scholarly journals Genetic and epigenetic characterization of posterior pituitary tumors

2021 ◽  
Author(s):  
Simone Schmid ◽  
David A. Solomon ◽  
Eilis Perez ◽  
Anne Thieme ◽  
Bette K. Kleinschmidt-DeMasters ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Copy Number ◽  
Pituitary Tumors ◽  
Granular Cell ◽  
Genetic Alterations ◽  
Outcome Analysis ◽  
Posterior Pituitary ◽  
Single Entity ◽  
Molecular Features ◽  
Favorable Group

AbstractPituicytoma (PITUI), granular cell tumor (GCT), and spindle cell oncocytoma (SCO) are rare tumors of the posterior pituitary. Histologically, they may be challenging to distinguish and have been proposed to represent a histological spectrum of a single entity. We performed targeted next-generation sequencing, DNA methylation profiling, and copy number analysis on 47 tumors (14 PITUI; 12 GCT; 21 SCO) to investigate molecular features and explore possibilities of clinically meaningful tumor subclassification. We detected two main epigenomic subgroups by unsupervised clustering of DNA methylation data, though the overall methylation differences were subtle. The largest group (n = 23) contained most PITUIs and a subset of SCOs and was enriched for pathogenic mutations within genes in the MAPK/PI3K pathways (12/17 [71%] of sequenced tumors: FGFR1 (3), HRAS (3), BRAF (2), NF1 (2), CBL (1), MAP2K2 (1), PTEN (1)) and two with accompanying TERT promoter mutation. The second group (n = 16) contained most GCTs and a subset of SCOs, all of which mostly lacked identifiable genetic drivers. Outcome analysis demonstrated that the presence of chromosomal imbalances was significantly associated with reduced progression-free survival especially within the combined PITUI and SCO group (p = 0.031). In summary, we observed only subtle DNA methylation differences between posterior pituitary tumors, indicating that these tumors may be best classified as subtypes of a single entity. Nevertheless, our data indicate differences in mutation patterns and clinical outcome. For a clinically meaningful subclassification, we propose a combined histo-molecular approach into three subtypes: one subtype is defined by granular cell histology, scarcity of identifiable oncogenic mutations, and favorable outcome. The other two subtypes have either SCO or PITUI histology but are segregated by chromosomal copy number profile into a favorable group (no copy number changes) and a less favorable group (copy number imbalances present). Both of the latter groups have recurrent MAPK/PI3K genetic alterations that represent potential therapeutic targets.

scholarly journals Clinical-Pathological, Immunohistochemical, and Genetic Characterization of a Series of Posterior Pituitary Tumors

2020 ◽  
Vol 80 (1) ◽  
pp. 45-51
Author(s):  
Valeria Barresi ◽  
Michele Simbolo ◽  
Marco Gessi ◽  
Sabrina Rossi ◽  
Maria Caffo ◽  
...  
Keyword(s):  
Loss Of Heterozygosity ◽  
Pituitary Tumors ◽  
Granular Cell ◽  
Genetic Alterations ◽  
Homozygous Deletion ◽  
Posterior Pituitary ◽  
Chromosome 1P ◽  
Genetic Features ◽  
Older Subjects

Abstract Posterior pituitary tumors are supposed to represent the morphological spectrum of a single entity. Herein, we report the clinical-pathological, immunohistochemical, and genetic features of 5 spindle cell oncocytomas (SCOs), 3 pituicytomas, and 1 granular cell tumor (GCT). SCOs had the highest local invasiveness and affected older subjects. The 3 histotypes differed in the content of spindle cells (predominant in pituicytoma and absent in GCT), presence of lymphocytic infiltrate (in SCO and GCT, but not in the pituicytoma) and EMA/GFAP staining (negative in GCT; EMA-positive/GFAP-negative in 4/5 SCO and GFAP-positive in 3/3 pituicytomas). Three SCOs and 1 pituicytoma analyzed with next-generation sequencing had no mutations in 409 genes. However, 1 SCO had previously unreported homozygous deletion of CDKN2A/B and another of SMARCA4, SMARCB1, and NF2. All 3 SCOs had loss of heterozygosity of chromosome 1p, while the pituicytoma had chromosome 19 homozygous loss and chromosomes 10, 13q, and 18q loss of heterozygosity. Since 1p and 13q losses were previously reported in 1 pituicytoma and 1 SCO, respectively, our data demonstrate that posterior pituitary tumors share common genetic alterations. The possibility that posterior pituitary tumors are SMARCA4/SMARCB1-deficient should be kept in mind in the differential diagnosis toward other entities.

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.

Comprehensive Genomic and DNA Methylation Analysis in Twins with ETV6-RUNX1 Acute Lymphoblastic Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 597-597
Author(s):  
Manoo Bhakta ◽  
Mathias Ehrich ◽  
Eric J. Gratias ◽  
James R. Downing ◽  
Charles G Mullighan
Keyword(s):  
Dna Methylation ◽  
Acute Lymphoblastic Leukemia ◽  
Copy Number ◽  
Lymphoblastic Leukemia ◽  
Genetic Alterations ◽  
Copy Number Alterations ◽  
Methylation Analysis ◽  
Dna Copy Number ◽  
Dna Copy Number Alterations ◽  
Control Samples

Abstract DNA methylation as a source for epigenetic variability has been implicated in a variety of different cancer types. Often these studies are confounded by inter-individual differences in the epigenetic profiles. The pattern of epigenetic marks can be altered by factors like age, nutrition, behavior or other environmental factors, which are difficult to control. We had the unique opportunity to study DNA methylation profiles in a pair of monozygotic twin boys who developed ETV6-RUNX1 B-progenitor acute lymphoblastic leukemia at 2 years of age within 3 weeks of each other. ETV6-RUNX1 ALL is characterized by a high frequency of recurring genetic alterations, but the full complement of genomic and epigenetic alterations contributing to leukemogenesis is unknown. For these twin cases, environmental influences upon epigenetic variation are largely eliminated. We used a mass spectrometry-based quantitative DNA methylation analysis technique (Sequenom’s® EpiTYPER™ application) to investigate 597 amplicons covering the promoter regions of 190 genes. The genomic target regions were selected to be enriched for genes involved in transcriptional regulation (n=130) and/or genes known to be targeted by recurring DNA copy number alterations in childhood leukemia (n= 60). Methylation analysis were performed on DNA extracted from cryopreserved, Ficoll enriched bone leukemic blasts obtained from diagnostic bone marrow aspirates, and non-leukemic peripheral blood leukocytes obtained at remission. We also examined DNA copy number alterations (CNAs) and loss-of- heterozygosity (LOH) using Affymetrix single nucleotide polymorphism (SNP) 6.0 arrays, which examine over 1.8 million loci, in both tumor and normal tissue for both twins. Analysis of SNP array data identified different somatic CNAs in the tumor samples of the two twins involving 9p21.3 (the CDKN2A/B tumor suppressor locus), 12p13.2 (ETV6) and trisomy 21, indicating that the shared ETV6-RUNX1 positive pre-leukemic clone acquired different secondary genetic alterations during leukemogenesis in each twin. Despite these genetic differences, the methylation profiles of the tumor samples were remarkably similar. Unsupervised two-dimensional clustering of quantitative methylation data revealed that the tumor samples clustered separately from the control samples. Based on these findings we calculated the methylation differences in each genomic target region. A total of 51 genomic regions were significantly differentially methylated between tumor and control samples (paired t-test P<0.001, and an average methylation difference > 10%). Within the differentially methylated genomic regions, a subset of approximately 20 exhibited strong regional differences, indicating that DNA methylation changes can be limited to certain areas of the promoter. In the group of genes known to be involved in transcriptional regulation, 32% were differentially methylated, including the HOXA, HOXB, HOXC and HOXD regions, while in the remaining genes only 15% were differentially methylated. This enrichment is significant on the level of 0.05 (Fisher’s exact test, odds ratio: 2.7). This represents the first study comparing genomic and epigenetic alterations in B-precursor ALL involving monozygotic twins. Notably, different DNA copy number alterations are acquired in each twin during leukemogeneis. In contrast, the tumor samples exhibit similar methylation patterns that are strikingly different to control samples obtained from the same individuals. These results indicate that combined genomic and epigenetic analyses will be important to characterize the full repertoire of genomic alterations in acute lymphoblastic leukemia.

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 Systematic Investigation of mRNA N6-Methyladenosine Machinery in Primary Prostate Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-21
Author(s):  
Mei Jiang ◽  
Yali Lu ◽  
Dongxia Duan ◽  
Hongxiang Wang ◽  
Gaoya Man ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Methylation ◽  
Copy Number ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
In Vitro Assays ◽  
Molecular Features ◽  
Primary Prostate Cancer ◽  
And Migration ◽  
Proliferation And Migration

Background. Appreciable findings have pointed out pivotal roles of N6-methyladenosine (m6A) machinery in cancer onset and progression. However, limited efforts have been directed towards relevant research in the prostate cancer area. Methods. A PubMed search was conducted to acquire components of the mRNA m6A machinery. Multiomics integration was performed to systematically investigate the mRNA m6A machinery in primary prostate cancer. Furthermore, RNA interference assays of two prognostic m6A readers EIF3D and HNRNPA2B1 were conducted to explore m6A dependence of their functions in prostate cancer cell proliferation and migration. Results. A total of 41 mRNA m6A regulators have been identified to date. A small degree of copy number aberrations and an extremely low frequency of somatic mutations were observed in the regulators across prostate tumors. Enrichment of CpG sites and extensive changes of DNA methylation in the m6A machinery were also found. Impact of copy number variation on m6A regulator expression was stronger than that of DNA methylation disturbance. Furthermore, our study identified a set of m6A regulators related to clinical features and/or survival which were largely m6A-binding proteins. The translation initiation factor subunit EIF3D and the splicing factor HNRNPA2B1 can be independent prognostic factors which may contribute to retardation and promotion of cancer progression, respectively, through affecting cancer-related processes such as cell cycle. Moreover, in vitro assays demonstrated that m6A impacted the EIF3D and HNRNPA2B1 roles in proliferation and migration of prostate cancer cells. Conclusions. Our report systematically described molecular features of the mRNA m6A machinery and their potential roles in primary prostate cancer. Knowledge gained from this work may pave the way for further studies on the m6A system in prostate cancer.

scholarly journals P01.02 Serum-derived DNA methylation markers distinguish functional and invasiveness subtypes in patients harboring pituitary tumors

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii24-iii24
Author(s):  
A V Castro ◽  
M Wells ◽  
K Asmaro ◽  
T S Sabedot ◽  
M S Mosella ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Pituitary Tumors ◽  
Clinical Value ◽  
Molecular Features ◽  
Genome Wide ◽  
Wilcoxon Rank Sum Test ◽  
Control Serum ◽  
Invasive Status ◽  
Paired Serum ◽  
Patients With Epilepsy

Abstract BACKGROUND Molecular profiling of circulating biomarkers released by tumors has a relevant clinical value in central nervous system (CNS) tumors, but its feasibility has not been investigated in pituitary tumors (PT) despite being the second common intraaxial tumors of the CNS (~15%). Although usually benign and slow-growing, they can be nonfunctioning and invade surrounding structures resulting in significant comorbidities. DNA methylation aberrations distinguish PT according to their functional status but their role in invasiveness is still unclear. Pre-surgical detection of clinically relevant molecular markers associated with tumor behavior can address current diagnostic and therapeutic challenges. We hypothesized that PT release cell-free DNA (cfDNA) into the bloodstream allowing for the profiling of epigenetic markers associated with relevant clinicopathological features. MATERIAL AND METHODS Genome-wide methylome profile of paired serum cfDNA (EPIC array) and tissue from 13 patients with pituitary macroadenomas (9 males; median age: 62; 9 NFPT, 6 invasive) and 3 controls serum (patients with epilepsy). RESULTS 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. CONCLUSION This is the first study to show the feasibility to profile the methylome in the serum of 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.

Granular Cell Tumor and Spindle Cell Oncocytoma of the Pituitary Gland: Imaging and Intraoperative Cytology Diagnostic Dilemmas and Management Challenges

2021 ◽  
Author(s):  
Sandeep Kandregula ◽  
Abhinith Shashidhar ◽  
Shilpa Rao ◽  
Manish Beniwal ◽  
Dhaval Shukla ◽  
...  
Keyword(s):  
Pituitary Adenoma ◽  
Pituitary Gland ◽  
Vision Loss ◽  
Spindle Cell ◽  
Pituitary Tumors ◽  
Granular Cell ◽  
Preoperative Imaging ◽  
Posterior Pituitary ◽  
Intraoperative Cytology ◽  
Transcranial Approach

Abstract Background Tumors arising from the posterior pituitary gland are rare and closely resemble pituitary adenoma in presentation and imaging. Most of them come as a histopathologic surprise. We have analyzed the posterior pituitary tumors managed in our institute and have discussed the dilemmas in imaging, challenges in intraoperative squash cytology, and surgical management. Methods We retrospectively reviewed our operative database of pituitary tumors over the past 10 years, which included five posterior pituitary tumors (three granular cell tumors [GCTs] and two spindle cell oncocytomas [SCOs]). Clinical, imaging, and endocrine characteristics; intraoperative details; histopathologic features; and postoperative outcomes were collected and analyzed. Results The mean age of the patients was 47 years. All patients presented with varying degrees of vision loss. Radiology revealed a sellar / suprasellar lesion with the pituitary gland seen separately in two of three GCTs, whereas a separate pituitary gland could not be identified in both the SCOs. Pituitary adenoma was a radiologic diagnosis in only two of five cases. Three patients underwent a transsphenoidal surgery, whereas two underwent surgery by the transcranial approach. Intraoperative cytology was challenging, though a possibility of posterior pituitary tumor was considered in three of four cases, whereas one was considered meningioma. All the tumors were very vascular and influenced the extent of resection. Conclusions GCTs and SCOs are relatively uncommon tumors that are difficult to diagnose on preoperative imaging. Intraoperative squash cytology too can pose challenges. A preoperative suspicion can prepare the surgeon for surgery of these hypervascular tumors. The transcranial approach may be necessary in cases of uncertainty in imaging.

scholarly journals Copy number-dependent DNA methylation of the Pyricularia oryzae MAGGY retrotransposon is triggered by DNA damage

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Ba Van Vu ◽  
Quyet Nguyen ◽  
Yuki Kondo-Takeoka ◽  
Toshiki Murata ◽  
Naoki Kadotani ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Copy Number ◽  
Rna Silencing ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Pyricularia Oryzae ◽  
Transcriptional Gene Silencing ◽  
Physical Interaction ◽  
Uncharacterized Protein ◽  
Form Complex

AbstractTransposable elements are common targets for transcriptional and post-transcriptional gene silencing in eukaryotic genomes. However, the molecular mechanisms responsible for sensing such repeated sequences in the genome remain largely unknown. Here, we show that machinery of homologous recombination (HR) and RNA silencing play cooperative roles in copy number-dependent de novo DNA methylation of the retrotransposon MAGGY in the fungusPyricularia oryzae. Genetic and physical interaction studies revealed thatRecAdomain-containing proteins, includingP. oryzaehomologs ofRad51, Rad55, andRad57, together with an uncharacterized protein, Ddnm1, form complex(es) and mediate either the overall level or the copy number-dependence of de novo MAGGY DNA methylation, likely in conjunction with DNA repair. Interestingly,P. oryzaemutants of specific RNA silencing components (MoDCL1andMoAGO2)were impaired in copy number-dependence of MAGGY methylation. Co-immunoprecipitation of MoAGO2 and HR components suggested a physical interaction between the HR and RNA silencing machinery in the process.

scholarly journals Nongenotoxic ABCB1 activator tetraphenylphosphonium can contribute to doxorubicin resistance in MX-1 breast cancer cell line

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Raimonda Kubiliute ◽  
Indre Januskeviciene ◽  
Ruta Urbanaviciute ◽  
Kristina Daniunaite ◽  
Monika Drobniene ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Line ◽  
Protein Level ◽  
Copy Number ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Common Mechanism ◽  
Dna Hypomethylation ◽  
Mesenchymal Transition ◽  
Molecular Features

AbstractHyperactivation of ABC transporter ABCB1 and induction of epithelial–mesenchymal transition (EMT) are the most common mechanism of acquired cancer chemoresistance. This study describes possible mechanisms, that might contribute to upregulation of ABCB1 and synergistically boost the acquisition of doxorubicin (DOX) resistance in breast cancer MX-1 cell line. DOX resistance in MX-1 cell line was induced by a stepwise increase of drug concentration or by pretreatment of cells with an ABCB1 transporter activator tetraphenylphosphonium (TPP+) followed by DOX exposure. Transcriptome analysis of derived cells was performed by human gene expression microarrays and by quantitative PCR. Genetic and epigenetic mechanisms of ABCB1 regulation were evaluated by pyrosequencing and gene copy number variation analysis. Gradual activation of canonical EMT transcription factors with later activation of ABCB1 at the transcript level was observed in DOX-only treated cells, while TPP+ exposure induced considerable activation of ABCB1 at both, mRNA and protein level. The changes in ABCB1 mRNA and protein level were related to the promoter DNA hypomethylation and the increase in gene copy number. ABCB1-active cells were highly resistant to DOX and showed morphological and molecular features of EMT. The study suggests that nongenotoxic ABCB1 inducer can possibly accelerate development of DOX resistance.

scholarly journals EPCO-29. EPIGENOMICS OF THE GLIOMA LONGITUDINAL ANALYSIS (GLASS) CONSORTIUM

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii75-ii75
Author(s):  
Thais Sabedot ◽  
Michael Wells ◽  
Indrani Datta ◽  
Tathiane Malta ◽  
Ana Valeria Castro ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Longitudinal Analysis ◽  
Copy Number ◽  
Large Scale ◽  
Molecular Classification ◽  
Tumor Burden ◽  
Copy Number Alterations ◽  
Unsupervised Analysis ◽  
Diffuse Gliomas ◽  
New Biomarkers

Abstract Adult diffuse gliomas are central nervous system (CNS) tumors that arise from the malignant transformation of glial cells. Nearly all gliomas will recur despite standard treatment however, current histopathological grading fails to predict which of them will relapse and/or progress. The Glioma Longitudinal AnalySiS (GLASS) consortium is a large-scale collaboration that aims to investigate the molecular profiling of matched primary and recurrent glioma samples from multiple institutions in order to better understand the dynamic evolution of these tumors. At this time, the cohort comprises 946 samples across 11 institutions and among those, 864 have DNA methylation data available. The current molecular classification based on 7 subtypes published by TCGA in 2016 was applied to the dataset. Among the IDH wildtype tumors, 33% (16/49) of the patients showed a change of subtype upon recurrence, whereas most of them (9/16) were Classic-like at the primary stage but changed to either Mesenchymal-like or PA-like at the recurrent level. Among the IDH mutant tumors, 15% (22/142) showed a change of subtype at recurrent stage, in which 16 out of 22 progressed from G-CIMP-high to G-CIMP-low. Although some tumors progressed to a different subtype upon recurrence, an unsupervised analysis showed that the samples tend to cluster by patient instead of by subtype. By estimating the copy number alterations of these tumors using DNA methylation, the overall copy number profile of the recurrent samples remains similar to their primary counterpart. From this initial analysis using epigenomic data, we were able to characterize some aspects of glioma evolution and how the DNA methylation is associated with the progression of these tumors to different subtypes. These findings corroborate the importance of epigenetics in gliomas and can potentially lead to the identification of new biomarkers that can reflect tumor burden and predict its development.

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