Genetics of Glioblastomas in Rare Anatomical Locations: Spinal Cord and Optic Nerve

Shows, Jared; Marshall, Carrie B.; Perry, Arie; Kleinschmidt-DeMasters, B.K.

doi:10.1111/bpa.12327

Cited by 13 publications

(9 citation statements)

References 11 publications

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“…In this cohort, nearly all grade IV IMAs were H3K27M mutants (92%), in line with previous reports, which described a range between 38 and 100% of H3K27M-mutant tumors among HG spinal astrocytomas [1,8,17,25,27,32,35,41,42,44,53]. All of the H3F3A mutations identified in our cohort consisted of the recurrent hotspot p.K27M mutation.…”

Section: Discussionsupporting

confidence: 91%

Clinical, radiological and molecular characterization of intramedullary astrocytomas

Lebrun¹,

Meléndez²,

Blanchard³

et al. 2020

acta neuropathol commun

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Intramedullary astrocytomas (IMAs) are rare tumors, and few studies specific to the molecular alterations of IMAs have been performed. Recently, KIAA1549-BRAF fusions and the H3F3A p.K27M mutation have been described in low-grade (LG) and high-grade (HG) IMAs, respectively. In the present study, we collected clinico-radiological data and performed targeted next-generation sequencing for 61 IMAs (26 grade I pilocytic, 17 grade II diffuse, 3 LG, 3 grade III and 12 grade IV) to identify KIAA1549-BRAF fusions and mutations in 33 genes commonly implicated in gliomas and the 1p/19q regions. One hundred seventeen brain astrocytomas were analyzed for comparison. While we did not observe a difference in clinico-radiological features between LG and HG IMAs, we observed significantly different overall survival (OS) and event-free survival (EFS). Multivariate analysis showed that the tumor grade was associated with better OS while EFS was strongly impacted by tumor grade and surgery, with higher rates of disease progression in cases in which only biopsy could be performed. For LG IMAs, EFS was only impacted by surgery and not by grade. The most common mutations found in IMAs involved TP53, H3F3A p.K27M and ATRX. As in the brain, grade I pilocytic IMAs frequently harbored KIAA1549-BRAF fusions but with different fusion types. Noncanonical IDH mutations were observed in only 2 grade II diffuse IMAs. No EGFR or TERT promoter alterations were found in IDH wild-type grade II diffuse IMAs. These latter tumors seem to have a good prognosis, and only 2 cases underwent anaplastic evolution. All of the HG IMAs presented at least one molecular alteration, with the most frequent one being the H3F3A p.K27M mutation. The H3F3A p.K27M mutation showed significant associations with OS and EFS after multivariate analysis. This study emphasizes that IMAs have distinct clinico-radiological, natural evolution and molecular landscapes from brain astrocytomas.

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Section: Discussionsupporting

confidence: 91%

Clinical, radiological and molecular characterization of intramedullary astrocytomas

Lebrun¹,

Meléndez²,

Blanchard³

et al. 2020

acta neuropathol commun

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“…We have been utilizing the H3 K27M IHC for assessment of midline glial tumors from our joint adult and pediatric neuropathology practice since 2013. We now extend our previous studies with H3 K27M- mutant tumors [ 2 , 15 ], focusing on comparing features in these two cohorts in terms of histological appearance, leptomeningeal dissemination, and survival.…”

Section: Introductionmentioning

confidence: 82%

“…H3 K27M mutations were first described in pediatric diffuse pontine gliomas (DIPGs) [ 1 ], but soon thereafter were found in midline gliomas in adults by our group [ 2 ] and Solomon et al [ 3 ]. The presence of H3 K27M mutation in DIPGs was recognized to portend an adverse prognosis regardless of the histological grade of the lesion [ 4 ] and thus a grade of IV was assigned by the 2016 World Health Organization [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

H3 K27M-mutant gliomas in adults vs. children share similar histological features and adverse prognosis

Kleinschmidt‐DeMasters¹,

Levy²

2018

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Background: H3 K27M mutation was originally described in pediatric diffuse intrinsic pontine gliomas (DIPGs), but has been recently recognized to occur also in adult midline diffuse gliomas, as well as midline tumors with other morphologies, including gangliogliomas (GGs), anaplastic GGs, pilocytic astrocytomas (PAs), and posterior fossa ependymomas. In a few patients with H3 K27M-mutant tumors with these alternate morphologies, longer survival has been reported, making grading difficult for the neuropathologist. Few series compare tumors in adult vs. pediatric cohorts; we report our 4-year experience. Materials and methods: Text Word database searches using “H3 K27M” in reports generated between January 2013 and November 10, 2017 were used to identify patients. Clinical and histological features as well as survival were evaluated for each case. Results: 28 H3 K27M-mutant tumors were identified, with equal numbers of adults (13) vs. children (15). For adults, mean and median age was 52 years (range = 27 – 81 years), 2 decades older than a recently-published adult series. Tumors involved thalamic (adult = 7; pediatric = 7), spinal cord (adult = 4; pediatric = 2), pons (adult = 1; pediatric = 6), and hypothalamic (n = 1) sites. Other morphologies at presentation included pure GG (n = 3, pediatric) and PA (n = 1, adult). One adult and 1 pediatric patient each presented with leptomeningeal dissemination or developed leptomeningeal dissemination within 1 year after diagnosis, with transformation from PA or GG histology to glioblastoma. Mean survival was 9.3 (adults) vs. 8.9 (pediatric) months. Patients with tumors of other morphologies (GG, PA) did not enjoy extended survival. Conclusion: H3 K27M-mutant tumors can affect patients at advanced ages, may show leptomeningeal dissemination at time of presentation, and “pure” GG or PA morphology is not rare. Regardless of patient age or tumor morphology, patients fare equally poorly.

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“…There are almost no data on the frequency of the ATRX mutation in SCA. A total of two cases have been reported describing such a mutation in grades II and III diffuse astrocytoma of the spinal cord [55, 56]. The summary data of the analysis of the two groups of patents (≤ 20 years and > 20 years) with high-grade spinal cord gliomas indicate an absence of this mutation in the younger group ( n = 5) and its presence in 43% of older patients ( n = 7) [57].…”

Section: Introductionmentioning

confidence: 99%

Molecular Biomarkers of Brain and Spinal Cord Astrocytomas

et al. 2019

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Spinal cord astrocytomas are rare diseases of the central nervous system. The localization of these tumors and their infiltrative growth complicate their surgical resection, increase the risk of postoperative complications, and require more careful use of radio- and chemotherapy. The information on the genetic mutations associated with the onset and development of astrocytomas provides a more accurate neoplasm diagnosis and classification. In some cases, it also allows one to determine the optimal methods for treating the neoplasm, as well as to predict the treatment outcomes and the risks of relapse. To date, a number of molecular markers that are associated with brain astrocytomas and possess prognostic value have been identified and described. Due to the significantly lower incidence of spinal cord astrocytomas, the data on similar markers are much more sparse and are presented with a lesser degree of systematization. However, due to the retrospective studies of clinical material that have been actively conducted abroad in recent years, the formation of statistically significant genetic landscapes for various types of tumors, including intradural spinal cord tumors, has begun. In this regard, the purpose of this review is to analyze and systematize the information on the most significant genetic mutations associated with various types of astrocytomas, as well as discuss the prospects for using the corresponding molecular markers for diagnostic and prognostic purposes.

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Genetics of Glioblastomas in Rare Anatomical Locations: Spinal Cord and Optic Nerve

Cited by 13 publications

References 11 publications

Clinical, radiological and molecular characterization of intramedullary astrocytomas

Clinical, radiological and molecular characterization of intramedullary astrocytomas

H3 K27M-mutant gliomas in adults vs. children share similar histological features and adverse prognosis

Molecular Biomarkers of Brain and Spinal Cord Astrocytomas

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