH1 (17/62; 27.42%), VHL (17/62; 27.42%), FLT3 (16/62; 25.81%), PTCH1 (15/62; 24.19%), BRCA2 (13/62; 20.97%), KDR (10/62; 16.13%), KIT (9/62; 14.52%), MLH1 (9/62; 14.52%), ATM (8/62; 12.90%), CBL (8/62; 12.90%), and DNMT3A (7/62; 11.29%). The mutated genes were enriched in the PI3K-Akt signaling pathway by the KEGG pathway analysis. Furthermore, the CNVs of these genes were also identified in these 62 samples. The mutated genes in CSF samples receiving intrathecal chemotherapy and systemic therapy were enriched in the ERK1/2 signaling pathway. Conclusions: This study identified gene mutations in all CSF ctDNA samples, indicating that these mutated genes may be acted as a kind of biomarker for diagnosis of NM, and these mutated genes may affect meningeal metastasis through PI3K-Akt signaling pathway.

scholarly journals Detection of genes mutations in cerebrospinal fluid circulating tumor DNA from neoplastic meningitis patients using next generation sequencing

2020 ◽  
Author(s):  
Yue Zhao ◽  
JunYing He ◽  
JunZhao Cui ◽  
Zi-Qi Meng ◽  
YueLi Zou ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Next Generation Sequencing ◽  
Signaling Pathway ◽  
Gene Mutations ◽  
Circulating Tumor Dna ◽  
Akt Signaling ◽  
Neoplastic Meningitis ◽  
Akt Signaling Pathway ◽  
Tumor Dna ◽  
Generation Sequencing

Abstract Background: This study profiled the somatic gene mutations and the copy number variations (CNVs) in cerebrospinal fluid (CSF)-circulating tumor DNA (ctDNA) from patients with neoplastic meningitis (NM). Methods: A total of 62 CSF ctDNA samples were collected from 58 NM patients for the next generation sequencing. The data were bioinformatically analyzed by (Database for Annotation, Visualization and Integrated Discovery) DAVID software. Results: The most common mutated gene was TP53 (54/62; 87.10%), followed by EGFR (44/62; 70.97%), PTEN (39/62; 62.90%), CDKN2A (32/62; 51.61%), APC (27/62: 43.55%), TET2 (27/62; 43.55%), GNAQ (18/62; 29.03%), NOTCH1 (17/62; 27.42%), VHL (17/62; 27.42%), FLT3 (16/62; 25.81%), PTCH1 (15/62; 24.19%), BRCA2 (13/62; 20.97%), KDR (10/62; 16.13%), KIT (9/62; 14.52%), MLH1 (9/62; 14.52%), ATM (8/62; 12.90%), CBL (8/62; 12.90%), and DNMT3A (7/62; 11.29%). The mutated genes were enriched in the PI3K-Akt signaling pathway by the KEGG pathway analysis. Furthermore, the CNVs of these genes were also identified in these 62 samples. The mutated genes in CSF samples receiving intrathecal chemotherapy and systemic therapy were enriched in the ERK1/2 signaling pathway. Conclusions: This study identified gene mutations in all CSF ctDNA samples, indicating that these mutated genes may be acted as a kind of biomarker for diagnosis of NM, and these mutated genes may affect meningeal metastasis through PI3K-Akt signaling pathway.

scholarly journals Detection of genes mutations in cerebrospinal fluid circulating tumor DNA from neoplastic meningitis patients using next generation sequencing

2020 ◽  
Author(s):  
Yue Zhao ◽  
JunYing He ◽  
JunZhao Cui ◽  
Zi-Qi Meng ◽  
YueLi Zou ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Next Generation Sequencing ◽  
Signaling Pathway ◽  
Circulating Tumor Dna ◽  
Akt Signaling ◽  
Neoplastic Meningitis ◽  
Next Generation ◽  
Akt Signaling Pathway ◽  
Tumor Dna ◽  
Generation Sequencing

Abstract Background: This study profiled the somatic genes mutations and the copy number variations (CNVs) in cerebrospinal fluid (CSF)-circulating tumor DNA (ctDNA) from patients with neoplastic meningitis (NM). Methods: A total of 62 CSF ctDNA samples were collected from 58 NM patients for the next generation sequencing. The data were bioinformatically analyzed by (Database for Annotation, Visualization and Integrated Discovery) DAVID software. Results: The most common mutated gene was TP53 (54/62; 87.10%), followed by EGFR (44/62; 70.97%), PTEN (39/62; 62.90%), CDKN2A (32/62; 51.61%), APC (27/62: 43.55%), TET2 (27/62; 43.55%), GNAQ (18/62; 29.03%), NOTCH1 (17/62; 27.42%), VHL (17/62; 27.42%), FLT3 (16/62; 25.81%), PTCH1 (15/62; 24.19%), BRCA2 (13/62; 20.97%), KDR (10/62; 16.13%), KIT (9/62; 14.52%), MLH1 (9/62; 14.52%), ATM (8/62; 12.90%), CBL (8/62; 12.90%), and DNMT3A (7/62; 11.29%). The mutated genes were enriched in the PI3K-Akt signaling pathway by the KEGG pathway analysis. Furthermore, the CNVs of these genes were also identified in these 62 samples. The mutated genes in CSF samples receiving intrathecal chemotherapy and systemic therapy were enriched in the ERK1/2 signaling pathway. Conclusions: This study identified genes mutations in all CSF ctDNA samples, indicating that these mutated genes may be acted as a kind of biomarker for diagnosis of NM, and these mutated genes may affect meningeal metastasis through PI3K-Akt signaling pathway.

scholarly journals Detection of genes mutations in cerebrospinal fluid circulating tumor DNA from neoplastic meningitis patients using next generation sequencing

2019 ◽  
Author(s):  
Yue Zhao ◽  
JunYing He ◽  
Li Guo ◽  
YueLi Zou ◽  
JunZhao Cui ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Next Generation Sequencing ◽  
Gene Mutations ◽  
Circulating Tumor Dna ◽  
Copy Number Variations ◽  
Neoplastic Meningitis ◽  
Diagnostic Strategy ◽  
Next Generation ◽  
Tumor Dna ◽  
Generation Sequencing

Abstract Background This study profiled the somatic gene mutations and the copy number variations (CNVs) in cerebrospinal fluid (CSF)-circulating tumor DNA (ctDNA) from patients with neoplastic meningitis (NM).Methods A total of 62 CSF ctDNA samples were collected from 58 NM patients for the next generation sequencing. The data were blasted in GenBank and bioinformatically analyzed.Results Cancer-associated gene mutations occurred in all 62 CSF ctDNA samples in TP53 (54/62; 87.10%), EGFR (44/62; 70.97%), PTEN (39/62; 62.90%), CDKN2A (32/62; 51.61%), APC (27/62: 43.55%), TET2 (27/62; 43.55%), GNAQ (18/62; 29.03%), NOTCH1 (17/62; 27.42%), VHL (17/62; 27.42%), FLT3 (16/62; 25.81%), PTCH1 (15/62; 24.19%), BRCA2 (13/62; 20.97%), KDR (10/62; 16.13%), KIT (9/62; 14.52%), MLH1 (9/62; 14.52%), ATM (8/62; 12.90%), CBL (8/62; 12.90%), and DNMT3A (7/62; 11.29%). The mutated genes enriched by the KEGG pathway analysis were the PI3K-Akt, which included the genes of TP53 , EGFR , PTEN , KIT and KDR. After receiving intrathecal and systemic chemotherapy, the ERK1/2 signaling pathways of these CSF samples were activated. Furthermore, the CNVs of these genes were also identified in these 62 samples.Conclusions This study identified gene mutations in all CSF ctDNA samples, indicating that such an approach could be useful as a second-line diagnostic strategy for NM patients. PI3K-Akt signaling may be the potential NM metastasis mechanism.

scholarly journals Detection of genes mutations in cerebrospinal fluid circulating tumor DNA from neoplastic meningitis patients using next generation sequencing

2020 ◽  
Author(s):  
Yue Zhao ◽  
JunYing He ◽  
JunZhao Cui ◽  
Zi-Qi Meng New ◽  
YueLi Zou ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Next Generation Sequencing ◽  
Gene Mutations ◽  
Circulating Tumor Dna ◽  
Copy Number Variations ◽  
Neoplastic Meningitis ◽  
Next Generation ◽  
Somatic Gene ◽  
Tumor Dna ◽  
Generation Sequencing

Abstract Background: This study profiled the somatic gene mutations and the copy number variations (CNVs) in cerebrospinal fluid (CSF)-circulating tumor DNA (ctDNA) from patients with neoplastic meningitis (NM). Methods: A total of 62 CSF ctDNA samples were collected from 58 NM patients for the next generation sequencing. The data were blasted in GenBank and bioinformatically analyzed. Results: Cancer-associated gene mutations occurred in all 62 CSF ctDNA samples in TP53 (54/62; 87.10%), EGFR (44/62; 70.97%), PTEN (39/62; 62.90%), CDKN2A (32/62; 51.61%), APC (27/62: 43.55%), TET2 (27/62; 43.55%), GNAQ (18/62; 29.03%), NOTCH1 (17/62; 27.42%), VHL (17/62; 27.42%), FLT3 (16/62; 25.81%), PTCH1 (15/62; 24.19%), BRCA2 (13/62; 20.97%), KDR (10/62; 16.13%), KIT (9/62; 14.52%), MLH1 (9/62; 14.52%), ATM (8/62; 12.90%), CBL (8/62; 12.90%), and DNMT3A (7/62; 11.29%). The mutated genes enriched by the KEGG pathway analysis were the PI3K-Akt, which included the genes of TP53, EGFR, PTEN, KIT and KDR. After receiving intrathecal and systemic chemotherapy, the ERK1/2 signaling pathways of these CSF samples were activated. Furthermore, the CNVs of these genes were also identified in these 62 samples. Conclusions: This study identified gene mutations in all CSF ctDNA samples, indicating that these mutated genes may be acted as a kind of biomarker for diagnosis of NM, and these mutated genes may affect meningeal metastasis through PI3K-Akt signaling pathway.

scholarly journals Genomic signatures in pediatric advanced stage Burkitt lymphoma/leukemia in a Chinese population detected by next generation sequencing

2020 ◽  
Author(s):  
Xiaoying Lei ◽  
Nange Yin ◽  
Yuxia Guo ◽  
Ling Song ◽  
Jin Zhu ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Signaling Pathway ◽  
Burkitt Lymphoma ◽  
Gene Mutations ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Resistance Pathway ◽  
Tki Resistance ◽  
Egfr Tki ◽  
Generation Sequencing

Abstract Background: Burkitt lymphoma/leukemia (BL/BAL) is the most common lymphoma in children, and the sporadic subtype is dominant in Chinese populations. MYC gene translocations are essential for sporadic BL/BAL (sBL/BAL), but other gene mutations also play important roles in the development of sBL/BAL. Methods: The clinical data of ten Chinese children with sBL/BAL were collected, and next generation sequencing of their tumor tissues was conducted. Cases of BL and diffuse large B cell lymphoma (DLBCL) were also collected from a database, and bioinformatics analysis was conducted.Results: Nine boys and one girl were enrolled in the study, including six BL patients (stage III) and four BAL patients (stage IV). The average age at diagnosis was 100.10±13.39m; overexpression of CD20 was detectable, and MYC rearrangements were confirmed. The patients received combination treatment of chemotherapy and rituximab. All patients achieved complete remission and survived. Germline causal gene mutations were detected in four (40%) patients by whole-exome sequencing (WES); ID3, BRCA2, ARID1A and SMARCA4 mutations, in addition to MYC mutations, were the most common somatic mutations. The gene functions in etiology were different between the BL and DLBCL datasets. The identified mutated genes were enriched and connected by GO or KEGG pathways, and it seemed that the PI3K-Akt signaling pathway or the EGFR-TKI resistance pathway played important roles in the etiology of sBL/BAL. Conclusion: sBL/BAL is a highly aggressive but curable lymphoma; its etiology and pathology require additional research. The molecular hallmark of sBL/BAL is MYC translocation, whereas additional chromosomal abnormalities and gene mutations also occur and play roles in the progression of the disease. The PI3K-Akt signaling pathway seems to play important roles in the development of sBL/BAL, and sBL/BAL may be inhibited by this signaling pathway. The EGFR-TKI resistance pathway was also analyzed in sBL/BAL patients, revealing that EGFR-TKI treatment is invalid in this disease. Further research is needed for hypothesis development and possible mechanism discovery.

scholarly journals Genomic signatures in pediatric advanced stage Burkitt lymphoma/ leukemia in Chinese population by next generation sequencing

2020 ◽  
Author(s):  
Xiaoying Lei ◽  
Nange Yin ◽  
Yuxia Guo ◽  
Ling Song ◽  
Jin Zhu ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Signaling Pathway ◽  
Chinese Population ◽  
Gene Mutations ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Resistance Pathway ◽  
Tki Resistance ◽  
Egfr Tki ◽  
Generation Sequencing

Abstract Background: Burkitt lymphoma/leukemia (BL/BAL) is the most common lymphoma in chidren and sporadic subtype is dominant in Chinese population. MYC gene translocation is essential for sporadic BL/BAL (sBL/BAL), whereas other gene mutations also play important roles in the development of sBL/BAL. Methods: The clinical data of ten Chinese children with sBL/BAL were collected; next generation sequencing of tumor tissues were detected. BL and diffused large B cell lymphoma (DLBCL) database was also collected and bioinformatics analyzed was done.Results: Nine male and one female were enrolled in the study, including six BL patients (stage III) and four BAL patients (stage IV). Average age at diagnosis was 100.10±13.39mon; overexpression of CD20 was detectable, MYC rearrangement were confirmed. The patients received combination treatment of chemotherapy and Rituximab, complete remission was achieved and all the patients survived. Germline causal gene mutations were detected in four (40%) patients by whole exome sequencing (WES); ID3, BRCA2, ARID1A and SMARCA4 mutations, except MYC mutation, were the most common somatic mutations. The gene functions in pathopoiesis were differ from BL to DLBCL in dataset. These identified mutated genes were enriched and connected by GO or KEGG pathway, it seemed that PI3K-Akt signaling pathway or EGFR-TKI resistance pathway play important roles in the pathopoiesis of sBL/BAL. Conclusion: sBL/BAL is a highly aggressive but curable lymphoma; the pathophysiolopoiesis is still in research. The molecular hallmark of sBL/BAL is MYC translocation, whereas additional chromosomal abnormalities and gene mutations also occur and play roles in the progression of the disease. PI3K-Akt signaling pathway seems play important roles in the pathopoiesis of sBL/BAL, and sBL/BAL may be inhibited by such signaling pathway; EGFR-TKI resistance pathway was also analyzed in sBL/BAL patients, it reveals that EGFR-TKI treatment is invalid. Further research is needed for the hypothesis and possible mechanisms.

scholarly journals Genomic signatures in pediatric advanced stage Burkitt lymphoma/leukemia in a Chinese population detected by next generation sequencing

2021 ◽  
Author(s):  
Xiaoying Lei ◽  
Jianwen Xiao ◽  
Nange Yin ◽  
Yuxia Guo ◽  
Ling Song ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Signaling Pathway ◽  
Burkitt Lymphoma ◽  
Gene Mutations ◽  
B Cell Lymphoma ◽  
Akt Signaling ◽  
Next Generation ◽  
Akt Signaling Pathway ◽  
Egfr Tki ◽  
Generation Sequencing

IntroductionBurkitt lymphoma/leukemia (BL/BAL) is the most common lymphoma in children, and the sporadic subtype is dominant in Chinese populations. MYC gene translocations are essential for sporadic BL/BAL (sBL/BAL), but other gene mutations also play important roles in sBL/BAL.Material and methodsClinical data of ten Chinese children with sBL/BAL were collected, next generation sequencing of tumor tissues was carried out. Cases of BL and diffuse large B cell lymphoma (DLBCL) were collected from a database, bioinformatics analysis was conductedResultsNine boys and one girl were enrolled, the average age at diagnosis was 100.10±13.39m; MYC rearrangements were confirmed. The patients received combination treatment of chemotherapy and rituximab. All patients achieved complete remission and were alive without relapse. Germline causal gene mutations were detected in four (40%) patients by whole-exome sequencing; ID3, BRCA2, ARID1A and SMARCA4 mutations, in addition to MYC mutations, were the most common somatic mutations. Gene functions in etiology were different between the BL and DLBCL datasets. The identified mutated genes were enriched and connected by GO or KEGG pathways, it seemed that the PI3K-Akt signaling pathway played important roles in the etiology of sBL/BAL; the EGFR-TKI resistance pathway was also analyzed.ConclusionsThe different gene mutations might be index to identify BL or DLBCL in case of difficult pathologic samples. Molecular hallmark of sBL/BAL is MYC translocation, whereas additional gene mutations also occur and play roles in the progression of the disease. sBL/BAL might be controlled by curbing the PI3K-Akt signaling pathway; the EGFR-TKI treatment might not be helpful in sBL/BAL.

scholarly journals Evaluating the cerebrospinal fluid ctDNA detection by next-generation sequencing in the diagnosis of meningeal Carcinomatosis

BMC Neurology ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Yue Zhao ◽  
Jun-Ying He ◽  
Yue-Li Zou ◽  
Xiao-Su Guo ◽  
Jun-Zhao Cui ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Next Generation Sequencing ◽  
Primary Tumor ◽  
Brain Mri ◽  
Gene Mutations ◽  
Circulating Tumor Dna ◽  
Meningeal Carcinomatosis ◽  
Next Generation ◽  
Csf Cytology ◽  
Generation Sequencing

Abstract Background Meningeal carcinomatosis (MC) is the most severe form of brain metastasis and causes significant morbidity and mortality. Currently, the diagnosis of MC is routinely confirmed on the basis of clinical manifestation, positive cerebrospinal fluid (CSF) cytology, and/or neuroimaging features. However, negative rate of CSF cytology and neuroimaging findings often result in a failure to diagnose MC from the patients who actually have the disease. Here we evaluate the CSF circulating tumor DNA (ctDNA) in the diagnosis of MC. Methods A total of 35 CSF samples were collected from 35 patients with MC for CSF cytology examination, CSF ctDNA extraction and cancer-associated gene mutations detection by next-generation sequencing (NGS) at the same time. Results The most frequent primary tumor in this study was lung cancer (26/35, 74%), followed by gastric cancer (2/35, 6%), breast cancer (2/35, 6%), prostatic cancer (1/35, 3%), parotid gland carcinoma (1/35, 3%) and lymphoma (1/35, 3%) while no primary tumor could be found in the remaining 2 patients in spite of using various inspection methods. Twenty-five CSF samples (25/35; 71%) were found neoplastic cells in CSF cytology examination while all of the 35 CSF samples (35/35; 100%) were revealed having detectable ctDNA in which cancer-associated gene mutations were detected. All of 35 patients with MC in the study underwent contrast-enhanced brain MRI and/or CT and 22 neuroimaging features (22/35; 63%) were consistent with MC. The sensitivity of the neuroimaging was 88% (95% confidence intervals [95% CI], 75 to 100) (p = 22/25) and 63% (95% CI, 47 to 79) (p = 22/35) compared to those of CSF cytology and CSF ctDNA, respectively. The sensitivity of the CSF cytology was 71% (95% CI, 56 to 86) (n = 25/35) compared to that of CSF ctDNA. Conclusions This study suggests a higher sensitivity of CSF ctDNA than those of CSF cytology and neuroimaging findings. We find cancer-associated gene mutations in ctDNA from CSF of patients with MC at 100% of our cohort, and utilizing CSF ctDNA as liquid biopsy technology based on the detection of cancer-associated gene mutations may give additional information to diagnose MC with negative CSF cytology and/or negative neuroimaging findings.

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