Biomedical subjects

Y Marie

Publications and source records attributed to Y Marie.

15 recordsLinked to original sources

PubMed2006

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 = 46.8%; p = 0.0006) corresponding to an odd ratio of 1.67 (1.24; 2.25). A modest difference in median survival was also associated with the TT genotype.

Adult↗

PubMed2005

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.

Astrocytoma↗

PubMed2005

Olig2 expression, GFAP, p53 and 1p loss analysis contribute to glioma subclassification.

The expression of Olig2, a basic helix-loop-helix (bHLH) transcription factor involved in oligodendroglial specification, was investigated by immunohistochemistry in a series of 146 tumours and control samples. Olig2 expression was restricted to glial tumours and nontumoral oligodendrocytes. It was higher in oligodendrogliomas as compared to astrocytomas and oligoastrocytomas, and in grade III as compared to grade II tumours. Olig 2 was absent or weakly expressed in glioblastoma (GBM), whereas strong expression was found in the oligodendroglial foci of GBM with oligodendroglial component (GBMO). Double labelling was performed on a subset of the most typical tumours, according to the WHO classification. It showed a mutual exclusion, at cell level, of Olig2 and GFAP expression. In pure oligodendrogliomas, tumour cells were Olig2+/GFAP-. In contrast, two main tumour populations, Olig2+/GFAP- and Olig2-/GFAP+, were found in both oligoastrocytomas and astrocytomas. Based on these data from selected samples, two separate entities can be established, corresponding to 'pure oligodendrogliomas' and 'astrocytomas and oligoastrocytomas'. The relevance of this subdivision is further supported by the association with 1p loss and a trend to better survival for pure oligodendrogliomas and with p53 expression and a trend to shorter survival for astrocytomas and oligoastrocytomas. Combined testing of Olig2, 1p status, GFAP and p53 expression may therefore be helpful in refining current classification and providing more homogeneous sets of gliomas for clinical studies.

Basic Helix-Loop-Helix Proteins↗

PubMed2004

Temozolomide as initial treatment for adults with low-grade oligodendrogliomas or oligoastrocytomas and correlation with chromosome 1p deletions.

PURPOSE: To determine the response rate of low-grade oligodendroglial tumors (LGOT) to temozolomide (TMZ) as initial treatment and to evaluate the predictive value of chromosome 1p deletion on the radiologic response. PATIENTS AND METHODS: Adult patients with pathologically proven LGOT with progressive disease on magnetic resonance imaging (MRI) were eligible for the study. TMZ was administered at the starting dose of 200 mg/m2/d for 5 days, repeated every 28 days. Response was evaluated clinically and by central review of MRIs. Chromosome 1p and 19q deletions were detected by the loss of heterozygosity technique. RESULTS: Sixty consecutive patients were included in the study. At the time of analysis, the median number of TMZ cycles delivered was 11. Clinically, 51% of patients improved, particularly those with uncontrolled epilepsy. The objective radiologic response rate was 31% (17% partial response and 14% minor response), whereas 61% of patients had stable disease and 8% experienced disease progression. The median time to maximum tumor response was 12 months (range, 5 to 20 months). Myelosuppression was the most frequent side effect, with grade 3 to 4 toxicity in 8% of patients. Loss of chromosome 1p was associated with objective tumor response (P < .004). CONCLUSION: TMZ is well tolerated and provides a substantial rate of response in LGOT. Chromosome 1p loss is correlated with radiographic response and could be a helpful marker for guiding therapeutic decision making in LGOT.

Adult↗

PubMed2003

Correlation between genetic alterations and growth of human malignant glioma xenografted in nude mice.

In order to develop preclinical models of malignant astrocytomas and oligodendrogliomas, a series of 54 resected gliomas (37 from oligodendroglial lineage and 17 from astrocytic lineage) were xenografted subcutaneously into nude mice. Molecular alterations commonly observed in gliomas subtypes, including LOH 1p and 1q, LOH 19q, LOH 10p and 10q, LOH 9p, TP53 and PTEN mutations, EGFR amplification, CDKN2A homozygous deletion and telomerase reactivation were systematically screened in the original and xenografted tumours. In all, 23 gliomas grew in nude mice. The most anaplastic tumours were selected as shown by pathological and molecular studies of the original tumour as well as shorter survival in patients whose tumours were successfully grafted. Comparison between the two growth profiles showed that 10q LOH and EGFR amplification gave a tumorigenic advantage. With a few exceptions, the genetic pattern was remarkably stable before and after growth in nude mice. These results suggest that subcutaneous xenografts are useful and reproducible models to analyse the molecular profile of malignant astrocytoma and oligodendroglioma. This represents the first step to improve our understanding of the correlations between molecular alterations and response to standard or experimental therapies.

Adult↗

PubMed2002

OLIG-1 and 2 gene expression and oligodendroglial tumours.

OLIG 1/2 genes encode basic helix-loop-helix transcription factors that play a critical role in motor neurone and oligodendrocyte fate specification during development. Two recent studies in which OLIG transcripts were detected by in situ hybridization have reported a high expression of the OLIG genes in oligodendrogliomas. This suggests that the detection of these lineage markers could become an adjunct to the classic morphological diagnosis of these tumours. There are problems in the diagnosis of oligodendroglioma. To date, all other known oligodendrocyte lineage markers have failed to label specifically neoplastic oligodendrocytes. Deletions on chromosome 1p and 19q are much more frequent in oligodendrogliomas than in astrocytomas but these molecular alterations are not constant. For the future, when routinely available, immunohistochemical techniques using anti-OLIG antibodies on paraffin embedded tissues will allow a systematic study of a large series of tumours so that we will know the specificity and sensitivity of this investigation in diagnosis. At another level, it is possible that expression of OLIG in neoplastic oligodendrocyte might participate in the oncogenesis of oligodendrogliomas. Initial work suggests that this is probably not the case. However further in vitro and in vivo studies analysing the functional consequence of OLIG overexpression in terms of proliferation and tumour progression are needed.

Animals↗

PubMed2001

Molecular heterogeneity of oligodendrogliomas suggests alternative pathways in tumor progression.

OBJECTIVE: To identify different genetic molecular profiles in oligodendrogliomas and to evaluate their prognostic significance. METHODS: The main genetic alterations reported in glial tumors were investigated in 26 oligodendrogliomas (10 World Health Organization grade II and 16 World Health Organization grade III). Correlation between identified molecular changes and pathologic grade or clinical course was subsequently analyzed using univariate and multivariate statistical analyses. RESULTS: Loss of heterozygosity (LOH) on chromosome 1p, 19q, and 10; P16/CDKN2A homozygous deletion; EGFR (epidermal growth factor receptor) amplification; and TP53 and PTEN mutations were observed in 14 (54%), 15 (58%), 9 (35%), 7 (27%), 5 (19%), 1 (4%), and 0 cases. LOH 1p and 19q were tightly associated (p < 0.0001). A mutual exclusion was found between LOH 1p/19q and EGFR amplification (p = 0.01), P16/CDKN2A deletions (p = 0.001), or LOH on 10q (p = 0.03), suggesting the existence of distinct genetic subsets in oligodendrogliomas. On univariate analysis, age <50 years (p = 0.002) and LOH 1p (p = 0.01) were associated with a longer progression-free survival (PFS) whereas LOH 10q (p = 0.03) and EGFR amplification (p = 0.007) were associated with a worse PFS. In multivariate analyses, age <50 years (p = 0.001) and LOH 1p (p = 0.006) remained independent predictive factors for PFS. CONCLUSION: These results provide evidence for two alternative molecular pathways of progression in oligodendrogliomas. The first one is associated with loss of 1p and 19q and the second one with P16/CDKN2A deletion, 10q loss, and EGFR amplification. The findings confirm the value of loss of 1p as predictor of longer progression-free survival; in addition, the study demonstrates the unfavorable impact of 10q loss and EGFR amplification on the prognosis.

Adult↗

PubMed2001

OLIG2 as a specific marker of oligodendroglial tumour cells.

OLIG2 is a recently identified transcription factor involved in the specification of cells in the oligodendroglial lineage. We investigated the expression of OLIG2 by in-situ hybridisation in 21 brain tumours: nine grade II and III oligodendrogliomas, three grade II oligoastrocytomas, and nine non-oligodendroglial tumours (four grade IV astrocytomas, two meningiomas, a dysembryoplastic neuroepithelial tumour, and two metastases). OLIG2-positive cells corresponding to neoplastic oligodendrocytes were present in all oligodendrogliomas and oligoastrocytomas. By contrast, OLIG2 expression was not detected in the non-oligodendroglial tumours. Thus, oligodendroglioma probably arise from oligodendrocyte precursor cells. OLIG2 should prove a useful marker for the diagnosis of oligodendroglial tumours.

Astrocytoma↗

PubMed2001

Glioblastomas with an oligodendroglial component: a pathological and molecular study.

Glioblastoma (GBM) is considered by the WHO classification to represent the most malignant grade of the astrocytic tumors. However, a subset of GBM includes recognizable areas with oligodendroglial features, suggesting that some GBM may also have an oligodendroglial origin. The aim of this study was to analyze the molecular profile of GBM associated with an oligodendroglial component (GBMO). We analyzed a series of 25 GBMO. Loss of heterozygosity (LOH) on 1p and 19q, known as common markers of oligodendroglial tumors, were observed in 40% and 60% of cases, respectively; 72% of the tumors displayed one or both of these markers. All but 4 tumors (84%) showed alterations known to be preferentially involved in the progression of astrocytic tumors to GBM, such as EGFR amplification (44%), P16 deletion (48%), LOH on 10q (64%), PTEN (20%), and TP53 (24%) mutations. Therefore, GBMO displayed all the genetic aberrations found in "standard" GBM with a comparable incidence, but differed from GBM by having a higher rate of LOH on 1p and 19q. These results suggest that GBMO might represent a subgroup of tumors of oligodendroglial origin that is distinct from the "standard" GBM in terms of tumorigenesis pathway.

Adult↗

PubMed2000

P18 tumor suppressor gene and progression of oligodendrogliomas to anaplasia.

P18INK4C is a good candidate to be the tumor suppressor gene involved in oligodendrogliomas on 1p32. Loss of heterozygosity on 1p, mutation(s), homozygous deletion(s), and expression of p18 in 30 oligodendroglial tumors were investigated. Loss of heterozygosity on 1p was found in 15 tumors. A p18 mutation was found at an recurrence of an anaplastic oligodendroglioma, but not in the primary, low-grade tumor. No homozygous deletions were found and p18 was expressed in all cases. These results show that p18 alteration is involved in tumor progression in a subset of oligodendrogliomas.

Alleles↗

PubMed2000

Frequent loss of 1p32 region but no mutation of the p18 tumor suppressor gene in meningiomas.

After chromosome 22 and NF2 inactivation, the loss of chromosome 1p is one of the most frequent abnormalities encountered in meningiomas. However the putative tumor suppressor gene located on 1p inactivated in meningiomas has still to be identified. We screened 68 meningiomas for LOH on chromosome 22 and 1. We found 34 LOH on the NF2 region on chromosome 22 (50%) and 19 LOH on 1p (28%), 16 being associated with loss of chromosome 22. Partial deletions delimited a candidate region located between D1S234 and D1S2797. The p18INK4C tumor suppressor gene, a member of the genes family coding for inhibitors of cyclin-dependent kinases, is located in this region. To determine whether p18 is involved in development of meningiomas, we performed a mutation analysis of the p18 gene and a search for homozygous deletion in the 19 meningiomas with 1p loss. Sequencing analysis of the p18 gene revealed one polymorphism, but no somatic mutations and no homozygous deletions were found. These results confirm that the loss of chromosome 1p32 is a frequent feature in meningiomas, however the p18 tumor suppressor gene which is located in this region, does not seem to be involved.

Alleles↗

PubMed2000

[Genes implicated in glial tumors].

Because of the absence of specific marker, the histological classification of gliomas remain controversial. Identifying the genetic alterations involved in gliomas makes it possible to define specific molecular pathway of tumoral progression and to define markers of prognostic and diagnostic relevance. For example, p53 mutations are frequent in low grade astrocytoma, anaplastic astrocytoma and secondary glioblastoma suggesting that it takes place at an early stage of development of astrocytic tumors, whereas inactivation of PTEN arises mainly in glioblastomas and EGFR amplification is preferentially associated with "de novo" glioblastoma. Loss of chromosomes 1p and 19q characterizes oligodendroglial tumors. However the putative tumor suppressor genes located on 1p and 19q and specifically inactivated are not known yet. Emerging technologies, like microarrays and microdissection, will allow to refine molecular data and provide a molecular classification of gliomas mechanism involved in the repair of the respiratory epithelium.

Cell Cycle Proteins↗

PubMed1999

Fas system up-regulation in experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is a T-cell-mediated disorder characterized by infiltration of the central nervous system (CNS) by mononuclear cells and macrophages, and serves as a model for multiple sclerosis. In acute monophasic and relapsing remitting forms of EAE, the CNS inflammatory infiltrates are cleared within a few days and, simultaneously, animals recover from their clinical disability. The mechanisms for rapid disappearance of the inflammatory cells are not fully understood. Fas and Fas-ligand (Fas-L) molecules are thought to play an important role in the deletion of autoimmune reactive T cells through apoptosis. However, recent observations in transgenic lpr and gld mice show that mutations inactivating Fas and Fas-L respectively ameliorate signs of EAE despite persistence of immune cell infiltrates into the CNS. In the current study, the expression of Fas and Fas-L was investigated by immunochemistry and in situ hybridization during the course of EAE in DA rats that were actively immunized with syngenic spinal cord homogenate. CNS apoptotic cells were simultaneously examined using terminal transferase dUTP nick end-labeling techniques. During the acute phase of the disease, a significant proportion of CNS CD4+ cells (80%) and macrophages (50%) expressed Fas and Fas-L (80 and 60%, respectively). Simultaneously, about 20% of CD4+ cells and 30% of macrophages were found to be apoptotic. Some astrocytes and neurons also expressed Fas and Fas-L, although they did not appear to be apoptotic. These results further support a role for Fas-mediated lymphocyte and macrophage apoptosis in this model of CNS autoimmune disease but they also suggest a more complex role for Fas/Fas-L interactions in CNS autoimmunity, including resident cells.

Animals↗

PubMed1998

Antiglycolipid antibodies in motor neuropathies.

In peripheral neuropathies with monoclonal gammopathy, mainly IgM, it appears clear from clinical, electrophysiological, and experimental data, that the target glycolipid or glycolipid epitope for the IgM is related to the type of neuropathy--purely sensory, predominantly sensory, or uniquely motor. Investigations have focused on chronic peripheral neuropathies associated with polyclonal IgM reactivity to glycolipids. Although IgM anti-GM1 antibodies are present in normal controls, there is a subgroup of motor neuropathies with high titer anti-GM1 antibodies, mainly multifocal neuropathies with conduction blocks (MMNCB). Another subgroup of MMNCB may include IgM anti-SGPG antibodies that do not cross-react with MAG. The importance of the fine structure of the epitope has to be considered in view of the pathogenicity of the antibody. It may bear consequences on its binding properties on the neuronal surfaces and on its biological implications.

Autoantibodies↗

PubMed1997

Expression of TNF alpha in central neurons of Lewis rat spinal cord after EAE induction.

Experimental allergic encephalomyelitis (EAE), an animal model for multiple sclerosis (MS), is a demyelinating autoimmune disease of the central nervous system (CNS). The proinflammatory cytokine TNF alpha, as an endogenous mediator of inflammation, plays an important role in the pathogenesis of EAE disease. In this study, we demonstrate the presence of TNF alpha in spinal cord of Lewis rats, during the critical phase of EAE. The expression of TNF alpha is observed mainly in the gray matter of thoracic and lumbar levels of the spinal cord, in the motoneurons and interneurons of the ventral horn. Surprisingly, one month after recovery, we still found an intense TNF alpha-neuronal expression, including in the cervical region, and this positivity lasted up to 40 days after recovery, with, however, a decrease in its intensity. These results suggest that central neurons respond directly to massive infiltration of lymphocytes and macrophages after the breakdown of the blood-brain barrier (BBB), by producing TNF alpha cytokine. In addition, neuronal-TNF alpha detection in the recovery stage of EAE may suggest a role other than its classical action in promoting inflammatory processes.

Animals↗