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A "weighted" fluorescence in situ hybridization strengthens the favorable prognostic value of 1p/19q codeletion in pure and mixed oligodendroglial tumors.

ABSTRACT: Evaluation of the molecular status of 1p and 19q is a major relevant diagnostic, prognostic, and predictive tool for oligodendroglial brain tumors. Fluorescence in situ hybridization (FISH) is the most commonly used technique for determining 1p and 19q allelic losses, but it lacks fully standardized criteria for analysis. This lack of standardization has led to interinstitutional disagreement in the interpretation of results, thereby contributing to a "gray prognostic zone" that includes codeleted patients with an unexpectedly unfavorable outcome. To optimize the prognostic potential of 1p/19q status determination, we first compared the actual criteria used for FISH reading (i.e. different ratio cutoff values and the percentage of neoplastic nuclei carrying this chromosomal deletion) in a retrospective series of 143 pure and mixed oligodendroglial tumors. We then created a "weighted" FISH reading based on the merged ratio and percentage of neoplastic cells carrying the deletion that was further differentially modulated for 1p and 19q, respectively. This weighted codeletion setting significantly strengthened the favorable prognostic power of 1p/19q losses by reducing the number of poor outcomes from 42% to 12.5% for patients with codeleted tumors. Thus, by identifying as codeleted only those cases with more than 50% of cells having a combined loss of 1p (using 0.7 ratio cutoff) and 19q (using 0.8 ratio cutoff) arms, we created a molecular report that bears higher clinical impact and strengthens the prognostic potential of 1p/19q allelic loss.

SUBMITTER: Senetta R

PROVIDER: S-EPMC3678883 | biostudies-other | 2013 May

REPOSITORIES: biostudies-other

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A "weighted" fluorescence in situ hybridization strengthens the favorable prognostic value of 1p/19q codeletion in pure and mixed oligodendroglial tumors.

Senetta Rebecca R Verdun di Cantogno Ludovica L Chiusa Luigi L Castellano Isabella I Gugliotta Patrizia P Sapino Anna A Cassoni Paola P

Journal of neuropathology and experimental neurology 20130501 5

Evaluation of the molecular status of 1p and 19q is a major relevant diagnostic, prognostic, and predictive tool for oligodendroglial brain tumors. Fluorescence in situ hybridization (FISH) is the most commonly used technique for determining 1p and 19q allelic losses, but it lacks fully standardized criteria for analysis. This lack of standardization has led to interinstitutional disagreement in the interpretation of results, thereby contributing to a "gray prognostic zone" that includes codelet ...[more]

PMID: 23584201

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Project description:The molecular genetic alterations of oligodendroglial tumors and mixed gliomas of the central nervous system were studied in a series of 37 cases (8 oligodendrogliomas, 13 anaplastic oligodendrogliomas, 8 oligoastrocytomas, and 8 anaplastic oligoastrocytomas). A total of 180 polymorphic loci and 5 nonpolymorphic gene loci, distributed over all chromosomes, were examined by restriction fragment length polymorphism analysis. Loss of heterozygosity was most frequently observed for loci on 19q with a commonly deleted region at 19q13.2-q13.4 distal to the CYP2a gene and proximal to the D19S22 locus. The incidence of allelic loss on 19q was particularly high (81%) in oligodendroglial tumors and equal to 31% in mixed gliomas. More than 75% of the tumors with allelic deletions on 19q also showed loss of heterozygosity for loci on 1p with one tumor showing only loss of alleles distal to the NGFB gene (1p13-pter). Seven (19%) tumors had lost alleles from 17p with the deleted region including the TP53 tumor suppressor gene in all cases. Sequencing of the TP53 transcripts from exons 2 to 10, however, did not reveal mutations of the remaining allele in any of these tumors. Anaplastic oligodendrogliomas and anaplastic oligoastrocytomas demonstrated an increased incidence of additional allelic losses involving most frequently chromosomes 9p and 10. Gene amplification was detected in two anaplastic tumors, affecting the epidermal growth factor receptor gene in both cases, with additional amplification of the renin gene at 1q32 in one of these cases. In total our results indicate both differences and similarities between the molecular genetic alterations in tumors with oligodendroglial and astrocytic differentiation. The loss of genetic information from 19q and 1p as well as the rarity of TP53 mutations in oligodendroglial tumors suggests that the early events in their oncogenesis are distinct from those associated with astrocytic tumors. However, similarities are indicated by the allelic losses on 9p and 10 in the anaplastic tumors, suggesting the utilization of common pathways of progression.

Project description:TERT promoter mutations are commonly associated with 1p/19q codeletion in IDH-mutated gliomas. However, whether these mutations have an impact on patient survival independent of 1p/19q codeletion is unknown. In this study, we investigated the impact of TERT promoter mutations on survival in IDH-mutated glioma cases. Detailed clinical information and molecular status data were collected for a cohort of 560 adult patients with IDH-mutated gliomas. Among these patients, 279 had both TERT promoter mutation and 1p/19q codeletion, while 30 had either TERT promoter mutation (n?=?24) or 1p/19q codeletion (n?=?6) alone. A univariable Cox proportional hazard analysis for survival using clinical and genetic factors indicated that a Karnofsky performance status score (KPS) of 90 or 100, WHO grade II or III, TERT promoter mutation, 1p/19q codeletion, radiation therapy, and extent of resection (90-100%) were associated with favorable prognosis (p?<?0.05). A multivariable Cox regression model revealed that TERT promoter mutation had a significantly favorable prognostic impact (hazard ratio?=?0.421, p?=?0.049), while 1p/19q codeletion did not have a significant impact (hazard ratio?=?0.648, p?=?0.349). Analyses incorporating patient clinical and genetic information were further conducted to identify subgroups showing the favorable prognostic impact of TERT promoter mutation. Among the grade II-III glioma patients with a KPS score of 90 or 100, those with IDH-TERT co-mutation and intact 1p/19q (n?=?17) showed significantly longer survival than those with IDH mutation, wild-type TERT, and intact 1p/19q (n?=?185) (5-year overall survival, 94% and 77%, respectively; p?=?0.032). Our results demonstrate that TERT promoter mutation predicts favorable prognosis independent of 1p/19q codeletion in IDH-mutated gliomas. Combined with its adverse effect on survival among IDH-wild glioma cases, the bivalent prognostic impact of TERT promoter mutation may help further refine the molecular diagnosis and prognostication of diffuse gliomas.

Project description:Background1p/19q co-deletion in low-grade gliomas (LGG, World Health Organization grade II and III) is of great significance in clinical decision making. We aim to use radiomics analysis to predict 1p/19q co-deletion in LGG based on amide proton transfer weighted (APTw), diffusion weighted imaging (DWI), and conventional MRI.MethodsThis retrospective study included 90 patients histopathologically diagnosed with LGG. We performed a radiomics analysis by extracting 8454 MRI-based features form APTw, DWI and conventional MR images and applied a least absolute shrinkage and selection operator (LASSO) algorithm to select radiomics signature. A radiomics score (Rad-score) was generated using a linear combination of the values of the selected features weighted for each of the patients. Three neuroradiologists, including one experienced neuroradiologist and two resident physicians, independently evaluated the MR features of LGG and provided predictions on whether the tumor had 1p/19q co-deletion or 1p/19q intact status. A clinical model was then constructed based on the significant variables identified in this analysis. A combined model incorporating both the Rad-score and clinical factors was also constructed. The predictive performance was validated by receiver operating characteristic curve analysis, DeLong analysis and decision curve analysis. P < 0.05 was statistically significant.ResultsThe radiomics model and the combined model both exhibited excellent performance on both the training and test sets, achieving areas under the curve (AUCs) of 0.948 and 0.966, as well as 0.909 and 0.896, respectively. These results surpassed the performance of the clinical model, which achieved AUCs of 0.760 and 0.766 on the training and test sets, respectively. After performing Delong analysis, the clinical model did not significantly differ in predictive performance from three neuroradiologists. In the training set, both the radiomic and combined models performed better than all neuroradiologists. In the test set, the models exhibited higher AUCs than the neuroradiologists, with the radiomics model significantly outperforming resident physicians B and C, but not differing significantly from experienced neuroradiologist.ConclusionsOur results suggest that our algorithm can noninvasively predict the 1p/19q co-deletion status of LGG. The predictive performance of radiomics model was comparable to that of experienced neuroradiologist, significantly outperforming the diagnostic accuracy of resident physicians, thereby offering the potential to facilitate non-invasive 1p/19q co-deletion prediction of LGG.

Project description:ObjectiveTo study the feasibility and the diagnostic and prognostic interest of automated analysis of 1p, 19q, 9p and 10q status by FISH technique in oligodendroglial tumors.MethodsWe analyzed a retrospective series of 33 consecutive gliomas with oligodendroglial histology (originally diagnosed as 24 oligodendrogliomas and 9 oligoastrocytomas). For all cases, automated FISH analysis of 1p, 19q, 9p and 10q status were performed and compared to clinical and histological data, ATRX, IDH1R132H and alpha-internexin status (studied by immunohistochemistry) and overall survival (OS). Manual analysis of 9p and 10q status were also performed and compared to automated analysis to verify the concordance of the two methods.ResultsThe 33 gliomas were reclassified into 13 low-grade oligodendrogliomas (OII), 10 anaplastic oligodendrogliomas (OIII), 3 diffuse astrocytomas (AII), 3 anaplastic astrocytomas (AIII) and 4 glioblastomas (GBM) according to the WHO 2016 histological criteria. The 1p and/or 19q imbalanced status were restricted to astrocytomas with no correlation to their grade or their OS. Chromosome 9p deletion was restricted to OIII (70%) and GBM (100%) and was correlated with a shorter OS in the total cohort (p = 0.0007), the oligodendroglioma cohort (p = 0.03) and the astrocytoma cohort (p = 0.001). Concordance between 9p manual and automated analysis was satisfactory (81%, κ = 0.69). Chromosome 10q deletion was restricted to GBMs (50%) and was correlated with a poor OS in both the total cohort (p = 0.003) and the astrocytoma (AS) cohort (p = 0.04). Concordance between manual and automated analysis was satisfactory (79%, κ = 0.62).ConclusionAutomated analysis of 1p, 19q, 9p and 10q status by FISH is a reliable technique which allows for refined classification of oligodendroglial tumors. 1p and/or 19q imbalanced status is evidence of astrocytic differentiation. 9p deletion is found in high grade oligodendrogliomas and astrocytomas with a poor OS. 10q is related to GBM status and a poor OS.

Dataset Information

A "weighted" fluorescence in situ hybridization strengthens the favorable prognostic value of 1p/19q codeletion in pure and mixed oligodendroglial tumors.

Publications

A "weighted" fluorescence in situ hybridization strengthens the favorable prognostic value of 1p/19q codeletion in pure and mixed oligodendroglial tumors.

Similar Datasets

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