Targetable molecular alterations in congenital glioblastoma

Gilani, Ahmed; Donson, Andrew M.; Davies, Kurtis D.; Whiteway, Susan L.; Lake, Jessica; DeSisto, John; Hoffman, Lindsey M.; Foreman, Nicholas; Kleinschmidt‐DeMasters, Bette K.; Green, Adam L.

doi:10.1007/s11060-019-03377-8

Cited by 26 publications

(23 citation statements)

References 31 publications

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“…Infantile high-grade glioma has a significantly better survival in comparison to older children with high-grade glioma [7,14]. Several of these large ALK-fusion driven infantile high-grade gliomas are congenital, and may have maturation/differentiation following chemotherapy [7,8,14]. Thus, in some cases, treatment with a less intense chemotherapeutic regimen may be warranted to limit overtly morbid therapy, especially with the availability of targeted agents; however, this should be individualized for the patient.…”

Section: Discussionmentioning

confidence: 99%

“…The tumor in this case report is a high-grade neuroepithelial tumor and difficult to classify, with glial, as well as ependymal features. With regards to gliomas, infantile high-grade gliomas have been described to be ALK driven and congenital glioblastomas have also been described with an EML4-ALK fusion [7,8]. ALK fusions including Kinectin 1 (KTN1)-ALK and Coiled-coil domain containing 88C (CCDC88A)-ALK have been shown in ependymoma [9].…”

Section: Introductionmentioning

confidence: 99%

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A Unique Case of a High-Grade Neuroepithelial Tumor With EML4-ALK Fusion in a Five-Month-Old

Mrowczynski¹,

Payne²,

Pu³

et al. 2020

Cureus

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We present a unique and challenging case of a high-grade neuroepithelial tumor with echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion in a five-month-old child. This tumor was difficult to classify, with glial and ependymal features, reinforcing the impact of a molecular-based diagnosis in correct classification and management. The patient had two tumor resections and underwent chemotherapy following the Head Start trial treatment regimen. The patient remains well, with no residual disease on MRI 15 months after initial resection. Further studies are needed to determine the frequency of EML4-ALK fusions in these types of tumors and to optimize therapeutic protocols for children and adults, alike, suffering from this disease.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Unique Case of a High-Grade Neuroepithelial Tumor With EML4-ALK Fusion in a Five-Month-Old

Mrowczynski¹,

Payne²,

Pu³

et al. 2020

Cureus

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“…Raw sequence data were analyzed with Archer analysis software (version 6.2.; Archer DX, Boulder, CO, USA) for the presence of single-nucleotide variants (SNVs) as well as insertions and deletions (indels) [17]. For the alignment, the human reference genome GRCh37 (equivalent UCSC version hg19) was built.…”

Section: Discussionmentioning

confidence: 99%

High Genetic Diversity and No Evidence of Clonal Relation in Synchronous Thyroid Carcinomas Associated with Hashimoto’s Thyroiditis: A Next-Generation Sequencing Analysis

et al. 2020

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The close association between pre-existing Hashimoto’s thyroiditis and thyroid cancer is well established. The simultaneous occurrence of multiple neoplastic foci within the same organ suggests a common genotoxic effect potentially contributing to carcinogenesis, the nature of which is still not clear. Next-generation sequencing (NGS) provides a potent tool to demonstrate and compare the mutational profile of the independent neoplastic foci. Our collection of 47 cases with thyroid carcinoma and Hashimoto’s thyroiditis included 14 with at least two tumorous foci. Detailed histological analysis highlighted differences in histomorphology, immunoprofile, and biological characteristics. Further, a 67-gene NGS panel was applied to demonstrate the mutational diversity of the synchronic tumors. Significant differences could be detected with a wide spectrum of pathogenic gene variants involved (ranging between 5 and 18, cutoff >5.0 variant allele frequencies (VAF)). Identical gene variants represented in both synchronous tumors of the same thyroid gland were found in only two cases (BRAF and JAK3 genes). An additional set of major driver mutations was identified at variable allele frequencies in a highly individual setup suggesting a clear clonal independence. The different BRAF statuses in coincident thyroid carcinoma foci within the same organ outline a special challenge for molecular follow-up and therapeutic decision-making.

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“…However, as some tumors may not be symptomatic at the time of birth, those presenting within the first few months of life are also likely congenital in origin. In the literature, the criteria used to classify a CNS tumor as being congenital varies greatly with cutoffs ranging between 4 weeks of life and 1 year at the time of symptom onset (2, 6, 8, 17–20, 29, 32, 34, 36). A few different classification schemes have been described.…”

Section: Introductionmentioning

confidence: 99%

“…Over the past decade, there has been a significant increase in molecular testing performed on brain tumor specimens which has led to the discovery that infantile CNS tumors, particularly the high-grade gliomas, have molecular characteristics that differ from tumors of older children. Specifically, alterations in ALK, ROS1, MET, NTRK and other genes are unique to high-grade gliomas of infants (4,8,9,18).…”

Section: Introductionmentioning

confidence: 99%

Congenital tumors of the central nervous system: an institutional review of 64 cases with emphasis on tumors with unique histologic and molecular characteristics

Viaene

Perry

et al. 2020

Brain Pathology

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Congenital brain tumors are rare accounting for 0.5%–1.9% of all pediatric brain tumors. While different criteria have been used to classify a tumor as congenital, those diagnosed prior to 6 months of age are considered to be “probably” congenital in origin. We performed an institutional review of all central nervous system (CNS) tumors (surgical and autopsy specimens from 1990 to 2019) in patients less than 6 months old. Sixty‐four unique cases were identified, and these accounted for 2.0% of all CNS tumor specimens at our institution. The most common tumor types were high‐grade gliomas, low‐grade gliomas and medulloblastomas. Atypical teratoid rhabdoid tumors, choroid plexus tumors and germ cell tumors also accounted for a significant portion of the cohort. Seven tumors were diagnosed prenatally. The most common clinical presentation at diagnosis was increased head circumference. At the conclusion of the study, over half of the patients were alive including all patients with WHO grade I and II tumors. Ninety‐two percent of cases were classifiable using the 2016 WHO system, and when available, molecular findings supported the histologic diagnoses. However, several gliomas had unusual histologic features and did not correspond to a well‐defined entity. Molecular testing was essential for accurate classification of a subset of these tumors, and several high‐grade gliomas exhibited fusions considered unique to infantile gliomas, including those involving the MET, ALK and NTRK genes. To our knowledge, this cohort represents the largest single‐institution study of congenital CNS tumors and highlights many ways in which congenital CNS tumors are distinct from CNS tumors of older pediatric patients and adults.

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Targetable molecular alterations in congenital glioblastoma

Cited by 26 publications

References 31 publications

A Unique Case of a High-Grade Neuroepithelial Tumor With EML4-ALK Fusion in a Five-Month-Old

A Unique Case of a High-Grade Neuroepithelial Tumor With EML4-ALK Fusion in a Five-Month-Old

High Genetic Diversity and No Evidence of Clonal Relation in Synchronous Thyroid Carcinomas Associated with Hashimoto’s Thyroiditis: A Next-Generation Sequencing Analysis

Congenital tumors of the central nervous system: an institutional review of 64 cases with emphasis on tumors with unique histologic and molecular characteristics

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