Distinct patterns of 1p and 19q alterations identify subtypes of human gliomas that have different prognoses†

Vogazianou, Artemis P.; Chan, Raymond; Bäcklund, L. Magnus; Pearson, Danita M.; Liu, Lu; Langford, Cordelia; Gregory, Simon G.; Collins, V. Peter; Ichimura, Koichi

doi:10.1093/neuonc/nop075

Cited by 69 publications

(54 citation statements)

References 45 publications

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“…A recent large‐scale molecular analysis of diffuse gliomas resulted in the development of a classification scheme based on TERT promoter mutation status in addition to 1p/19q co‐deletion and IDH mutation status, and did not include immunohistochemical or mutational analysis of ATRX. However, widely used fluorescent in‐situ hybridization analysis for 1p and 19q deletions does not always distinguish partial and total chromosome deletions, which have different clinical significance . Additionally, determining the mutational state of ATRX will be of benefit in therapeutic applications.…”

Section: Discussionmentioning

confidence: 99%

Utility of ATRX immunohistochemistry in diagnosis of adult diffuse gliomas

et al. 2016

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Section: Discussionmentioning

confidence: 99%

Utility of ATRX immunohistochemistry in diagnosis of adult diffuse gliomas

et al. 2016

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“…We found non-canonical 1p and 19q co-deletion events consisting of partial loss of a centromeric part of 1p and a telomeric part of 19q (ref. 30) in three TCGA subjects who lacked any detectable TP53 lesions (Fig. 1c).…”

Section: Genetic Features Of Grade II and Iii Glioma Subgroupsmentioning

confidence: 93%

Mutational landscape and clonal architecture in grade II and III gliomas

et al. 2015

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Grade II and III gliomas are generally slowly progressing brain cancers, many of which eventually transform into more aggressive tumors. Despite recent findings of frequent mutations in IDH1 and other genes, knowledge about their pathogenesis is still incomplete. Here, combining two large sets of high-throughput sequencing data, we delineate the entire picture of genetic alterations and affected pathways in these glioma types, with sensitive detection of driver genes. Grade II and III gliomas comprise three distinct subtypes characterized by discrete sets of mutations and distinct clinical behaviors. Mutations showed significant positive and negative correlations and a chronological hierarchy, as inferred from different allelic burdens among coexisting mutations, suggesting that there is functional interplay between the mutations that drive clonal selection. Extensive serial and multi-regional sampling analyses further supported this finding and also identified a high degree of temporal and spatial heterogeneity generated during tumor expansion and relapse, which is likely shaped by the complex but ordered processes of multiple clonal selection and evolutionary events.

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“…The cellular consequences of IDH mutations are currently unclear,12, 13 although they have recently been linked to a hypermethylation phenotype in glioma and acute myeloid leukemia (AML) 14–17. Mutations of IDH1/2 are also strongly associated with another prognostic marker, i.e ., total 1p/19q loss,5, 7, 8 a consequence of an unbalanced translocation t(1;19)(q10;p10)18, 19 seen in the majority of oligodendroglial tumors but only very occasionally in astrocytic tumors 20, 21. The total 1p/19q loss has been shown to predict longer survival in patients with anaplastic oligodendroglial tumors22, 23 as well as astrocytic tumors 21…”

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MGMT CpG island is invariably methylated in adult astrocytic and oligodendroglial tumors with IDH1 or IDH2 mutations

Mulholland

Pearson

Hamoudi

et al. 2012

Intl Journal of Cancer

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We have previously identified a region containing 16 CpGs within the MGMT CpG islands which is critical for the transcriptional control of MGMT (Malley, Acta Neuropathol 2011). To investigate the patterns and incidence of MGMT methylation in astrocytic and oligodendroglial tumors, we quantitatively assessed methylation at these 16 CpGs using bisulfite modification followed by pyrosequencing of 362 gliomas not treated with temozolomide, and correlated the findings with previously identified patterns of genetic abnormalities, patients' age and survival. The MGMT gene was considered to be methylated when the mean methylation of the 16 CpGs was 10% or higher. This cut-off value distinguished diffuse astrocytomas with high and low MGMT expression. Within each tumor type, the patterns of methylation were highly variable and also highly heterogeneous across the 16 CpGs. A high incidence of MGMT methylation was observed in all subtypes of gliomas included in this study. Among a subset of 97 tumors where conventional methylation-specific PCR (MSP) was also applied, methylation was detected by both methods in 54 tumors, while the pyrosequencing results identified a further 17 tumors. No additional cases were found using MSP alone, indicating that pyrosequencing is a robust method for methylation analysis. All tumors with IDH1/IDH2 mutations except two had MGMT methylation, while there were many tumors with MGMT methylation, particularly primary glioblastomas, which had no mutations of IDH1/2. We suggest that MGMT methylation may be one of the earliest events in the development of astrocytic and oligodendroglial tumors.Gliomas are the most common group of primary brain tumors consisting of clinically and biologically distinct subtypes. The three main subgroups of glioma are astrocytic, oligodendroglial and mixed gliomas, which are further malignancy graded into up to four grades according to the WHO classification. 1 Glioblastomas (WHO grade IV) are the most malignant and common astrocytic brain tumor in adults, the overall median survival being only just over 14 months despite modern combined therapies. 2 Most glioblastomas are primary glioblastoma (pGB), while secondary glioblastoma (sGB) generally develops by progression from astrocytomas WHO grade II or III. Patients with astrocytic or oligodendroglial tumors WHO grade II and III survive longer, however they always recur and are ultimately fatal.Among the many genetic and epigenetic abnormalities commonly found in adult gliomas, three have been reported to predict response to treatment and/or prognosis: IDH1/ IDH2 mutations, concurrent deletion of the entire 1p and 19q chromosomal arms (total 1p/19q loss) and MGMT methylation. 3,4 With the exception of pGB, mutations of either IDH1 or IDH2 occur in more than 50% of adult astrocytic, oligodendroglial and oligoastrocytic tumors. [5][6][7][8] It has been shown that the presence of IDH1/2 mutations is associated with longer patient survival. 5-7,9,10 IDH1/2 mutations have been proposed as the earliest genetic changes in a ...

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Distinct patterns of 1p and 19q alterations identify subtypes of human gliomas that have different prognoses†

Cited by 69 publications

References 45 publications

Utility of ATRX immunohistochemistry in diagnosis of adult diffuse gliomas

Utility of ATRX immunohistochemistry in diagnosis of adult diffuse gliomas

Mutational landscape and clonal architecture in grade II and III gliomas

MGMT CpG island is invariably methylated in adult astrocytic and oligodendroglial tumors with IDH1 or IDH2 mutations

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