Genetic Variants Related to Cell Cycle and Stability of Telomere in Patients with Glioma (original) (raw)
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Potential clinical role of telomere length in human glioblastoma
Translational medicine @ UniSa, 2011
Glioblastoma Multiforme (GBM) is the most common and lethal of human primary central nervous system (CNS) tumors. Due to the tumour's intrinsic clinical and molecular heterogeneity, choice of initial treatment, prediction of survival, stratification of patients, prediction and monitoring of response to therapy, represent some of the greatest challenges in the management of GBM patients. Patients, despite optimal surgery, radiation and chemotherapy, still have a median survival of 14-16 months. A reason for this dismal prognosis is because of the relative inaccuracy of current prognostic markers, so far based on clinical or pathological variables. Molecular markers that effectively predict response to therapy and survival outcomes are limited. Consequently, there is a strong need to develop novel and independent markers of prognosis. Ideal biomarkers for solid tumors would serve one or more important functions. Telomeres, guanine-rich tandem DNA repeats of the chromosomal end, pr...
Neuro-Oncology, 2013
Background. Genome-wide association studies have implicated single nucleotide polymorphisms (SNPs) in 7 genes as glioma risk factors, including 2 (TERT, RTEL1) involved in telomerase structure/function. We examined associations of these 7 established glioma risk loci with age at diagnosis among patients with glioma. Methods. SNP genotype data were available for 2286 Caucasian glioma patients from the University of California, San Francisco (n ¼ 1434) and the Mayo Clinic (n ¼ 852). Regression analyses were performed to test for associations between "number of risk alleles" and "age at diagnosis," adjusted for sex and study site and stratified by tumor grade/histology where appropriate. Results. Four SNPs were significantly associated with age at diagnosis. Carrying a greater number of risk alleles at rs55705857 (CCDC26) and at rs498872 (PHLDB1) was associated with younger age at diagnosis (P ¼ 1.4 × 10 222 and P ¼ 9.5 × 10 27 , respectively). These SNPs are stronger risk factors for oligodendroglial tumors, which tend to occur in younger patients, and their association with age at diagnosis varied across tumor subtypes. In contrast, carrying more risk alleles at rs2736100 (TERT) and at rs6010620 (RTEL1) was associated with older age at diagnosis (P ¼ 6.2 × 10 24 and P ¼ 2.5 × 10 24 , respectively). These SNPs are risk factors for all glioma grades/histologies, and their association with age at diagnosis was consistent across tumor subgroups. Conclusions. Carrying a greater number of risk alleles might be expected to decrease age at diagnosis. However, glioma susceptibility conferred by variation in telomerase-related genes did not follow this pattern. This supports the hypothesis that telomeraserelated mechanisms of telomere maintenance are more associated with gliomas that develop later in life than those utilizing telomerase-independent mechanisms (ie, alternative lengthening of telomeres).
Alternative lengthening of telomeres in molecular subgroups of paediatric high-grade glioma
Child's Nervous System
Purpose The maintenance of telomere length prevents cancer cell senescence and occurs via two mutually exclusive mechanisms: (a) reactivation of telomerase expression and (b) activation of alternative lengthening of telomeres (ALT). ALT is frequently related to alterations on ATRX, a chromatin-remodelling protein. Recent data have identified different molecular subgroups of paediatric high-grade glioma (pHGG) with mutations of H3F3A, TERTp and ATRX; however, differences in telomere length among these molecular subgroups were not thoroughly examined. Methods We investigated which genetic alterations trigger the ALT mechanism in 52 IDH-wildtype, 1p/19q-wildtype pHGG. Samples were analysed for telomere length using Tel-FISH. ATRX nuclear loss of expression was assessed by IHC, H3F3A and TERTp mutations by DNA sequencing, and TERTp methylation by MS-PCR. Results Mutant H3.3 was found in 21 cases (40.3%): 19.2% with K27M mutation and 21.1% with G34R mutation. All H3.3G34R-mutated cases s...
Alternative lengthening of telomeres and survival in patients with glioblastoma multiforme
Lancet, 2003
Despite advances in the molecular pathogenesis of glioblastoma multiforme, no reliable prognostic markers have been identified. We analysed telomerase activity and telomere lengths in glioblastoma multiformes from 77 patients. 19 patients (25%) had tumours with the alternative-lengthening-of-telomere (ALT) phenotype. Median survival for patients with this phenotype was 542 days (95% CI 114-970) compared with 247 days (224-270) for glioblastoma multiformes with normal telomeres (p=0.0003). Cox's regression analysis showed that this association is independent of age. In patients with non-ALT tumours, telomerase activity did not affect survival (median 287 [199-375] vs 236 [230-242] days, p=0.275). We conclude that ALT is a prognostic indicator for patients with glioblastoma multiforme.
A cytogenetic study of 19 recurrent gliomas
Cancer Genetics and Cytogenetics, 1994
A cytogenetic analysis was performed on 19 recurrent gliomas all of which had been treated by radiotherapy. All cases exhibited clonal chromosomal anomalies, the tumors were classified into four categories in relation to their mona-or polyclonality and to the presence or absence of a clonal evolution. Polyclonal tumors without clonal evolution had a delay of recurrence significantly longer than monoclonal or polyclonal tumors with clonal evolution. This difference could be related to the presence of clones with different malignant potential, which could be differentiated by their pattern of chromosomal aberrations. The malignant potential of "highly malignant" clones resulted from the juxtaposition of imbalances, such as monosomy 10, as in high-grade primary gliomas, and presumably radiation-induced structural rearrangements. That of clones of law malignancy was almost limited to the presence of multiple balanced structural rearrangements, probably induced by radiation.
Neuro-Oncology, 2021
BACKGROUND The integration of molecular markers into the WHO 2016 classification has clarified the complex diagnosis of gliomas. Among these biomarkers, the TERT promoter mutation and the loss of ATRX (ATRX loss) are mutually exclusive alterations associated with re-activation of telomerase or alternative lengthening of telomeres (ALT), respectively. Strangely, 25% of gliomas display neither or both these alterations, a situation referred to as abnormal telomere maintenance mechanism (aTMM). MATERIAL AND METHODS To investigate the TMM actually involved in gliomas, the C-circle (CC) assay was adapted to tumor (FFPE and frozen) samples. RESULTS We constructed a CC-based algorithm able to identify the TMM of 284 gliomas with either TERT or ATRX alteration, with a sensitivity of 100% and a specificity of 97.3%, and succeeded in deciphering the TMM involved in 122 aTMM gliomas. Additionally, the combination of the TMM, the mutational status of the Isocitrate dehydrogenase 1/2 (IDH) gene,...
Journal of Clinical Pathology, 1998
Aims/Background-Telomerase is an enzyme that is expressed in most human neoplasms and is associated with tumour immortality. Determination of the point in neoplastic transformation at which telomerase is expressed may aid the understanding of tumour pathogenesis and progression. Despite numerous reports on telomerase, few studies have investigated its expression in high grade glial tumours. These studies, performed on archival banked, single brain tumour specimens, have shown conflicting results for oligodendrogliomas and unexpectedly negative results for telomerase expression in high grade astrocytomas, with one third to one half of glioblastoma multiformes being negative. Methods-34 rapidly banked glioma specimens taken from patients undergoing gross total surgical resection of their tumours were studied. Telomerase expression was assessed across 3-8 sampled regions from each tumour by the telomeric repeat amplification protocol (TRAP) assay. Matched mirror image tissue samples were taken for histological analysis of tissue adequacy, statistical correlation of telomerase with tumour histological features, Mib-1 (a marker for cell cycling) labelling, and p53 immunohistochemistry. Results-All five well diVerentiated oligodendrogliomas were homogeneously telomerase negative and two of three untreated anaplastic oligodendrogliomas were homogeneously positive. In contrast, 10 of 14 high grade astrocytomas showed heterogeneity for telomerase expression across the multiple regions sampled. All glioblastoma multiformes and two of three anaplastic astrocytomas showed at least one region positive for telomerase. When test samples were individually assessed in both oligodendrogliomas and high grade astrocytomas, telomerase expression was associated with Mib-1 labelling (p < 0.001). For the entire group, telomerase expression was associated with grade of tumour, age of patient, and vascular endothelial proliferation (all p < 0.001).
Correlation of clinical features and telomerase activity in human gliomas
Journal of neuro-oncology, 1999
Telomerase is a ribonucleoprotein containing an RNA template that synthesizes telomeric DNA. The expression of telomerase activity is concomitant with the attainment of immortality in tumor tissues and cells. In this report, we analyzed telomerase activity in 39 human gliomas with different histological, and in 10 meningiomas, 3 neurinomas, and 2 normal brain tissues by using a polymerase chain reaction (PCR)-based telomeric repeat amplification protocol (TRAP) assay. Telomerase activity was detectable in almost all of the gliomas (36 of 39), but not in any of the meningiomas, neurinomas, or normal brain tissues. In addition, we also analyzed the level of telomerase activity in the 36 gliomas with positive telomerase activity. The relative telomerase activity of the glioma showed a clear association with the pathological grade of glioma; i.e., most of the tumors with high telomerase activity were pathologically of high grade. And also the relative level of telomerase activity could ...