scholarly journals Plasma Cell-Free DNA Methylomics of Bipolar Disorder With and Without Rapid Cycling

2021 ◽  
Vol 15 ◽  
Author(s):  
Ada Man-Choi Ho ◽  
Stacey J. Winham ◽  
Bryan M. McCauley ◽  
Marija Kundakovic ◽  
Keith D. Robertson ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Nervous System ◽  
Principal Component ◽  
Gene Set Enrichment Analysis ◽  
Rapid Decline ◽  
Rapid Cycling ◽  
Cell Free Dna ◽  
Cpg Sites ◽  
Free Dna ◽  
Gene Sets

Rapid cycling (RC) burdens bipolar disorder (BD) patients further by causing more severe disability and increased suicidality. Because diagnosing RC can be challenging, RC patients are at risk of rapid decline due to delayed suitable treatment. Here, we aimed to identify the differences in the circulating cell-free DNA (cfDNA) methylome between BD patients with and without RC. The cfDNA methylome could potentially be developed as a diagnostic test for BD RC. We extracted cfDNA from plasma samples of BD1 patients (46 RC and 47 non-RC). cfDNA methylation levels were measured by 850K Infinium MethylationEPIC array. Principal component analysis (PCA) was conducted to assess global differences in methylome. cfDNA methylation levels were compared between RC groups using a linear model adjusted for age and sex. PCA suggested differences in methylation profiles between RC groups (p = 0.039) although no significant differentially methylated probes (DMPs; q > 0.15) were found. The top four CpG sites which differed between groups at p < 1E-05 were located in CGGPB1, PEX10, NR0B2, and TP53I11. Gene set enrichment analysis (GSEA) on top DMPs (p < 0.05) showed significant enrichment of gene sets related to nervous system tissues, such as neurons, synapse, and glutamate neurotransmission. Other top notable gene sets were related to parathyroid regulation and calcium signaling. To conclude, our study demonstrated the feasibility of utilizing a microarray method to identify circulating cfDNA methylation sites associated with BD RC and found the top differentially methylated CpG sites were mostly related to the nervous system and the parathyroid.

scholarly journals PATH-27. MUTATION DETECTION USING PLASMA CELL-FREE DNA IN CHILDREN WITH CENTRAL NERVOUS SYSTEM TUMORS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii430-iii430
Author(s):  
Ross Mangum ◽  
Jacquelyn Reuther ◽  
Koel Sen Baksi ◽  
Ryan C Zabriskie ◽  
Ilavarasi Gandhi ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Plasma Cell ◽  
Pediatric Patients ◽  
Cns Tumors ◽  
Cell Free Dna ◽  
Pilot Studies ◽  
Dna And Rna ◽  
Free Dna ◽  
Initial Cohort

Abstract BACKGROUND The role of plasma cell-free DNA (cfDNA) as a cancer biomarker for tracking treatment response and detecting early relapse has been well described for solid tumors outside the central nervous system (CNS). However, the presence of a blood-brain barrier complicates the application of plasma cfDNA analysis for patients with CNS malignancies. METHODS cfDNA was extracted from plasma of pediatric patients with CNS tumors utilizing a QIAmp® MinElute® kit and quantitated with Qubit 2.0 Fluorometer. Extensive genomic testing, including targeted DNA and RNA solid tumor panels, exome and transcriptome sequencing, as well as copy number array, was performed on matched tumor samples as part of the Texas KidsCanSeq study. An Archer® Reveal ctDNA28 NGS kit was then used for assaying the sensitivity of detecting tumor-specific mutations in the plasma of these patients. RESULTS A median of 10.7ng cfDNA/mL plasma (Interquartile range: 6.4 – 15.3) was extracted from 78 patients at time of study enrollment. Longitudinal samples from 24 patients exhibited a median yield of 7.7ng cfDNA/mL plasma (IQR: 5.9 – 9.1). An initial cohort of 6 patients was identified with 7 somatic variants covered by the Archer® Reveal kit. Four of seven mutations identified in matched tumor specimens were detected in patient plasma at variant allele frequencies ranging from 0.2–1%. CONCLUSIONS While challenging, detection of cfDNA in the plasma of pediatric patients with CNS tumors is possible and is being explored in a larger patient cohort along with pilot studies investigating cerebrospinal fluid as an additional source for tumor-specific cfDNA.

scholarly journals Evaluating Cancer of the Central Nervous System Through Next-Generation Sequencing of Cerebrospinal Fluid

2016 ◽  
Vol 34 (20) ◽  
pp. 2404-2415 ◽  
Author(s):  
Elena I. Pentsova ◽  
Ronak H. Shah ◽  
Jiabin Tang ◽  
Adrienne Boire ◽  
Daoqi You ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Tumor Evolution ◽  
Cns Involvement ◽  
Liquid Biopsies ◽  
Cell Free Dna ◽  
Free Dna ◽  
Tumor Dissemination ◽  
The Central Nervous System

Purpose Cancer spread to the central nervous system (CNS) often is diagnosed late and is unresponsive to therapy. Mechanisms of tumor dissemination and evolution within the CNS are largely unknown because of limited access to tumor tissue. Materials and Methods We sequenced 341 cancer-associated genes in cell-free DNA from cerebrospinal fluid (CSF) obtained through routine lumbar puncture in 53 patients with suspected or known CNS involvement by cancer. Results We detected high-confidence somatic alterations in 63% (20 of 32) of patients with CNS metastases of solid tumors, 50% (six of 12) of patients with primary brain tumors, and 0% (zero of nine) of patients without CNS involvement by cancer. Several patients with tumor progression in the CNS during therapy with inhibitors of oncogenic kinases harbored mutations in the kinase target or kinase bypass pathways. In patients with glioma, the most common malignant primary brain tumor in adults, examination of cell-free DNA uncovered patterns of tumor evolution, including temozolomide-associated mutations. Conclusion The study shows that CSF harbors clinically relevant genomic alterations in patients with CNS cancers and should be considered for liquid biopsies to monitor tumor evolution in the CNS.

scholarly journals MYD 88 p.(L265P) detection on cell‐free DNA in liquid biopsies of patients with primary central nervous system lymphoma

2018 ◽  
Vol 185 (5) ◽  
pp. 974-977 ◽  
Author(s):  
Laura S. Hiemcke‐Jiwa ◽  
Roos J. Leguit ◽  
Tom J. Snijders ◽  
Jacoline E. C. Bromberg ◽  
Stefan Nierkens ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Central Nervous System Lymphoma ◽  
Liquid Biopsies ◽  
Cell Free Dna ◽  
Free Dna

scholarly journals Analysis of Driver Mutational Hot Spots in Blood-Derived Cell-Free DNA of Patients with Primary Central Nervous System Lymphoma Obtained before Intracerebral Biopsy

2020 ◽  
Vol 22 (10) ◽  
pp. 1300-1307
Author(s):  
Manuel Montesinos-Rongen ◽  
Anna Brunn ◽  
Armin Tuchscherer ◽  
Peter Borchmann ◽  
Elisabeth Schorb ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Hot Spots ◽  
Central Nervous System Lymphoma ◽  
Cell Free Dna ◽  
Free Dna

BIOM-18. METHYLATION ANALYSIS TO REVEAL THE CELLULAR ORIGIN OF PROGNOSTIC CIRCULATING CELL-FREE DNA IN GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi14-vi14
Author(s):  
Jacob Till ◽  
Aseel Abdalla ◽  
Zhuoyang Wang ◽  
Wanding Zhou ◽  
S Ali Nabavizadeh ◽  
...  
Keyword(s):  
Fragment Size ◽  
Progression Free Survival ◽  
Gene Set Enrichment Analysis ◽  
Newly Diagnosed ◽  
Methylation Analysis ◽  
Cell Free Dna ◽  
Free Dna ◽  
A Genome ◽  
Newly Diagnosed Glioblastoma ◽  
Circulating Cell Free Dna

Abstract We have previously demonstrated an independent association between high levels of plasma circulating cell-free DNA (ccfDNA) concentration and poor survival outcomes in patients with newly diagnosed glioblastoma. Given that somatic mutations are rarely detected in glioblastoma patient plasma, we reasoned that DNA shed by tumor (circulating tumor DNA, ctDNA) was not likely to be a driver of prognostic increases in ccfDNA. To investigate the tissue of origin for this prognostic ccfDNA, we analyzed the plasma ccfDNA methylation signatures of 23 patients with newly diagnosed glioblastoma using the Illumina Infinium EPIC array, a genome-wide DNA methylation technique covering over 850,000 CpG sites. Deconvolution of the ccfDNA methylation signatures based on published reference methylomes revealed an increased proportion of ccfDNA derived from granulocytes in glioblastoma specimens compared to healthy controls (p < 0.0001). Further, this granulocyte proportion was increased in patients with high ccfDNA levels (above median value) compared to patients with low ccfDNA (p = 0.0001). Granulocyte proportion correlated with ccfDNA concentration (Spearman r = 0.64, p = 0.001). The top two gene sets identified by differential methylation analysis followed by gene set enrichment analysis (methylGSA) between high- and low-ccfDNA specimens were “neutrophil activation involved in immune response” (GO:0002283, p = 3.4E-23) and “neutrophil degranulation” (GO:0043312, p = 3.4E-23). Additional analysis of ccfDNA fragment size identified larger fragments ( > 700 bp) as the major source of the prognostic signal (log-rank p = 0.002 for progression-free survival) compared to traditionally sized ccfDNA fragments (50-700 bp, log-rank p = 0.12). Taken together, these data suggest that granulocytes are the primary contributing source of prognostic ccfDNA in glioblastoma. Future studies are needed to determine the mechanism through which granulocyte-derived ccfDNA is associated with clinical outcomes in glioblastoma and to explore related therapeutic opportunities.

scholarly journals Nanopore sequencing methods detect cell-free DNA associated with minimal residual disease and central nervous system infiltration in pediatric Acute Lymphoblastic Leukemia

2021 ◽  
Author(s):  
Shilpa Sampathi ◽  
Yelena Chernyavskaya ◽  
Meghan G. Haney ◽  
L. Henry Moore ◽  
Isabel A. Snyder ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Nanopore Sequencing ◽  
Cell Free Dna ◽  
Free Dna ◽  
Minimal Residual

AbstractAcute Lymphoblastic Leukemia (ALL) patients that have minimal residual disease (MRD) after therapy or infiltration of ALL into the central nervous system (CNS) are considered high risk. These patients are often given intensified and/or additional rounds of chemotherapy in the hopes of eliminating their disease. Current methods to diagnose MRD and CNS infiltration rely on detecting ALL cells in patient samples using pathology, flow cytometry, or isolation of ALL genomic DNA for next-generation sequencing. However, blasts may be present in the patient but not detectable in a bone marrow biopsy or cerebrospinal (CSF) fluid sample, leading to incorrect or delayed patient diagnosis. We have developed a nanopore sequencing assay to detect B-ALL-associated cell-free DNA in patient blood and CSF samples. Quantitation of B-cell specific VDJ recombination events in cell-free DNA samples defined B-ALL clonal heterogeneity. Monitoring cfDNA in blood and CSF samples allowed us to track the response of individual B-ALL clones throughout each patient’s course of treatment. Detection of cell-free DNA predicted the clinical diagnosis of MRD and CNS disease. We also identified patients diagnosed as CNS negative who had low levels of cell-free DNA in their CSF sample. These data suggest that cell-free DNA assays may be useful in detecting the presence of ALL in the patient even when blasts are not in the biofluid sample. In total, nanopore analysis of cell-free DNA is a simple, rapid, and inexpensive assay that can serve as a useful complement to traditional clinical diagnostic approaches in the treatment of ALL.

scholarly journals ML-11 DETECTION OF MYD88 MUTATIONS FROM CELL FREE DNA AIDS IN THE DIAGNOSIS OF CENTRAL NERVOUS SYSTEM LYMPHOMAS

2019 ◽  
Vol 1 (Supplement_2) ◽  
pp. ii34-ii34
Author(s):  
Manabu Natsumeda ◽  
Jun Watanabe ◽  
Yu Kanemaru ◽  
Yoshihiro Tsukamoto ◽  
Masayasu Okada ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Pcr Analysis ◽  
Cns Lymphoma ◽  
Precision Oncology ◽  
Cell Free Dna ◽  
Free Dna

Abstract BACKGROUND Diagnosis of primary central nervous system lymphomas (PCNSL) can be challenging. We have shown that the detection of MYD88 mutation in cell free DNA (cfDNA) taken from cerebrospinal fluid (CSF) is reliable (JCO Precision Oncology, 2019; Leukemia and Lymphoma, 2019). We report four cases in which detection of MYD88 mutation aided in the diagnosis. CASE 1 A 67-year-old man with a history of systemic B-cell lymphoma, experienced right hemiparesis. MRI showed a slightly enhancing lesion located in the midbrain. MYD88 L265P mutation was found by digital droplet PCR analysis of cfDNA extracted from CSF. The patient underwent a needle biopsy, and was diagnosed as diffuse large B-cell lymphoma. CASE 2 A 32-year-old man was diagnosed as having a demyelinating lesion after experiencing severe headaches. A small enhancing lesion was found in the right frontal lobe, and the patient was treated with steroids. The lesions repeatedly disappeared and reappeared and finally, stopped responding to steroids. MYD88 mutation was detected. A biopsy was performed, and the diagnosis was PCNSL. CASE 3 A 49-year-old man underwent a biopsy for a right frontal lesion after experiencing memory loss; the pathology showed broad T-cell infiltration but only some perivascular B-cells with slight atypia. The patient was tapered off steroids, and the lesion spread rapidly. An open biopsy was performed, but the pathology was not typical for B-cell lymphoma. The patient’s symptoms rapidly worsened, and whole brain irradiation was performed. At recurrence, MYD88 mutation was detected. CASE 4 An 82-year-old man presented with blurred vision. Vitreous humor biopsy was inconclusive for ocular lymphoma. A head MRI showed an intracranial lesion which spontaneously regressed. MYD88 was detected, and the patient is being closely observed. CONCLUSION Detection of MYD88 mutation from cfDNA extracted from CSF can aid in the diagnosis of CNS lymphoma, especially in atypical cases.

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