Molecular Genetics of Secondary Glioblastoma

Mansouri, Alireza; Karamchandani, Jason; Das, Sunit

doi:10.15586/codon.glioblastoma.2017.ch2

Cited by 18 publications

(14 citation statements)

References 70 publications

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“…The average survival from diagnosis is less than 15 months, with survival rates at between 26%-33% at two years and 3%-10% at five years [5,6]. The development of GBM involves molecular pathways, which are different in primary and secondary lesions [7,8]. Standard treatment provides for maximum surgical resection followed by conformational radiotherapy (~60 Gy/30 fractions) for up to six weeks, concomitant with temozolomide (75 mg/m 2 /day) and then maintenance therapy with standard temozolomide schedule (150-200 mg/m 2 × 5 days, every 28, for 12 cycles) [6].…”

Section: Introductionmentioning

confidence: 99%

Retrospective and Randomized Analysis of Influence and Correlation of Clinical and Molecular Prognostic Factors in a Mono-Operative Series of 122 Patients with Glioblastoma Treated with STR or GTR

et al. 2020

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Glioblastoma is a solid, infiltrating, and the most frequent highly malignant primary brain tumor. Our aim was to find the correlation between sex, age, preoperative Karnofsky performance status (KPS), presenting with seizures, and extent of resection (EOR) with overall survival (OS), progression-free survival (PFS), and postoperative KPS, along with the prognostic value of IDH1, MGMT, ATRX, EGFR, and TP53 genes mutations and of Ki67 through the analysis of a single-operator series in order to avoid the biases of a multi-operator series, such as the lack of homogeneity in surgical and adjuvant nonsurgical treatments. A randomized retrospective analysis of 122 patients treated by a single first operator at Sapienza University of Rome was carried out. After surgery, patients followed standard Stupp protocol treatment. Exclusion criteria were: (1) patients with primary brainstem and spinal cord gliomas and (2) patients who underwent partial resections (resection < 90%) or a biopsy exclusively for diagnostic purposes. Statistical analysis with a simultaneous regression model was carried out through the use of SPSS 25® (IBM). Results showed statistically significant survival increase in four groups: (1) patients treated with gross total resection (GTR) (p < 0.030); (2) patients with mutation of IDH1 (p < 0.0161); (3) patients with methylated MGMT promoter (p < 0.005); (4) patients without EGFR amplification or EGFRvIII mutation (p < 0.035). Higher but not statistically significant survival rates were also observed in: patients <75 years, patients presenting with seizures at diagnosis, patients affected by lesions in noneloquent areas, as well as in patients with ATRX gene mutation and Ki-67 < 10%.

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Section: Introductionmentioning

confidence: 99%

Retrospective and Randomized Analysis of Influence and Correlation of Clinical and Molecular Prognostic Factors in a Mono-Operative Series of 122 Patients with Glioblastoma Treated with STR or GTR

et al. 2020

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“…mRNA-expression levels in control tissue (ie, non-pathological tissue obtained during surgical resection of epilepsy patients), grade III anaplastic astrocytoma, and GBM were assessed using custom-designed TaqMan lowdensity arrays containing primer and probe sets for 384 proteases. Transcript levels of MMPs 1,2,7,9,10,11,12,14,19, and 21 were significantly increased in GBM relative to control. Notably, MMP19 was also increased in anaplastic astrocytoma relative to control, but decreased in grade IV GBM relative to grade III anaplastic gliomas.…”

Section: Mmp Gene Expression In Gbmmentioning

confidence: 89%

“…The progression of a lower grade to a high grade is associated with mutations in IDH1 and IDH2. 2 GBM produces heterogeneous tumors even within the same patient, with intratumoral heterogeneity presenting regional differences in critical drives of tumor growth and treatment response. 3 Prevalent vascular disorganization, angiogenesis, and invasion are key features.…”

Section: Introductionmentioning

confidence: 99%

Current insights into matrix metalloproteinases and glioma progression: transcending the degradation boundary

Pullen¹,

Pickford²,

Perry³

et al. 2018

MNM

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Glioblastoma multiforme (GBM) remains one of the most deadly cancers, with modest advances in overall survival despite significant improvements in imaging, surgery, and molecular genomic understanding. The highest-grade glioma, GBM is a primary brain cancer that is molecularly heterogeneous among patients and even within the same patient. Key hallmarks include glioma-cell invasion, angiogenesis, and therapeutic resistance. While once considered a major player in glioma invasion, members of the MMP family are also associated with other key pathological hallmarks of glioma. Investigations into understanding MMP function in GBM were slowed due to the failed MMP-inhibitor trials for GBM in the 2000s. In contrast, the field of MMPs in other brain pathologies has flourished in such areas as traumatic brain injury, multiple sclerosis, and stroke. In the past decade, the increase in publicly available data sets documenting patient-biopsy molecular information has empowered laboratory investigations into the spectrum of genomic, transcriptomic, and proteomic changes associated with glioma, including MMPs. In this review, we selected one of these data sets to illustrate a small sample of information that can be obtained from such analyses. Combined with recent reports on the use of MMP-cleavable peptides for imaging and the multifunctionality of MMPs, including intracellular nonproteolytic actions in various cell types, this paves the way for new avenues of MMP research. Understanding the function of MMPs in host-tumor interactions both spatially and temporally during tumor progression and in response to treatment will be crucial for the advancement of targeting specific MMPs in GBM. The opportunities to explore MMP regulation, expression, and function further in GBM have never been so great with progress in modern bioinformatics and molecular techniques, and it is hoped that advancements will translate in some way to patients diagnosed with GBM.

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“…51,52 Verhaak et al and other studies analyzing somatic mutations and gene expression identified four transcriptional subtypes of GBMs: classic, proneural, neural, and mesenchymal. 8,21,51,53,54 The classic category showed a greater preponderance of EGFR amplification and CDKN2A alterations, decreased rates of TP53 mutation, loss of chromosome 10, and amplification of chromosome 7 and mitogen-activated protein kinase. 53 The proneural category is associated with PDGFR amplification, IDH1 and TP53 mutations, and activation of the phosphatidylinositol 3-kinase (PI3K).…”

Section: Primary Gbmsmentioning

confidence: 98%

Glioblastoma Multiforme and Genetic Mutations: The Issue Is Not Over Yet. An Overview of the Current Literature

Montemurro

2019

J Neurol Surg A Cent Eur Neurosurg

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Background and Objective Glioblastoma multiforme (GBM) is still a deadly disease with a poor prognosis and high mortality, despite the discovery of new biomarkers and new innovative targeted therapies. The role of genetic mutations in GBM is still not at all clear; however, molecular markers are an integral part of tumor assessment in modern neuro-oncology. Material and Methods We performed a Medline search for the key words “glioblastoma,” “glioblastoma multiforme,” and “genetic” or “genetics” from 1990 to the present, finding an exponential increase in the number of published articles, especially in the past 7 years. Results The understanding of molecular subtypes of gliomas recently led to a revision of the World Health Organization classification criteria for these tumors, introducing the concept of primary and secondary GBMs based on genetic alterations and gene or protein expression profiles. Some of these genetic alterations are currently believed to have clinical significance and are more related to secondary GBMs: TP53 mutations, detectable in the early stages of secondary GBM (found in 65%), isocitrate dehydrogenase 1/2 mutations (50% of secondary GBMs), and also O6-methylguanine-DNA methyltransferase promoter methylation (75% of secondary GBMs). Conclusion From the introduction of the first standard of care (SOC) established in 2005 in patients with a new diagnosis of GBM, a great number of trials have been conducted to improve the actual SOC, but the real turning point has never been achieved or is yet to come. Surgical gross total resection, with at least one more reoperation, radiation therapy plus concomitant and adjuvant temozolomide chemotherapy currently remains the current SOC for patients with GBM.

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Molecular Genetics of Secondary Glioblastoma

Cited by 18 publications

References 70 publications

Retrospective and Randomized Analysis of Influence and Correlation of Clinical and Molecular Prognostic Factors in a Mono-Operative Series of 122 Patients with Glioblastoma Treated with STR or GTR

Retrospective and Randomized Analysis of Influence and Correlation of Clinical and Molecular Prognostic Factors in a Mono-Operative Series of 122 Patients with Glioblastoma Treated with STR or GTR

Current insights into matrix metalloproteinases and glioma progression: transcending the degradation boundary

Glioblastoma Multiforme and Genetic Mutations: The Issue Is Not Over Yet. An Overview of the Current Literature

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