Methylation profiling identifies 2 groups of gliomas according to their tumorigenesis.

Extensive genomic and gene expression studies have been performed in gliomas, but the epigenetic alterations that characterize different subtypes of gliomas remain largely unknown. Here, we analyzed the methylation patterns of 807 genes (1536 CpGs) in a series of 33 low-grade gliomas (LGGs), 36 glioblastomas (GBMs), 8 paired initial and recurrent gliomas, and 9 controls. This analysis was performed with Illumina's Golden Gate Bead methylation arrays and was correlated with clinical, histological, genomic, gene expression, and genotyping data, including IDH1 mutations.

Epidermal growth factor receptor extracellular domain mutations in primary glioblastoma.

Aims: Novel missense mutations of the epidermal growth factor receptor (EGFR) extracellular domain have been recently described in a large series of glioblastomas.

Methods: The exons 2, 3, 7, 8 and 15 coding for the EGFR extracellular domain were sequenced in a series of 161 consecutive primary glioblastomas and correlated with clinical features of patients in order to determine whether these alterations are linked to specific clinical characteristics of the disease.

Results: Missense mutations were observed in 18 cases (11.

No association of (-131C-->G) variant of CHI3L1 gene with risk of glioblastoma and prognosis.

Expression of CHI3L1 (YKL-40) has been correlated with prognosis of glioblastoma. The variant allele (-131C-->G) of CHI3L1 promoter results in a lower transcription of CHI3L1. Therefore, we tested the hypothesis that the G variant could protect against the risk of gliomas or have a favorable prognostic impact.

Identification of regions correlating MGMT promoter methylation and gene expression in glioblastomas.

The O(6)-methylguanine-DNA methyltransferase gene (MGMT) is methylated in several cancers, including gliomas. However, the functional role of cysteine-phosphate-guanine (CpG) island (CGI) methylation in MGMT silencing is still controversial. The aim of this study was to investigate whether MGMT CGI methylation correlates inversely with RNA expression of MGMT in glioblastomas and to determine the CpG region whose methylation best reflects the level of expression.

TP53 codon 72 polymorphism is associated with age at onset of glioblastoma.

Background: Functional single nucleotide polymorphisms (SNP) in codon 72 of TP53 have been shown to be a risk factor, a prognostic marker, and related factor to age at onset in various cancers.

Methods: We investigated blood samples from 254 patients with glioblastoma and 238 healthy controls.

Results: TP53 codon 72 status was not correlated with prognosis and did not differ between glioblastoma and control populations.

alpha-Internexin expression identifies 1p19q codeleted gliomas.

Background: alpha-Internexin (INA) is a proneural gene encoding a neurofilament interacting protein that is upregulated in some gliomas, particularly oligodendrogliomas.

Methods: INA expression was evaluated by immunohistochemistry in a series of 122 gliomas, and correlated to the 1p19q codeletion, a favorable prognostic marker of oligodendroglial tumors.

Results: INA expression was strong (>10% positive cells) in 22 cases (22 oligodendroglial tumors and 0 astrocytic tumors), weak (<10% cells) in 14 cases (12 oligodendroglial tumors, 2 glioblastoma with an oligodendroglial component, and 0 astrocytic tumors), and negative in 86 cases (49 oligodendroglial tumors, 9 glioblastoma with an oligodendroglial component, and 28 astrocytic tumors).

Genomic changes in progression of low-grade gliomas.

Using a one-megabase BAC-based array comparative genomic hybridization technique (aCGH), we have investigated a series of 16 low-grade gliomas (LGGs) and their subsequent progression to higher-grade malignancies. The most frequent chromosome imbalances in primary tumors were gains of chromosomes 7q, 8q, and 22q, and losses of chromosomes 1p, 13q, and 19q. In tumor progression, gains of chromosomes 11q, 7q, 20q, and 21q, and losses of chromosomes 9p, including CDKN2A locus, 19q, 14q, 1p, and 6q were the most frequent genomic disequilibria.

Gene amplification is a poor prognostic factor in anaplastic oligodendrogliomas.

Various gene amplifications have been observed in gliomas. Prognostic-genomic correlations testing simultaneously all these amplified genes have never been conducted in anaplastic oligodendrogliomas. A set of 38 genes that have been reported to be amplified in gliomas and investigated as the main targets of amplicons were studied in a series of 52 anaplastic oligodendrogliomas using bacterial artificial chromosome-array based comparative genomic hybridization and quantitative polymerase chain reaction.

Anaplastic oligodendrogliomas with 1p19q codeletion have a proneural gene expression profile.

Background: In high grade gliomas, 1p19q codeletion and EGFR amplification are mutually exclusive and predictive of dramatically different outcomes. We performed a microarray gene expression study of four high grade gliomas with 1p19q codeletion and nine with EGFR amplification, identified by CGH-array.

Results: The two groups of gliomas exhibited very different gene expression profiles and were consistently distinguished by unsupervised clustering analysis.

Genetic markers predictive of chemosensitivity and outcome in gliomatosis cerebri.

Background: Up-front temozolomide (TMZ) has been recently proposed as a treatment for gliomatosis cerebri (GC), but no predictive or prognostic markers have been identified so far. Because 1p19q codeletion and methylguanine methyl transferase promoter (MGMTP) methylation have been correlated with chemosensitivity of gliomas, their value was investigated in a cohort of patients with GC treated with TMZ.

Methods: A cohort of 25 GC patients who were treated with TMZ was investigated for 1p19q codeletion and O6-methylguanine DNA.

Expression of TLR9 within human glioblastoma.

Immunostimulating oligonucleotides containing CpG motifs (CpG-ODN) have shown promising antitumor activity in preclinical glioma models. CpG motifs are specifically recognized by the Toll-like receptor 9 (TLR9), mainly expressed in plasmacytoid dendritic cells (pDCs) and B cells. Expression of TLR9 within human glioma samples has not been investigated.

MGMT prognostic impact on glioblastoma is dependent on therapeutic modalities.

MGMT promoter methylation, which has been correlated with the response to alkylating agents, was investigated in a retrospective series of 219 glioblastomas (GBMs) treated with various modalities. MGMT methylation had no impact on survival for the whole group, but showed a significant advantage (17.1 months vs.

MGMT methylation: a marker of response to temozolomide in low-grade gliomas.

The methylation status of the O6-methylguanine-methyltransferase promoter (MGMTP) was evaluated in 68 low-grade gliomas treated by neoadjuvant temozolomide. Methylated MGMTP was detected in 63 of 68 (92.6 %) patients and was a favorable predictor of progression-free survival as compared with unmethylated MGMTP tumors (p < 0.

The 61 A/G EGF polymorphism is functional but is neither a prognostic marker nor a risk factor for glioblastoma.

The A/G61 polymorphism located in the 5'UTR of the EGF gene has been found to be both a risk factor and a prognostic factor in glioblastoma (GBM), but the functional consequences have not been investigated. Here we show, in vitro, that this polymorphism is functional, in that the G allele promoter is 40% more active than the A variant (P < 0.001).

Prognostic stratification of patients with anaplastic gliomas according to genetic profile.

Background: There is a need to improve the current, controversial, and poorly reproducible classification of anaplastic gliomas, which represent a highly heterogeneous entity in terms of survival.

Methods: The impact of the most common genetic alterations on survival was investigated based on 156 anaplastic gliomas: Among the patients who were included, the gender ratio was 1.32, the median age was 45.

Genetic alterations associated with acquired temozolomide resistance in SNB-19, a human glioma cell line.

Gliomas are highly lethal neoplasms that cannot be cured by currently available therapies. Temozolomide is a recently introduced alkylating agent that has yielded a significant benefit in the treatment of high-grade gliomas. However, either de novo or acquired chemoresistance occurs frequently and has been attributed to increased levels of O6-methylguanine-DNA methyltransferase or to the loss of mismatch repair capacity.

Polymorphism in Sp1 recognition site of the EGF receptor gene promoter and risk of glioblastoma.

We investigated two polymorphisms of the epidermal growth factor receptor promoter as potential risk factors and prognostic markers for glioblastoma. The -216T allele (which results in a 30% higher activity) was more frequent in the patients compared with the control population (224/376 = 59.6% vs 165/352 = 46.

Prognostic impact of molecular markers in a series of 220 primary glioblastomas.

Background: In contrast to oligodendrogliomas, molecular predictors of prognosis have not been consistently found in glioblastomas. However, genetic studies show that glioblastomas consist of several genetic subtypes and raise the possibility that molecular alterations could be predictive of survival.

Methods: A search for loss of heterozygosity (LOH) on chromosome 1p, 9p, 10q, 19q, EGFR (epidermal growth factor receptor), CDK4, and MDM2 (mouse double minute) amplifications, CDKN2A (INK4A/ARF) homozygous deletions, p53 expression, was performed in a series of 220 primary glioblastomas.

Chromosome 1p loss: a favorable prognostic factor in low-grade gliomas.

Search for loss of heterozygosity on chromosomes 1p, 9p, 10q, and 19q, epidermal growth factor receptor (EGFR) gene amplification, and p53 expression was performed in a series of 131 low-grade gliomas. The profile of molecular changes, clinical findings, and histology were subsequently correlated with the course of the disease, mainly progression-free survival. When these parameters were considered as candidate variables in a multivariate analysis, only loss of heterozygosity on chromosome 1p was associated with increased progression-free survival (hazard ratio, 0.

EGFR tyrosine kinase domain mutations in human gliomas.

Gefitinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor effective in patients with lung cancer with mutations in exons 19 and 21 of the EGFR tyrosine kinase domain. In this study, the authors tested the presence of such mutations in 95 gliomas including glioblastomas, anaplastic oligodendrogliomas, and low-grade gliomas. No mutation was found, which suggests that the biology of EGFR in gliomas is different from lung cancer and that this may be a factor in the resistance of glioblastomas to gefitinib.

Molecular changes in gliomas.

Purpose Of Review: Despite optimal clinical treatment, the prognosis for gliomas remains poor, and little progress has been observed during the last few years. Meanwhile, understanding of glioma oncogenesis has improved greatly. This review focuses on recent advances in molecular biology of glial tumors, with particular emphasis on lineage markers, genetic mechanisms underlying tumor progression, new diagnostic and prognostic markers, and potential therapeutic targets.

Correlations between molecular profile and radiologic pattern in oligodendroglial tumors.

Objective: To investigate possible correlations between tumor location and genetic alterations in a series of oligodendrogliomas.

Methods: A series of 158 consecutive oligodendrogliomas were retrospectively reviewed. In each case, the radiologic picture and the chromosome 1p (chr 1p) status of the tumor detected by the loss of heterozygosity technique were analyzed.

Transcription factor sterol regulatory element binding protein 2 regulates scavenger receptor Cla-1 gene expression.

Objective: The human scavenger receptor class B type I (Cla-1) plays a key role in cellular cholesterol movement in facilitating transport of cholesterol between cells and lipoproteins. Indirect evidence has suggested that Cla-1 gene expression is under the feedback control of cellular cholesterol content. To define the molecular mechanisms underlying such putative regulation, we evaluated whether Cla-1 is a target gene of the sterol regulatory element binding protein (SREBP) transcription factor family.

Common promoter C516T polymorphism in the ApoB gene is an independent predictor of carotid atherosclerotic disease in subjects presenting a broad range of plasma cholesterol levels.

Objective: A common polymorphism in the promoter of the apolipoprotein B (apoB) gene, a C to T change at position -516, increases the transcription rate of apoB, resulting in elevated circulating levels of low-density lipoprotein (LDL) cholesterol.

Methods And Results: We tested the hypothesis that carriers of the -516T allele, who may display consistent elevation in plasma cholesterol over their lifetime, may present more extensive atherosclerotic disease than noncarriers. Genotyping of the apoB 516 C/T promoter polymorphism was performed in 326 subjects at low cardiovascular risk.