Molecular profiling of CNS tumors for the treatment and management of disease

Nie, Qian; Hsiao, Meng-Chang; Chandok, Harshpreet; Rowe, Shannon; Prego, Matthew; Meyers, Bridgette; Omerza, Gregory; Hesse, Andrew; Uvalic, Jasmina; Soucy, Melissa; Bergeron, Daniel; Peracchio, Michael; Burns, Shelbi; Kelly, Kevin; Rueter, Jens; Reddi, Honey V.

doi:10.1016/j.jocn.2019.11.035

Cited by 6 publications

(5 citation statements)

References 9 publications

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“…IDH1, PTEN, and TP53 pathogenic variants exhibited high incidence in mutational spectrum, with TP53 being the most prevalent. These results were in line with those of other studies since the p53 pathway was deregulated in many cancers and these three genes, along with EGFR, were the most frequently altered genes in gliomas (26)(27)(28)(29). Table II.…”

Section: Discussionsupporting

confidence: 92%

“…Moreover, we observed that patients with TP53 positive tumors were more likely to be diagnosed with cancer at a younger age than patients with wild-type TP53 tumors, as expected (47). Interestingly, PTEN mutations were mutually exclusive with IDH1 mutations and wild-type TP53 tumors were presented in IDH1 wild-type tumors only (14,26,48). However, these data should be regarded with caution due to the small examined number of tumors.…”

Section: Idh1 Mutation Pten Mutation Tp53 Mutationsupporting

confidence: 53%

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Molecular profile and clinical features of patients with gliomas using a broad targeted next generation‑sequencing panel

Romanidou¹,

Apostolou

Kouvelakis

et al. 2022

Oncol Lett

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Gliomas are the most common malignant primary brain tumors characterized by poor prognosis. The genotyping of tumors using next generation sequencing (NGS) platforms enables the identification of genetic alterations that constitute diagnostic, prognostic and predictive biomarkers. The present study investigated the molecular profile of 32 tumor samples from 32 patients with high-grade gliomas by implementing a broad 80-gene targeted NGS panel while reporting their clinicopathological characteristics and outcomes. Subsequently, 14 of 32 tumor specimens were also genotyped using a 55-gene NGS panel to validate the diagnostic accuracy and clinical utility of the extended panel. The median follow-up was 19.2 months. In total, 129 genetic alterations including 33 structural variants were identified in 38 distinct genes. Among 96 variants (single nucleotide variants and insertions and deletions), 38 were pathogenic and 58 variants of unknown clinical significance. TP53 was the most frequently mutated gene, followed by PTEN and IDH1 genes. Glioma patients with IDH1 mutant tumors were younger and had significantly longer overall survival compared to patients with wild-type IDH1 tumors. Similarly, tumors with TP53 mutations were more likely observed in younger patients with glioma. Subsequently, a comparison of mutational profiles of samples analyzed by both panels was also performed. Implementation of the comprehensive pan-cancer and the MOL panels resulted in the identification of 37 and 15 variants, respectively. Of those, 13 were common. Comprehensive pan-cancer panel identified 24 additional variants, 22 of which were located in regions that were not targeted by the MOL panel. By contrast, the MOL panel identified two additional variants. Overall, the present study demonstrated that using an extended tumor profile assay instead of a glioma-specific tumor profile panel identified additional genetic changes that may be taken into consideration as potential therapeutic targets for glioma diagnosis and molecular classification.

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Section: Discussionsupporting

confidence: 92%

Section: Idh1 Mutation Pten Mutation Tp53 Mutationsupporting

confidence: 53%

Molecular profile and clinical features of patients with gliomas using a broad targeted next generation‑sequencing panel

Romanidou¹,

Apostolou

Kouvelakis

et al. 2022

Oncol Lett

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“…Analysis of actionable variants detected in our cohort were cross referenced with captured genetic alterations in previous cohort studies to determine whether the actionable mutational landscape observed in this study is in keeping with previous genomic findings in glioblastoma. Potentially actionable variants identified in 46 glioblastoma samples using the JAX ActionSeq™ NGS Panel correlated significantly with our findings [21]. The overall frequency of actionable SNVs identified in this study were tightly correlated with their frequency in the JAX study (r2 = 0.88), TP53, PTEN, IDH1 and NF1 variants being identified at high frequency in both studies.…”

Section: Plos Onesupporting

confidence: 85%

Utilisation of semiconductor sequencing for the detection of predictive biomarkers in glioblastoma

Williams¹,

Llewelyn²,

Thatcher³

et al. 2022

PLoS ONE

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The standard treatment for glioblastoma involves a combination of surgery, radiation and chemotherapy but have limited impact on survival. The exponential increase in targeted agents directed at pivotal oncogenic pathways now provide new therapeutic opportunities for this tumour type. However, lack of comprehensive precision oncology testing at diagnosis means such therapeutic opportunities are potentially overlooked. To investigate the role of semiconductor sequencing for detection of predictive biomarkers in routine glioblastoma samples we have undertaken analysis of test trending data generated by a clinically validated next generation sequencing platform designed to capture actionable genomic variants distributed across 505 genes. Analysis was performed across a cohort of 55 glioblastoma patients. Analysis of trending data has revealed a complex and rich actionable mutational landscape in which 166 actionable mutations were detected across 36 genes linked to 17 off label targeted therapy protocols and 111 clinical trials. The majority of patients harboured three or more actionable mutations affecting key cancer related regulatory networks including the PI3K/AKT/MTOR and RAS/RAF/MEK/MAPK signalling pathways, DNA-damage repair pathways and cell cycle checkpoints. Linkage with immunotherapy and PARP inhibitors was identified in 44% of glioblastoma patients as a consequence of alterations in DNA-damage repair genes. Taken together our data indicates that precision oncology testing utilising semiconductor sequencing can be used to identify a broad therapeutic armamentarium of targeted therapies and immunotherapies that can be potentially employed for the improved clinical management of glioblastoma patients.

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“…The diagnostic efficacy of medium-sized gene panels has been demonstrated, allowing to detect mutations and CNV even with limited input material [22]. These results were confirmed by more recent studies employing larger gene panels (e.g., IDH1/IDH2, TERT, TP53, ATRX, BRAF, H3F3A, H3F3B) [23][24][25][26]. By using these assays, diagnostically relevant alterations can be detected in more than half of the analyzed CNS tumors.…”

Section: Dna and Rna Sequencingmentioning

confidence: 58%

Molecular neuropathology: an essential and evolving toolbox for the diagnosis and clinical management of central nervous system tumors

Bertero,

Mangherini,

Ricci

et al. 2023

Virchows Arch

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Molecular profiling has transformed the diagnostic workflow of CNS tumors during the last years. The latest WHO classification of CNS tumors (5th edition), published in 2021, pushed forward the integration between histopathological features and molecular hallmarks to achieve reproducible and clinically relevant diagnoses. To address these demands, pathologists have to appropriately deal with multiple molecular assays mainly including DNA methylation profiling and DNA/RNA next generation sequencing. Tumor classification by DNA methylation profiling is now a critical tool for many diagnostic tasks in neuropathology including the assessment of complex cases, to evaluate novel tumor types and to perform tumor subgrouping in hetereogenous entities like medulloblastoma or ependymoma. DNA/RNA NGS allow the detection of multiple molecular alterations including single nucleotide variations, small insertions/deletions (InDel), and gene fusions. These molecular markers can provide key insights for diagnosis, for example, if a tumor-specific mutation is detected, but also for treatment since targeted therapies are progressively entering the clinical practice. In the present review, a brief, but comprehensive overview of these tools will be provided, discussing their technical specifications, diagnostic value, and potential limitations. Moreover, the importance of molecular profiling will be shown in a representative series of CNS neoplasms including both the most frequent tumor types and other selected entities for which molecular characterization plays a critical role.

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Molecular profiling of CNS tumors for the treatment and management of disease

Cited by 6 publications

References 9 publications

Molecular profile and clinical features of patients with gliomas using a broad targeted next generation‑sequencing panel

Molecular profile and clinical features of patients with gliomas using a broad targeted next generation‑sequencing panel

Utilisation of semiconductor sequencing for the detection of predictive biomarkers in glioblastoma

Molecular neuropathology: an essential and evolving toolbox for the diagnosis and clinical management of central nervous system tumors

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