Abstract A12: DNA methylation-based liquid biopsy detects primary and recurrent meningioma

2020 ◽  
Author(s):  
Thais S. Sabedot ◽  
Tathiane M. Malta ◽  
James Snyder ◽  
Tobias Walbert ◽  
Ian Lee ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Liquid Biopsy ◽  
Recurrent Meningioma

scholarly journals GENE-61. METHYLATION-BASED LIQUID BIOPSY OF MENINGIOMA PRIMARY AND RECURRENT SAMPLES

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi111-vi111
Author(s):  
Thais Sarraf Sabedot ◽  
Tathiane Malta ◽  
James Snyder ◽  
Tobias Walbert ◽  
Ian Lee ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Tumor Cells ◽  
Liquid Biopsy ◽  
Malignant Tumors ◽  
Fragment Size ◽  
Point Mutations ◽  
Tumor Burden ◽  
P Value ◽  
Minimal Risk ◽  
Dna Fragments

Abstract Meningiomas are mostly benign CNS tumors, however a subset of these tumors may become atypical or malignant. The standard of care to monitor patients after diagnosis requires serial MRI assessments, which have limited value in distinguishing malignant tumors from benign disease. Therefore the discovery of non-invasive methodologies that reflect meningioma tumor burden and its dynamic evolution in real-time is highly desirable. Liquid biopsy (LB) could be used to fine-tune surveillance and treatment with minimal risk to patients. Evidence of circulating tumor cells and cell-free (cf) tumor DNA in the blood has been shown in several tumor types, however limited progress has been made for brain tumors with known biomarkers; possibly due to the unlikelihood of capturing point mutations in circulating DNA fragments. On the other hand, DNA methylation signatures are maintained even in small DNA fragments, which suggests that DNA methylation is an attractive marker to be studied in liquid biopsy of brain cancers. In order to identify DNA methylation-based biomarkers using archival serum and tissue specimens, we analyzed the epigenome (Illumina Human EPIC array) of patients with primary (n=10) and recurrent (n=4) meningiomas and epileptic patients (n=5) as control. cfDNA fragment size distribution revealed peaks with 150~200bp on average. We identified 482 CpGs (p-value< 0.001) differentially methylated between primary meningiomas and controls, which 294 (61%) show a DNA methylation profile similar to the matched tumor tissue. Overall, we observed that recurrent samples are hypermethylated (56%) compared to primary. From this pilot data, we were able to investigate the LB methylome of meningioma patients and identify potential markers to detect tumor cells in the serum of these patients, which could eventually allow clinicians to monitor impending disease progression and recurrence.

scholarly journals GENE-24. DNA METHYLATION SIGNATURES DETECTED IN A SERUM-BASED LIQUID BIOPSY DISTINGUISH FUNCTIONAL AND INVASIVENESS FEATURES IN PITUITARY ADENOMAS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi102-vi102
Author(s):  
Michael Wells ◽  
Thais Sarraf Sabedot ◽  
Karam Asmaro ◽  
Maritza Mosella ◽  
Tathiane Malta ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Liquid Biopsy ◽  
Pituitary Tumors ◽  
Blood Draw ◽  
Tumor Subtypes ◽  
Molecular Features ◽  
Control Serum ◽  
Resected Tumor ◽  
Invasive Status ◽  
Tissue Specimens

Abstract Pituitary tumors are the second most common CNS neoplasia (~15%). Despite mostly benign and slow-growing, they may be nonfunctioning and invade surrounding structures resulting in significant comorbidities. Currently, classification of PT according to their risk for aggressiveness is mainly based on invasiveness detected by imaging methods and histopathological features which requires surgically resected tumor. Being able to detect molecular markers associated with tumor subtypes and behavior pre-surgically using minimally invasive approaches (blood draw) is desirable in these tumors and may help to address current diagnostic and therapeutic challenges. In tissue specimens, distinct DNA methylation patterns distinguish PT according to their functional status but their role in invasiveness is still unclear. We hypothesized that profiling cell-free DNA (cfDNA) released by PT into the bloodstream allow the identification of epigenetic markers associated with relevant clinicopathological features. Genome-wide methylome profile of paired serum cfDNA (EPIC array) and tissue from 13 patients with pituitary macroadenomas (9 males; median age: 62; 9 Nonfunctioning/4 functioning, 6 invasive/7 noninvasive) and 3 controls serum (patients with epilepsy). Unsupervised analysis of the serum methylome from patients harboring PT was distinct from controls and other diseases (hypopituitarism, glioma and colorectal cancer) and supervised analysis (Wilcoxon Rank-sum Test) identified significant differentially methylated probes (DMP) that segregated PT from control serum specimens. Nonfunctioning and invasive-specific DMPs identified in the serum also defined functional, and less prominently invasive status, in the tissue of an independent cohort of PT. This is the first study to show the feasibility to profile the serum methylome from patients with PT using cfDNA. In addition, we identified unique methylation signatures that distinguished PT according to functional and invasiveness subtypes. These results underpin the potential role of methylation profile and liquid biopsy as a noninvasive approach to assess clinically relevant molecular features in the serum of patients harboring PT.

scholarly journals OR32-03 Serum Cell-Free Methylation-Based Signatures Distinguishes Pituitary Tumors According to Functional Status and from Other Neoplasia: A Liquid Biopsy Approach

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Michael Wells ◽  
Karam P Asmaro ◽  
Thais S Sabedot ◽  
Maritza S Mosella ◽  
Tathiane M Malta, PharmD ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Functional Status ◽  
Liquid Biopsy ◽  
Pituitary Tumors ◽  
Cns Tumors ◽  
Surgical Approaches ◽  
Molecular Features ◽  
Cell Material ◽  
Independent Cohort

Abstract BACKGROUND: Several reports have indicated that distinct epigenomic patterns of pituitary tumors (PT), specifically DNA methylation, distinguish these tumor tissues according to their functionality and could be involved in their pathogenesis. Thus far, molecular diagnosis and classification criteria that guide clinical management of these tumors rely on the tissue profiling obtained by invasive surgical approaches (e.g. excision). However, increasing evidence confirmed that central nervous system (CNS) tumors release cell material into the circulation creating an opportunity for molecular profiling of these tumors using a blood-based liquid biopsy. Considering that 1) the pituitary portal system and the invasion of the cavernous system by PT may facilitate the spillage of tumor cell material into the bloodstream and 2) the stability, cell-specificity and reportedly the role of DNA methylation in PT, we hypothesized that liquid biopsy would be feasible to detect and define specific methylation-based signatures in the serum of patients harboring PT. Methods and Findings: We conducted analyses of the methylomes of paired serum circulating cell-free DNA (cfDNA) and tumor tissue from patients harboring PT (EPIC array) to identify serum-derived pituitary tumor-specific methylation-based signatures (sPTMet n=37) in a cohort comprised by 13 patients with pituitary macroadenomas (9 males; median age: 62; 9 Nonfunctioning/4functioning, 6 invasive/7noninvasive), 4 controls (non-tumor) and patients with other CNS tumors or conditions (114 gliomas, 6 meningiomas, 1 brain metastasis, 1 colloid cyst, 6 radiation necrosis). Unsupervised and supervised analysis indicated that the serum methylome from patients harboring PT was distinct from controls and other CNS diseases. Using the sPTMet as input into a machine learning algorithm, we generated a PT score that classified the serum of an independent cohort as PT or non-PT, with high accuracy. We identified serum-derived differentially methylated probes (DMP, n=3288) that distinguished PT according to their function (functioning and nonfunctioning). When overlapped with an independent cohort, these DMP also distinguished PT tissue according to their functional status. Conclusion: Our results showed the feasibility to identify PT-specific methylation signatures by profiling the methylome of serum cfDNA from patients with PT. These signatures distinguished PT from other CNS tumors and according to their subtypes. These results underpin the potential role of methylation profile and liquid biopsy as a noninvasive approach to assess clinically relevant molecular features. Potentially, tumor-specific serum-derived methylation signature may be used as a diagnostic, prognostic and surveillance tool as well to identify actionable molecular markers in patients with PT.

scholarly journals Liquid Biopsy Test Based on a Sensitive DNA Methylation Assay for Diagnosing Hepatocellular Carcinoma：Which Is a Better Marker, Methylated SST Or SEPT9?

2021 ◽  
Vol 70 (3) ◽  
pp. 89-98
Author(s):  
Ayano YAMASAKI ◽  
Yutaka SUEHIRO ◽  
Tomomi HOSHIDA ◽  
Issei SAEKI ◽  
Yurika YAMAUCHI（KOTOH） ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Liquid Biopsy ◽  
Methylation Assay

scholarly journals OTME-5. Meningioma liquid biopsy specimens exhibit contrasting immune-cell landscapes across methylation-subtypes and estimated recurrence risk subgroups

2021 ◽  
Vol 3 (Supplement_2) ◽  
pp. ii14-ii14
Author(s):  
Grayson Herrgott ◽  
Ruicong She ◽  
Thais Sabedot ◽  
Michael Wells ◽  
Karam Asmaro ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Random Forest ◽  
Liquid Biopsy ◽  
Immune Cell ◽  
Cell Types ◽  
Recurrence Risk ◽  
Random Forest Classifier ◽  
Serum Samples ◽  
Biopsy Specimens ◽  
Genome Wide

Abstract Background Tumor-infiltrating immune cell compositions have been previously correlated to encouragement or inhibition of tumor growth. This association highlights immune-landscape profiling through non-invasive methods as a crucial step in approaches to treatment of patients with meningioma (MNG), a prevalent primary intracranial tumor. Genome-wide DNA methylation patterns can aid in definition and assessment of cell compositions in liquid biopsy serum specimens, and allow for development of machine-learning models with predictive capabilities. Methods We profiled the cfDNA methylome (EPIC array) in liquid biopsy specimens from patients with MNG (n = 63) and nontumor controls (n = 6). We conducted both unsupervised epigenome-wide and supervised analyses of the meningioma methylome. Estimation of immune cell composition was conducted using Python-based methodology, where a reference methylome atlas of chosen cell types (B-cells, CD4- and CD8T-cells, neutrophils, natural killer cells, monocytes, cortical neuron, vascular endothelial cells, and healthy meninge) was used to deconvolute the MNG samples. Recurrence risk was estimated using an existing methylation-based Random-Forest classifier previously reported and validated, adapted to our serum-based cohort through employment of translatable meningioma subgroup-specific methylation markers (differentially methylated probes). Results We identified four distinct genome-wide methylation subgroups (k-clusters) of MNG which presented differential tumor micro-environments across all cell types investigated. Application of the DNA methylation-based Random-Forest classifier allowed for categorization of primary MNG serum samples into estimated recurrence-risk subgroups. Significantly contrasting micro-environments for the subgroups were observed across several cell-types, with those MNG more likely to recur displaying depletion in cell types reported to improve anti-tumoral response in many tumors (e.g. T-Cells). Conclusions DNA methylation based deconvolution allowed for detection of contrasting tumor microenvironment compositions across MNG methylation subtypes and recurrence-risk estimation subgroups. These results suggest that microenvironment profiling can be informative of probable tumor behavior and prognostic outcomes, helping guide therapeutic approaches towards treatment of patients with MNG.

Abstract LB-234: Pre-surgical identification of diagnostic, prognostic and predictive DNA methylation-based markers in serum (liquid biopsy) of patients harboring gliomas

2019 ◽  
Author(s):  
Houtan Noushmehr ◽  
Thais S. Sabedot ◽  
Tathiane M. Malta ◽  
Kevin K. Nelson ◽  
James Snyder ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Liquid Biopsy

Abstract A62: Clinical translation of liquid biopsy DNA methylation biomarkers: Lessons from two systematic reviews

2020 ◽  
Author(s):  
Kim Lommen ◽  
Zheng Feng ◽  
Cary J.G. Oberije ◽  
Alouisa J. P. van de Wetering ◽  
Selena Odeh ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Systematic Reviews ◽  
Liquid Biopsy ◽  
Clinical Translation

scholarly journals Prognostic Significance of Gene Expression and DNA Methylation Markers in Circulating Tumor Cells and Paired Plasma Derived Exosomes in Metastatic Castration Resistant Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 780
Author(s):  
Martha Zavridou ◽  
Areti Strati ◽  
Evangelos Bournakis ◽  
Stavroula Smilkou ◽  
Victoria Tserpeli ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Dna Methylation ◽  
Tumor Cells ◽  
Liquid Biopsy ◽  
Prognostic Significance ◽  
Comparison Study ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
First Time

Liquid biopsy, based on the analysis of circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), provides non-invasive real-time monitoring of tumor evolution and therapeutic efficacy. We performed for the first time a direct comparison study on gene expression and DNA methylation markers in CTCs and paired plasma-derived exosomes and evaluated their prognostic significance in metastatic castration resistant prostate cancer. This prospective liquid biopsy (LB) study was based on a group of 62 metastatic castration resistant prostate cancer (mCRPC) patients and 10 healthy donors (HD) as controls. Identical blood draws were used to: (a) enumerate CTC and tumor-derived extracellular vesicles (tdEVs) using CellSearch (CS) and (b) analyze CTCs and paired plasma-derived exosomes at the gene expression and DNA methylation level. CTCs were enumerated using CellSearch in 57/62 patients, with values ranging from 5 to 854 cells/7.5 mL PB. Our results revealed for the first time a significantly higher positivity of gene expression markers (CK-8, CK-18, TWIST1, PSMA, AR-FL, AR-V7, AR-567 and PD-L1 mRNA) in EpCAM-positive CTCs compared to plasma-derived exosomes. GSTP1, RASSF1A and SCHLAFEN were methylated both in CTC and exosomes. In CTCs, Kaplan–Meier analysis revealed that CK-19 (p = 0.009), PSMA (p = 0.001), TWIST1 (p = 0.001) expression and GSTP1 (p = 0.001) methylation were correlated with OS, while in exosomes GSTP1 (p = 0.007) and RASSF1A (p = 0.001) methylation was correlated with OS. Our direct comparison study of CTCs and exosomes at gene expression and DNA methylation level, revealed for the first time a significantly higher positivity in EpCAM-positive CTCs compared to plasma-derived exosomes. Future perspective of this study should be the evaluation of clinical utility of molecular biomarkers in CTCs and exosomes on independent multicentric cohorts with mCRPC patients.

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