scholarly journals Novel Molecular Markers in Glioblastoma—Benefits of Liquid Biopsy

2020 ◽  
Vol 21 (20) ◽  
pp. 7522
Author(s):  
Zsuzsanna Birkó ◽  
Bálint Nagy ◽  
Álmos Klekner ◽  
József Virga
Keyword(s):  
Molecular Markers ◽  
Growth Factor ◽  
Nucleic Acids ◽  
Liquid Biopsy ◽  
Dna Methyltransferase ◽  
Methylation Status ◽  
Differential Diagnostics ◽  
Circular Rnas ◽  
The Future

Glioblastoma is a primary Central Nervous System (CNS) malignancy with poor survival. Treatment options are scarce and despite the extremely heterogeneous nature of the disease, clinicians lack prognostic and predictive markers to characterize patients with different outcomes. Certain immunohistochemistry, FISH, or PCR-based molecular markers, including isocitrate dehydrogenase1/2 (IDH1/2) mutations, epidermal growth factor receptor variant III (EGFRvIII) mutation, vascular endothelial growth factor overexpression (VEGF) overexpression, or (O6-Methylguanine-DNA methyltransferase promoter) MGMT promoter methylation status, are well-described; however, their clinical usefulness and accuracy is limited, and tumor tissue samples are always necessary. Liquid biopsy is a developing field of diagnostics and patient follow up in multiple types of cancer. Fragments of circulating nucleic acids are collected in various forms from different bodily fluids, including serum, urine, or cerebrospinal fluid in order to measure the quality and quantity of these markers. Multiple types of nucleic acids can be analyzed using liquid biopsy. Circulating cell-free DNA, mitochondrial DNA, or the more stable long and small non-coding RNAs, circular RNAs, or microRNAs can be identified and measured by novel PCR and next-generation sequencing-based methods. These markers can be used to detect the previously described alterations in a minimally invasive method. These markers can be used to differentiate patients with poor or better prognosis, or to identify patients who do not respond to therapy. Liquid biopsy can be used to detect recurrent disease, often earlier than using imaging modalities. Liquid biopsy is a rapidly developing field, and similarly to other types of cancer, measuring circulating tumor-derived nucleic acids from biological fluid samples could be the future of differential diagnostics, patient stratification, and follow up in the future in glioblastoma as well.

scholarly journals A practical review of prognostic correlations of molecular biomarkers in glioblastoma

2015 ◽  
Vol 38 (3) ◽  
pp. E4 ◽  
Author(s):  
Michael Karsy ◽  
Jayson A. Neil ◽  
Jian Guan ◽  
Mark A. Mahan ◽  
Howard Colman ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Molecular Markers ◽  
Growth Factor ◽  
Dna Methyltransferase ◽  
Growth Factor Receptor ◽  
Predictive Biomarker ◽  
Isocitrate Dehydrogenase 1 ◽  
Tensin Homolog ◽  
Formidable Challenge ◽  
Phosphoinositide 3 Kinase

Despite extensive efforts in research and therapeutics, achieving longer survival for patients with glioblastoma (GBM) remains a formidable challenge. Furthermore, because of rapid advances in the scientific understanding of GBM, communication with patients regarding the explanations and implications of genetic and molecular markers can be difficult. Understanding the important biomarkers that play a role in GBM pathogenesis may also help clinicians in educating patients about prognosis, potential clinical trials, and monitoring response to treatments. This article aims to provide an up-to-date review that can be discussed with patients regarding common molecular markers, namely O-6-methylgua-nine-DNA methyltransferase (MGMT), isocitrate dehydrogenase 1 and 2 (IDH1/2), p53, epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), Phosphatase and tensin homolog (PTEN), phosphoinositide 3-kinase (PI3K), and 1p/19q. The importance of the distinction between a prognostic and a predictive biomarker as well as clinical trials regarding these markers and their relevance to clinical practice are discussed.

Low-grade oligodendroglioma: an indolent but incurable disease?

2009 ◽  
Vol 111 (2) ◽  
pp. 265-271 ◽  
Author(s):  
Hamdy El-Hateer ◽  
Luis Souhami ◽  
David Roberge ◽  
Rolando del Maestro ◽  
Richard Leblanc ◽  
...  
Keyword(s):  
Disease Progression ◽  
Contrast Enhancement ◽  
Dna Methyltransferase ◽  
Methylation Status ◽  
Low Grade ◽  
Gene Methylation ◽  
Methylguanine Dna Methyltransferase ◽  
Presenting Symptoms ◽  
Promoter Gene

Object The authors reviewed their institutional experience with pure low-grade oligodendroglioma (LGO), correlating outcomes with several variables of possible prognostic values. Methods Sixty-nine patients with WHO-classified LGOs were treated between 1992 and 2006 at the McGill University Health Center. Clinical, pathological, and radiological records were carefully reviewed. Demographic characteristics; the nature and duration of presenting symptoms; baseline neurological function; extent of resection; Karnofsky Performance Scale score; preoperative radiological findings including tumor size, location, and absence/presence of enhancement; and pathological data including chromosome arms 1p/19q codeletion and O-methylguanine-DNA methyltransferase promoter gene methylation status were all compiled. The timing and dose of radio- and/or chemotherapy, date of tumor progression, pathological finding at disease progression, treatment at time of disease progression, and status at the last follow-up were also recorded. Results The median follow-up period was 6.1 years (range 1.3–16.3 years). The majority (78%) of patients presented with seizures; contrast enhancement was initially seen in 16 patients (25%). All patients had undergone an initial surgical procedure: gross-total resection in 27%, partial resection in 59%, and biopsy only in the remaining 13%. Fifteen patients received adjuvant radiotherapy. Data on O-methylguanine-DNA methyltransferase promoter gene methylation status was available in 47 patients (68%) and in all but 1 patient for 1p/19q status. Survival at 5, 10, and 15 years was 83, 63, and 29%, respectively. Multivariate analysis showed that seizures at presentation and the absence of contrast enhancement were the only independent favorable prognostic factors for survival. The 5-, 10-, and 15-year progression-free survival rates were 46, 7.7, and 0%, respectively. Conclusions This retrospective review confirms the indolent but progressively fatal nature of LGOs. Contrast enhancement was the most evident single prognostic factor. New treatment strategies are clearly needed in the management of this disease.

scholarly journals A serum-based DNA methylation assay provides accurate detection of glioma

2021 ◽  
Author(s):  
Thais Sabedot ◽  
Tathiane Malta ◽  
James Snyder ◽  
Kevin Nelson ◽  
Michael Wells ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Liquid Biopsy ◽  
Somatic Mutations ◽  
Methylation Status ◽  
Experimental Treatment ◽  
Cell Free Dna ◽  
Invasive Approach ◽  
Non Invasive ◽  
Free Dna

Abstract Background The detection of somatic mutations in cell-free DNA (cfDNA) from liquid biopsy has emerged as a non-invasive tool to monitor the follow-up of cancer patients. However, the significance of cfDNA clinical utility remains uncertain in patients with brain tumors, primarily because of the limited sensitivity cfDNA has to detect real tumor-specific somatic mutations. This unresolved challenge has prevented accurate follow-up of glioma patients with non-invasive approaches. Methods Genome-wide DNA methylation profiling of tumor tissue and serum cell-free DNA of glioma patients. Results Here, we developed a non-invasive approach to profile the DNA methylation status in the serum of patients with gliomas and identified a cfDNA-derived methylation signature that is associated with the presence of gliomas and related immune features. By testing the signature in an independent discovery and validation cohorts, we developed and verified a score metric (the “glioma epigenetic liquid biopsy score” or GeLB) that optimally distinguished patients with or without glioma (sensitivity: 100%, specificity: 97.78%). Furthermore, we found that changes in GeLB score reflected clinicopathological changes during surveillance (e.g., progression, pseudoprogression or response to standard or experimental treatment). Conclusions Our results suggest that the GeLB score can be used as a complementary approach to diagnose and follow up patients with glioma.

scholarly journals Circulating Cell-Free Nucleic Acids: Main Characteristics and Clinical Application

2020 ◽  
Vol 21 (18) ◽  
pp. 6827 ◽  
Author(s):  
Melinda Szilágyi ◽  
Ondrej Pös ◽  
Éva Márton ◽  
Gergely Buglyó ◽  
Beáta Soltész ◽  
...  
Keyword(s):  
Nucleic Acids ◽  
Liquid Biopsy ◽  
Genetic Disorders ◽  
Prenatal Testing ◽  
Future Directions ◽  
Diagnosis And Prognosis ◽  
Non Coding Rna ◽  
Mutation Profile ◽  
Non Coding Rnas

Liquid biopsy recently became a very promising diagnostic method that has several advantages over conventional invasive methods. Liquid biopsy may serve as a source of several important biomarkers including cell-free nucleic acids (cf-NAs). Cf-DNA is widely used in prenatal testing in order to characterize fetal genetic disorders. Analysis of cf-DNA may provide information about the mutation profile of tumor cells, while cell-free non-coding RNAs are promising biomarker candidates in the diagnosis and prognosis of cancer. Many of these markers have the potential to help clinicians in therapy selection and in the follow-up of patients. Thus, cf-NA-based diagnostics represent a new path in personalized medicine. Although several reviews are available in the field, most of them focus on a limited number of cf-NA types. In this review, we give an overview about all known cf-NAs including cf-DNA, cf-mtDNA and cell-free non-coding RNA (miRNA, lncRNA, circRNA, piRNA, YRNA, and vtRNA) by discussing their biogenesis, biological function and potential as biomarker candidates in liquid biopsy. We also outline possible future directions in the field.

Instruction Helps and Hinders Young Children’s Feature Learning

2018 ◽  
Author(s):  
Charles Kalish ◽  
Nigel Noll
Keyword(s):  
Young Children ◽  
Feature Learning ◽  
Irrelevant Information ◽  
Diagnostic Feature ◽  
Older Children ◽  
Prediction Task ◽  
Feature Correlation ◽  
The Future

Existing research suggests that adults and older children experience a tradeoff where instruction and feedback help them solve a problem efficiently, but lead them to ignore currently irrelevant information that might be useful in the future. It is unclear whether young children experience the same tradeoff. Eighty-seven children (ages five- to eight-years) and 42 adults participated in supervised feature prediction tasks either with or without an instructional hint. Follow-up tasks assessed learning of feature correlations and feature frequencies. Younger children tended to learn frequencies of both relevant and irrelevant features without instruction, but not the diagnostic feature correlation needed for the prediction task. With instruction, younger children did learn the diagnostic feature correlation, but then failed to learn the frequencies of irrelevant features. Instruction helped older children learn the correlation without limiting attention to frequencies. Adults learned the diagnostic correlation even without instruction, but with instruction no longer learned about irrelevant frequencies. These results indicate that young children do show some costs of learning with instruction characteristic of older children and adults. However, they also receive some of the benefits. The current study illustrates just what those tradeoffs might be, and how they might change over development.

scholarly journals Ex vivo ultrasonic samples of human brain tumors in the molecular era

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Alastair J Kirby ◽  
José P Lavrador ◽  
Istvan Bodi ◽  
Francesco Vergani ◽  
Ranjeev Bhangoo ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Cellular Proliferation ◽  
Aminolevulinic Acid ◽  
Ex Vivo ◽  
Methylation Status ◽  
Protoporphyrin Ix ◽  
Intratumor Heterogeneity ◽  
Power Relationship ◽  
Surgical Biopsy ◽  
Glioma Surgery

Abstract Background Gliomas are composed of multiple clones of tumor cells. This intratumor heterogeneity contributes to the ability of gliomas to resist treatment. It is vital that gliomas are fully characterized at a molecular level when a diagnosis is made to maximize treatment effectiveness. Methods We collected ultrasonic tissue fragments during glioma surgery. Large tissue fragments were separated in the operating theater and bathed continuously in oxygenated artificial cerebrospinal fluid to keep them alive. The ex vivo tissue fragments were transferred to a laboratory and incubated in 5-aminolevulinic acid (5-ALA). 5-ALA is metabolized to Protoporphyrin IX (PpIX), which accumulates in glioma cells and makes them fluorescent. The molecular and neuropathological features of the PpIX fluorescent ultrasonic tissue fragments were studied. Results We show that PpIX fluorescence can rapidly identify tissue fragments infiltrated by glioma in the laboratory. Ultrasonic tissue fragments from the tumor core provided molecular and neuropathological information about the glioma that was comparable to the surgical biopsy. We characterized the heterogeneity within individual gliomas by studying ultrasonic tissue fragments from different parts of the tumor. We found that gliomas exhibit a power relationship between cellular proliferation and tumor infiltration. Tissue fragments that deviate from this relationship may contain foci of more malignant glioma. The methylation status of the O6-methylguanine DNA methyltransferase gene promoter varied within each glioma. Conclusions Ex vivo ultrasonic tissue fragments can be rapidly screened for glioma infiltration. They offer a viable platform to characterize heterogeneity within individual gliomas, thereby enhancing their diagnosis and treatment.

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