Molecular alterations in the integrated diagnosis of pediatric glial and glioneuronal tumors: A single center experience

Colli, Sandra; Cardoso, Nazarena; Massone, Carla Antonella; Cores, María; Lombardi, Mercedes García; Matteo, Elena Noemí de; Lorenzetti, Mario Alejandro; Preciado, María Victoria

doi:10.1371/journal.pone.0266466

Cited by 4 publications

(4 citation statements)

References 36 publications

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“…One would argue that assessing only druggable molecular markers with prognostic value using IHC, FISH, and Sanger sequencing is more realistic in an LMIC setting. This was the made by Colli et al (15) from Argentina after they tested 102 pediatric glial and glioneuronal tumors and corelated PFS and OS with several alterations (KIAA1549-BRAF gene fusion, BRAFV600E mutation, H3K27M and H3G34R mutations). While these alterations are the most prevalent, NGS is superior in detecting a wider range of alterations that may change the diagnosis or management.…”

Section: Discussionmentioning

confidence: 96%

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Next-generation sequencing for pediatric CNS tumors: does it add value in a middle-income country setup?

Amayiri,

Al-Hussaini,

Maraqa

et al. 2024

Front. Oncol.

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IntroductionAdvances in molecular diagnostics led to improved targeted interventions in the treatment of pediatric CNS tumors. However, the capacity to test for these is limited in LMICs, and thus their value needs exploration.MethodsWe reviewed our experience with NGS testing (TruSight RNA Pan-Cancer-seq panel) for pediatric CNS tumors at KHCC/Jordan (March/2022–April/2023). Paraffin blocks’ scrolls were shipped to the SickKids laboratory based on the multidisciplinary clinic (MDC) recommendations. We reviewed the patients’ characteristics, the tumor types, and the NGS results’ impact on treatment.ResultsOf 237 patients discussed during the MDC meetings, 32 patients (14%) were included. They were 16 boys and 16 girls; the median age at time of testing was 9.5 years (range, 0.9–21.9 years). There were 21 samples sent at diagnosis and 11 upon tumor progression. The main diagnoses were low-grade-glioma (15), high-grade-glioma (10), and other histologies (7). Reasons to request NGS included searching for a targetable alteration (20) and to better characterize the tumor behavior (12). The median turnaround time from samples’ shipment to receiving the results was 23.5 days (range, 15–49 days) with a median laboratory processing time of 16 days (range, 8–39 days) at a cost of US$1,000/sample. There were 19 (59%) tumors that had targetable alterations (FGFR/MAPK pathway inhibitors (14), checkpoint inhibitors (2), NTRK inhibitors (2), and one with PI3K inhibitor or IDH1 inhibitor). Two rare BRAF mutations were identified (BRAFp.G469A, BRAFp.K601E). One tumor diagnosed initially as undifferentiated round cell sarcoma harbored NAB2::STAT6 fusion and was reclassified as an aggressive metastatic solitary fibrous tumor. Another tumor initially diagnosed as grade 2 astroblastoma grade 2 was reclassified as low-grade-glioma in the absence of MN1 alteration. NGS failed to help characterize a tumor that was diagnosed histologically as small round blue cell tumor. Nine patients received targeted therapy; dabrafenib/trametinib (6), pembrolizumab (2), and entrectinib (1), mostly upon tumor progression (7).ConclusionIn this highly selective cohort, a high percentage of targetable mutations was identified facilitating targeted therapies. Outsourcing of NGS testing was feasible; however, criteria for case selection are needed. In addition, local capacity-building in conducting the test, interpretation of the results, and access to “new drugs” continue to be a challenge in LMICs.

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Section: Discussionmentioning

confidence: 96%

“…LGG (15) Targetable alteraƟon was found (11) Used in treatment (6) Tumor stable/ responded (6) Not used in treatment (5) Stable tumor (4) Family refusal (1) No alteraƟon was found (4) HGG (10) No alteraƟon was found (2) Targetable alteraƟon was found (8) Not used in treatment (…”

Section: Discussionmentioning

confidence: 99%

Next-generation sequencing for pediatric CNS tumors: does it add value in a middle-income country setup?

Amayiri,

Al-Hussaini,

Maraqa

et al. 2024

Front. Oncol.

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“…LGGs often carry BRAF gene fusions (e.g., KIAA1549-BRAF) or activating mutations (e.g., BRAF V600E), NF1 mutations, RAF fusions, FGFR1 mutation or rearrangement, impacting both the RAS/MAPK and PI3K/AKT/ mTOR pathways. The BRAF V600E mutation seems to correlate with a poorer prognosis across a broad spectrum of pediatric LGG (34). Gangliogliomas, a subset of glioneuronal tumors, often harbor the activating BRAF V600E mutation as well (94).…”

Section: Low-grade Gliomasmentioning

confidence: 99%

Targeted treatment of solid tumors in pediatric precision oncology

Bertacca,

Pegoraro,

Tondo

et al. 2023

Front. Oncol.

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The treatment of childhood solid cancer has markedly evolved in recent years following a refined molecular characterization and the introduction of novel targeted drugs. On one hand, larger sequencing studies have revealed a spectrum of mutations in pediatric tumors different from adults. On the other hand, specific mutations or immune dysregulated pathways have been targeted in preclinical and clinical studies, with heterogeneous results. Of note, the development of national platforms for tumor molecular profiling and, in less measure, for targeted treatment, has been essential in the process. However, many of the available molecules have been tested only in relapsed or refractory patients, and have proven poorly effective, at least in monotherapy. Our future approaches should certainly aim at improving the access to molecular characterization, to obtain a deeper picture of the distinctive phenotype of childhood cancer. In parallel, the implementation of access to novel drugs should not only be limited to basket or umbrella studies but also to larger, multi-drug international studies. In this paper we reviewed the molecular features and the main available therapeutic options in pediatric solid cancer, focusing on available targeted drugs and ongoing investigations, aiming at providing a useful tool to navigate the heterogeneity of this promising but complex field.

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“…The incidence of H3.3-G34R/V mutant gliomas peaked in adolescence with a median age at diagnosis between 15 and 17 years of age [4,54]. H3.3-G34R/V mutant gliomas made up approximately 5-15% of pediatric HGGs/GBMs [81][82][83]106,107]. When studies included adults with HGG or GBM, the prevalence of the H3.3-G34 mutant glioma subgroup was 1% [96] and 8.6% [8], respectively, although the selection criteria for adult patients in the study by Sturm et al were not well delineated.…”

Section: Baseline Information and Clinical Presentation Of Patients W...mentioning

confidence: 99%

H3G34-Mutant Gliomas—A Review of Molecular Pathogenesis and Therapeutic Options

et al. 2023

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The 2021 World Health Organization Classification of Tumors of the Central Nervous System reflected advances in understanding of the roles of oncohistones in gliomagenesis with the introduction of the H3.3-G34R/V mutant glioma to the already recognized H3-K27M altered glioma, which represent the diagnoses of pediatric-type diffuse hemispheric glioma and diffuse midline glioma, respectively. Despite advances in research regarding these disease entities, the prognosis remains poor. While many studies and clinical trials focus on H3-K27M-altered-glioma patients, those with H3.3-G34R/V mutant gliomas represent a particularly understudied population. Thus, we sought to review the current knowledge regarding the molecular mechanisms underpinning the gliomagenesis of H3.3-G34R/V mutant gliomas and the diagnosis, treatment, long-term outcomes, and possible future therapeutics.

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Molecular alterations in the integrated diagnosis of pediatric glial and glioneuronal tumors: A single center experience

Cited by 4 publications

References 36 publications

Next-generation sequencing for pediatric CNS tumors: does it add value in a middle-income country setup?

Next-generation sequencing for pediatric CNS tumors: does it add value in a middle-income country setup?

Targeted treatment of solid tumors in pediatric precision oncology

H3G34-Mutant Gliomas—A Review of Molecular Pathogenesis and Therapeutic Options

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