Molecular tools for the pathologic diagnosis of central nervous system tumors

Priesterbach-Ackley, Loudy P.; Wesseling, Pieter; Snijders, Tom J.; Vos, Filip Y.F. De; Leng, Wendy W.J. de

doi:10.1093/nop/npy041

Cited by 11 publications

(9 citation statements)

References 61 publications

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“…Simpler techniques such as Sanger sequencing, FISH and LOH analysis can provide very valuable molecular information but have their shortcomings. For example, for the detection of 1p/19q codeletion in diffuse gliomas preferably a platform is used that allows for discriminating partial 1p and/or 19q losses from the clinically relevant, complete 1p/19q codeletion [9].…”

Section: Discussionmentioning

confidence: 99%

“…The rapidly growing number of mutations to detect and the increased possibilities for targeted therapies has propelled the development of NGS panels, where multiple mutations can be detected in a single analysis. Some of these panels allow for simultaneous detection of fusions and chromosomal copy number aberration, as well [9]. More recently, genome-wide methylation profiling has been reported as a very valuable tool for CNS tumor diagnostics [113, 114].…”

Section: Discussionmentioning

confidence: 99%

“…For more detailed information on purely predictive markers for the efficacy of particular therapeutic approaches such as targeted treatment, the reader is referred to other reviews [5–8]. For a recent overview of the molecular diagnostic tools that may be used, see our recent review on this topic [9].…”

Section: Introductionmentioning

confidence: 99%

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Molecular pathology of tumors of the central nervous system

et al. 2019

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Since the update of the 4th edition of the WHO Classification of Central Nervous System (CNS) Tumors published in 2016, particular molecular characteristics are part of the definition of a subset of these neoplasms. This combined ‘histo-molecular’ approach allows for a much more precise diagnosis of especially diffuse gliomas and embryonal CNS tumors. This review provides an update of the most important diagnostic and prognostic markers for state-of-the-art diagnosis of primary CNS tumors. Defining molecular markers for diffuse gliomas are IDH1/IDH2 mutations, 1p/19q codeletion and mutations in histone H3 genes. Medulloblastomas, the most frequent embryonal CNS tumors, are divided into four molecularly defined groups according to the WHO 2016 Classification: wingless/integrated (WNT) signaling pathway activated, sonic hedgehog (SHH) signaling pathway activated and tumor protein p53 gene ( TP53 ) - mutant, SHH-activated and TP53- wildtype, and non-WNT/non-SHH-activated. Molecular characteristics are also important for the diagnosis of several other CNS tumors, such as RELA fusion-positive subtype of ependymoma, atypical teratoid rhabdoid tumor (AT/RT), embryonal tumor with multilayered rosettes, and solitary fibrous tumor/hemangiopericytoma. Immunohistochemistry is a helpful alternative for further molecular characterization of several of these tumors. Additionally, genome-wide methylation profiling is a very promising new tool in CNS tumor diagnostics. Much progress has thus been made by translating the most relevant molecular knowledge into a more precise clinical diagnosis of CNS tumors. Hopefully, this will enable more specific and more effective therapeutic approaches for the patients suffering from these tumors.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Molecular pathology of tumors of the central nervous system

et al. 2019

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“…To improve identification of CNVs in general, incorporation of highly polymorphic SNPs (single‐nucleotide polymorphisms) across relevant chromosomes in the panel would significantly improve the assessment of combined losses on 1p and 19q, combined +7/−10 as well as deletions of CDKN2A/B, with the latter becoming diagnostically relevant for prognostic assessment of IDH‐mutant astrocytic gliomas [50]. The principle of SNP incorporation into a targeted gene panel enables a single test for routine brain tumour diagnostics in a molecular pathology laboratory and offers an attractive alternative to methods such as FISH and immunohistochemistry [53].…”

Section: Discussionmentioning

confidence: 99%

Targeted next‐generation sequencing of adult gliomas for retrospective prognostic evaluation and up‐front diagnostics

Petersen

Boldt

Sørensen

et al. 2020

Neuropathology Appl Neurobio

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Aims We aimed to reclassify a population‐based cohort of 529 adult glioma patients to evaluate the prognostic impact of the 2016 World Health Organization (WHO) central nervous system tumour classification. Moreover, we evaluated the feasibility of gene panel next‐generation sequencing (NGS) in daily diagnostics of 225 prospective glioma patients. Methods The retrospective cohort was reclassified according to WHO 2016 criteria by immunohistochemistry for IDH‐R132H, fluorescence in situ hybridization for 1p/19q‐codeletion and gene panel NGS. All tumours of the prospective cohort were subjected to NGS analysis up‐front. Results The entire population‐based cohort was successfully reclassified according to WHO 2016 criteria. NGS results were obtained for 98% of the prospective patients. Survival analyses in the population‐based cohort confirmed three major prognostic subgroups, that is, isocitrate dehydrogenase (IDH)‐mutant and 1p/19q‐codeleted oligodendrogliomas, IDH‐mutant astrocytomas and IDH‐wildtype glioblastomas. The distinction between WHO grade II and III was prognostic in patients with IDH‐mutant astrocytoma. The survival of patients with IDH‐wildtype diffuse astrocytomas carrying TERT promoter mutation and/or EGFR amplification overlapped with the poor survival of IDH‐wildtype glioblastoma patients. Conclusions Gene panel NGS proved feasible in daily diagnostics. In addition, our study confirms the prognostic role of glioma classification according to WHO 2016 in a large population‐based cohort. Molecular features of glioblastoma in IDH‐wildtype diffuse glioma were linked to poor survival corresponding to IDH‐wildtype glioblastoma patients. The distinction between WHO grade II and III retained prognostic significance in patients with IDH‐mutant diffuse astrocytic gliomas.

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“…Recently, according to the revised fourth edition of the World Health Organization (WHO) classification of central nervous system (CNS) tumors, the integration of histology and genetic analysis for the diagnosis of specific neoplastic entities are recommended, such as isocitrate dehydrogenase 1 and 2 ( IDH1/2 ) mutations, 1p/19q chromosomal codeletion, point mutations in tumor protein 53 ( TP53 ), and O6-methylguanine methyltransferase ( MGMT ) promoter methylation for adults diffuse glioma ( 10 ). Other genetic alterations are meaningful for the molecular characterization of different types of brain tumors, including mutation in the promoter of telomerase reverse transcriptase ( TERT ) for oligodendroglioma, the v-RAF murine sarcoma viral oncogene homolog B1 ( BRAF ) V600E mutation for non-diffuse glioma, and v-rel avian reticuloendotheliosis viral oncogene homolog A ( RELA ) fusion for supratentorial ependymomas ( 11 , 12 ). Recently, the next-generation sequencing (NGS) technologies have drawn increasing attention as a result of several advantages, such as globally interrogating the genetic composition of biological samples, significantly reduced sequencing cost, improved accuracy of detection, and real-time monitoring progression of tumors, with high sensitivity for detecting extremely low levels of mutation frequency; therefore, the technology allows early screening and diagnosis of brain tumors ( 13 ).…”

Section: Introductionmentioning

confidence: 99%

Next-Generation Sequencing Analysis of ctDNA for the Detection of Glioma and Metastatic Brain Tumors in Adults

Liang

Zhao

et al. 2020

Front. Neurol.

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Background and aims: The next-generation sequencing technologies and their related assessments of circulating tumor DNA in both glioma and metastatic brain tumors remain largely limited. Methods: Based largely on a protocol approved by the institutional review board at Peking University International Hospital, the current retrospective, single-center study was conducted. Genomic DNA was extracted from blood samples or tumor tissues. With the application of NextSeq 500 instrument (Illumina), Sequencing was performed with an average coverage of 550-fold. Paired-end sequencing was employed utilized with an attempt to achieve improved sensitivity of duplicate detection and therefore to increase the detection reliability of possible fusions. Results: A total of 28 patients (21 men and 7 women) with brain tumors in the present study were involved in the study. The patients enrolled were assigned into two groups, including glioma group ( n = 21) and metastatic brain tumor group ( n = 7). The mean age of metastatic brain tumor group (59.86 ± 8.85 y), (43.65 ± 13.05 y) reported significantly higher results in comparison to that of glioma group (45.3 ± 12.3 years) ( P < 0.05). The mutant genes in metastatic brain tumor group included ALK, MDM2, ATM, BRCA1, FGFR1, MDM4 and KRAS ; however, there were no glioma-related mutant genes including MGMT, IDH1 , IDH2, 1p/19q , and BRAF et al. Interesteringly, only two patient (28.3%) was detected blood ctDNA in metastatic brain tumor group; In contrast, blood ctDNA was found in ten glioma patients (47.6%) including 1p/19q, MDM2, ERBB2, IDH1, CDKN2A, CDK4, PDGFRA, CCNE1, MET . The characterizations of IDH mutations in the glioma included IDH1 mutation (p.R132H) and IDH2 mutation (p.R172K). The mutation rate of IDH in tumor tissues was 37.06 ± 8.32%, which was significantly higher than blood samples ( P < 0.05). Conclusion: The present study demonstrated that the mutant genes among glioma and metastatic brain tumors are shown to be different. Moreover, the ctDNAs in the metastatic brain tumors included ALK and MDM2 , and glioma-related ctDNAs included 1p/19q and MDM2 followed by frequencies of ERBB2, IDH1, CDKN2A, CDK4, PDGFRA, CCNE1, MET . These ctDNAs might be biomarkers and therapeutic responders in brain tumor.

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Molecular tools for the pathologic diagnosis of central nervous system tumors

Cited by 11 publications

References 61 publications

Molecular pathology of tumors of the central nervous system

Molecular pathology of tumors of the central nervous system

Targeted next‐generation sequencing of adult gliomas for retrospective prognostic evaluation and up‐front diagnostics

Next-Generation Sequencing Analysis of ctDNA for the Detection of Glioma and Metastatic Brain Tumors in Adults

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