Intratumoral Heterogeneity of Genomic Imbalance in a Case of Epithelioid Glioblastoma with <scp><i>BRAF</i> V</scp>600<scp>E</scp> Mutation

Nobusawa, Sumihito; Hirato, Junko; Kurihara, Hideyuki; Okura, Naoki; Nagaishi, Masaya; Ikota, Hayato; Yokoo, Hideaki; Nakazato, Yoichi

doi:10.1111/bpa.12114

Cited by 39 publications

(62 citation statements)

References 33 publications

(50 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is not known what mutational event leads to epithelioid formation in high grade gliomas, although a recent, in-depth study of a single case by array comparative genomic hybridization separately performed for epithelioid versus non-epithelioid areas of a GBM hinted at possibly causation [17]. Specifically, Nobusawa et al demonstrated BRAF V600E mutation both in epithelioid tumor cells and in diffusely infiltrating less atypical astrocytoma cells in the same tumor [17].…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, Nobusawa et al demonstrated BRAF V600E mutation both in epithelioid tumor cells and in diffusely infiltrating less atypical astrocytoma cells in the same tumor [17]. In contrast, eight shared copy number alterations (CNAs) and three CNAs were observed only in epithelioid cells; one of the latter was a homozygous deletion of a tumor suppressor gene, LSAMP , at 3q13.31 [17]. Thus the BRAF mutation was not confined to the epithelioid component, even when confined to focal areas within a tumor.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

BRAF VE1 Immunoreactivity Patterns in Epithelioid Glioblastomas Positive for BRAF V600E Mutation

Kleinschmidt‐DeMasters

Aisner²,

Foreman

2015

American Journal of Surgical Pathology

View full text Add to dashboard Cite

Background Epithelioid glioblastomas (E-GBMs) manifest BRAF V600E mutation in up to fifty percent of cases, compared to a small percentage of ordinary GBMs, suggesting they are best considered variants rather than a different pattern of GBM. Availability of a targeted therapy, vemurafenib, may make testing BRAF status important for treatment. It is unclear whether BRAF VE1 immunohistochemistry (IHC) can substitute for Sanger sequencing in these tumors. Design BRAF VE1 IHC was correlated with Sanger sequencing results on our original cohort of E-GBMs, and then new E-GBM cases were tested with both techniques (n=20). Results were compared to those in similarly-assessed giant cell GBMs, anaplastic pleomorphic xanthoastrocytomas (A-PXAs). Results All tumors tested showed 1:1 correlation between BRAF V600E mutational results and IHC. However, heavy background immunostaining in some negatively-mutated cases resulted in equivocal results that required repeat IHC testing and additional mutation testing using a different methodology to confirm lack of detectable BRAF mutation. Mutated/ BRAF VE1 IHC+ E-GBMs and A-PXAs tended to manifest strong, diffuse cytoplasmic immunoreactivity, compared to previously-studied GGs which demonstrate more intense immunoreactivity in the ganglion, than glial, tumor component. One of our E-GBM patients with initial gross total resection quickly recurred within 4 months, required a second resection, and then was placed on vemurafenib; she remains tumor-free 21 months after second resection without neuroimaging evidence of residual disease, adding to the growing number of reports of successful treatment of BRAF-mutated glial tumors with drug. Conclusions E-GBMs show good correlation between mutational status and IHC, albeit with limitations to IHC. E-GBMs can respond to targeted therapy.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

BRAF VE1 Immunoreactivity Patterns in Epithelioid Glioblastomas Positive for BRAF V600E Mutation

Kleinschmidt‐DeMasters

Aisner²,

Foreman

2015

American Journal of Surgical Pathology

View full text Add to dashboard Cite

show abstract

“…Most E‐GBMs are recognized as a primary lesion, although there are a few reports of E‐GBM preceded by low‐grade glioma . E‐GBM cases with coexisting low‐grade glioma have also been reported . In many of these cases, low‐ and high‐grade lesions shared an identical BRAF V600E mutation …”

Section: Introductionmentioning

confidence: 99%

Concurrent TERT promoter and BRAF V600E mutation in epithelioid glioblastoma and concomitant low‐grade astrocytoma

et al. 2016

Self Cite

View full text Add to dashboard Cite

Epithelioid glioblastoma (E-GBM) is a rare variant of glioblastoma (GBM), characterized by epithelioid cells with eosinophilic round cytoplasm devoid of stellate cytoplasmic processes. A number of studies have demonstrated that more than half of E-GBMs harbor a valine to glutamic acid substitution at position 600 of the serine/threonine-protein kinase BRAF (BRAF V600E). However, there are no previous reports on E-GBM with telomerase reverse transcriptase (TERT) promoter mutation in addition to BRAF V600E mutation. Here, we report an E-GBM case in an 18-year-old man with BRAF V600E and TERT promoter mutations. The tumor composed of 80% E-GBM and 20% diffuse astrocytoma-like components, and BRAF V600E and TERT promoter mutations were detected in both. E-GBM generally arises as a primary lesion; however, a few previous cases have been demonstrated to accompany low-grade areas. Demonstration of concurrent BRAF V600E and TERT promoter mutations in low- and high-grade lesions strongly suggested their identical origin, and acquisition of each mutation may be an early event, possibly playing a pivotal role in the genesis and subsequent progression to E-GBM.

show abstract

“…While one study makes a distinction between eGBM and rhabdoid GBM based on the focal loss of INI1 immunoreactivity in rhabdoid areas (9), there is considerable overlap and others use these terms interchangeably (11,17,27). The diagnosis of eGBM is often challenging and only a few small series have been reported in the adult and pediatric populations (2,8,19). Excluding other CNS tumors with epithelioid features is critical and it has been noted that a subset of anaplastic pleomorphic xanthoastrocytomas (PXAs) have similar pathologic features (7,14) and even some overlapping molecular findings (5,8).…”

Section: Introductionmentioning

confidence: 99%

“…A recent case report of an eGBM with BRAF V600E mutation used comparative genomic hybridization (CGH) to identify three copy number alterations located in different morphologic areas; there were three alterations restricted to the epithelioid areas: a homozygous deletion in intron 3 of LSAMP at 3q13, a hemizygous deletion of ODZ3 at 4q34.3-4q35.1 and a hemizygous deletion in LRP1B on chromosome 2 (19). ODZ3 gene was reported as a potent tumor suppressor gene, which has also been implicated in the pathogenesis of lung adenocarcinoma, adrenal carcinoma and neuroblastoma (13,16,18).…”

Section: Introductionmentioning

confidence: 99%

Epithelioid Glioblastomas and Anaplastic Epithelioid Pleomorphic Xanthoastrocytomas—Same Entity or First Cousins?

et al. 2015

View full text Add to dashboard Cite

Epithelioid glioblastoma (eGBM) and pleomorphic xanthoastrocytoma (PXA) with anaplastically transformed foci (ePXA) show overlapping features. Eleven eGBMs and 5 ePXAs were reviewed and studied immunohistochemically. Fluorescence in situ hybridization for EGFR amplification, PTEN deletion and ODZ3 deletion was also performed, with Ilumina 450 methylome analysis obtained in five cases. The average age for eGBM was 30.9 (range 2-79) years, including five pediatric cases and a M : F ratio of 4.5. The ePXA patients had a M : F ratio of 4 and averaged 21.2 (range 10-38) years in age, including two pediatric cases. Six eGBMs and two ePXAs recurred (median recurrence interval of 12 and 3.3 months, respectively). All tumors were composed of solid sheets of loosely cohesive, "melanoma-like" cells with only limited infiltration. ePXAs showed lower grade foci with classic features of PXA. Both tumor types showed focal expression of epithelial and glial markers, retained INI1 and BRG1 expression, occasional CD34 positivity, and lack of mutant IDH1 (R132H) immunoreactivity. BRAF V600E mutation was present in four eGBMs and four ePXAs. ODZ3 deletion was detected in seven eGBMs and two ePXAs. EGFR amplification was absent. Methylome analysis showed that one ePXA and one eGBM clustered with PXAs, one eGBM clustered with low-grade gliomas, and two eGBMs clustered with pediatric-type glioblastomas. Common histologic, immunohistochemical, molecular and clinical features found in eGBM and ePXA suggest that they are closely related or the same entity. If the latter is true, the nomenclature and WHO grading remains to be resolved.

show abstract

Intratumoral Heterogeneity of Genomic Imbalance in a Case of Epithelioid Glioblastoma with BRAF V600E Mutation

Cited by 39 publications

References 33 publications

BRAF VE1 Immunoreactivity Patterns in Epithelioid Glioblastomas Positive for BRAF V600E Mutation

BRAF VE1 Immunoreactivity Patterns in Epithelioid Glioblastomas Positive for BRAF V600E Mutation

Concurrent TERT promoter and BRAF V600E mutation in epithelioid glioblastoma and concomitant low‐grade astrocytoma

Epithelioid Glioblastomas and Anaplastic Epithelioid Pleomorphic Xanthoastrocytomas—Same Entity or First Cousins?

Contact Info

Product

Resources

About