BRAF activating mutations involving the β3-αC loop in V600E-negative anaplastic pleomorphic xanthoastrocytoma.
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ABSTRACT:
SUBMITTER: Pratt D
PROVIDER: S-EPMC5855983 | biostudies-literature | 2018 Mar
REPOSITORIES: biostudies-literature
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BRAF activating mutations involving the β3-αC loop in V600E-negative anaplastic pleomorphic xanthoastrocytoma.
Pratt Drew D Camelo-Piragua Sandra S McFadden Kathryn K Leung Denise D Mody Rajen R Chinnaiyan Arul A Koschmann Carl C Venneti Sriram S
Acta neuropathologica communications 20180315 1
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Project description:Pleomorphic xanthoastrocytoma (PXA) is a rare localized glioma characterized by frequent BRAF V600E mutation and CDKN2A/B deletion. We explored the association of copy-number variants (CNVs) with BRAF mutations, tumor grade, and patient survival in a cohort of 41 PXA patients using OncoScan chromosomal microarray. Primary resection specimens were available in 38 cases, including 24 PXA and 14 anaplastic PXA (A-PXA), 23 BRAF V600E mutant tumors (61%). CNVs were identified in all cases and most frequently involved chromosome 9 with homozygous CDKN2A/B deletion (n = 33, 87%), a higher proportion than previously detected by comparative genomic hybridization (50%-60%) (37). CDKN2A/B deletion was present in similar proportion of PXA (83%), A-PXA (93%), BRAF V600E (87%), and wild-type (87%) tumors. Whole chromosome gains/losses were frequent, including gains +7 (n = 15), +2 (n = 11), +5 (n = 10), +21 (n = 10), +20 (n = 9), +12 (n = 8), +15 (n = 8), and losses -22 (n = 11), -14 (n = 7), -13 (n = 5). Losses and copy-neutral loss of heterozygosity were significantly more common in A-PXA, involving chromosomes 22 (P = 0.009) and 14 (P = 0.03). Amplification of 8p and 12q was identified in a single tumor. Histologic grade was a robust predictor of overall survival (P = 0.003), while other copy-number changes, including CDKN2A/B deletion, did not show significant association with survival. Distinct histologic patterns of anaplasia included increased mitotic activity in an otherwise classic PXA or associated with small cell, fibrillary, or epithelioid morphology, with loss of SMARCB1 expression in one case. In 10 cases, matched specimens were compared, including A-PXA with areas of distinct low- and high-grade morphology (n = 2), matched primary/tumor recurrence (n = 7), or both (n = 1). Copy-number changes on recurrence/anaplastic transformation were complex and highly variable, from nearly identical profiles to numerous copy-number changes. Overall, we confirm CDKN2A/B deletion as key a feature of PXA not associated with tumor grade or BRAF mutation, but central to the underlying genetics of PXA.
| S-EPMC5807227 | biostudies-literature
Project description:BackgroundHigh frequencies of the BRAF V600E mutation have been reported in pleomorphic xanthoastrocytoma (PXA). Recently, a BRAF V600E mutation-specific antibody has been developed and validated. We evaluated the immunohistochemical (IHC) detection of BRAF V600E mutation in PXA by comparing to gold standard molecular analysis and investigating the interobserver variability of the IHC scoring. We performed BRAF V600E IHC in 46 cases, of which 37 (80%) cases had sufficient tumor tissue for molecular analysis. IHC detection was performed using monoclonal mouse antibody VE1 (Spring Bioscience). IHC slides were scored independently by four reviewers blind to molecular data, including a primary (gold standard) and three additional reviewers. BRAF V600E mutation status was assessed by allele-specific polymerase chain reaction (PCR) with fragment analysis.ResultsAll 46 cases showed interpretable BRAF V600E IHC results: 27 (59%) were positive (strong cytoplasmic staining), 19 (41%) were negative (6 of these cases with focal/diffuse weak cytoplasmic staining, interpreted as nonspecific by the primary reviewer). By molecular analysis, all 37 cases that could be tested had evaluable results: 22 (59%) cases were positive for BRAF V600E mutation and were scored as "IHC-positive", and 15 (41%) were negative (including 11 cases scored as "IHC-negative" and 4 cases scored as negative with minimal nonspecific staining). IHC detection of BRAF V600E mutant protein was congruent in all 37 cases that were successfully evaluated by molecular testing (sensitivity and specificity of 100%). Agreement for IHC scoring among the 4 reviewers was almost perfect (kappa 0.92) when cases were scored as "positive/negative" and substantial (kappa 0.78) when minimal nonspecific staining was taken into account.ConclusionsWe conclude that detection of BRAF V600E mutation by immunohistochemistry is highly sensitive and specific. BRAF V600E IHC interpretation is usually straightforward, but awareness of possible nonspecific staining is necessary and training is recommended. It is a practical rapid method that may avoid the need of labor-intensive molecular testing and may be most valuable in small biopsies unsuitable for molecular analysis.
| S-EPMC3893490 | biostudies-literature
Project description:Pleomorphic xanthoastrocytoma (PXA) is an astrocytic neoplasm that is typically well circumscribed and can have a relatively favorable prognosis. Tumor progression to anaplastic PXA (WHO grade III), however, is associated with a more aggressive biologic behavior and worse prognosis. The factors that drive anaplastic progression are largely unknown. We performed comprehensive genomic profiling on a set of 23 PXAs from 19 patients, including 15 with anaplastic PXA. Four patients had tumor tissue from multiple recurrences, including two with anaplastic progression. We find that PXAs are genetically defined by the combination of CDKN2A biallelic inactivation and RAF alterations that were present in all 19 cases, most commonly as CDKN2A homozygous deletion and BRAF p.V600E mutation but also occasionally BRAF or RAF1 fusions or other rearrangements. The third most commonly altered gene in anaplastic PXA was TERT, with 47% (7/15) harboring TERT alterations, either gene amplification (n = 2) or promoter hotspot mutation (n = 5). In tumor pairs analyzed before and after anaplastic progression, two had increased copy number alterations and one had TERT promoter mutation at recurrence. Less commonly altered genes included TP53, BCOR, BCORL1, ARID1A, ATRX, PTEN, and BCL6. All PXA in this cohort were IDH and histone H3 wildtype, and did not contain alterations in EGFR. Genetic profiling performed on six regions from the same tumor identified intratumoral genomic heterogeneity, likely reflecting clonal evolution during tumor progression. Overall, anaplastic PXA is characterized by the combination of CDKN2A biallelic inactivation and oncogenic RAF kinase signaling as well as a relatively small number of additional genetic alterations, with the most common being TERT amplification or promoter mutation. These data define a distinct molecular profile for PXA and suggest additional genetic alterations, including TERT, may be associated with anaplastic progression.
| S-EPMC7837273 | biostudies-literature
Project description:Giant Cell Glioblastoma (gcGBM) and Pleomorphic Xanthoastrocytoma (PXA) are rare astroglial tumors of the central nervous system. Although they share certain histomorphological and immunohistochemical features, they are characterized by different clinical behavior and prognosis. Nevertheless, few cases remain uncertain, as their histomorphological hallmarks and immunophenotypes do correspond to the typical pattern neither of gcGBM nor PXA. Therefore, in addition to the routinely used diagnostic histochemical and immunohistochemical markers like Gömöri, p53 and CD34, we analyzed if genetic variations like MGMT promoter methylation, mutations in the IDH1/2 genes, or BRAF mutations, which are actually used as diagnostic, prognostic and predictive molecular markers in anaplastic glial tumors, could be helpful in the differential diagnostic of both tumor entities. We analyzed 34 gcGBM and 20 PXA for genetic variations in the above-named genes and found distinct distributions between both groups. MGMT promoter hypermethylation was observed in 3 out of 20 PXA compared to 14 out of 34 gcGBM (15% vs. 41.2%, p-value 0.09). BRAF V600E mutations were detected in 50% of the PXA but not in any of the gcGBM (50% vs. 0%, p-value < 0.001). IDH1 R132 and IDH R172 mutations were not present in any of the PXA and gcGBM cases. Our data indicate, that in addition to the histological and immunohistochemical evaluation, investigation of MGMT promoter methylation and in particular BRAF V600E mutations represent reliable additional tools to sustain differentiation of gcGBM from PXA on a molecular basis. Based on these data specific BRAF kinase inhibitors could represent a promising agent in the therapy of PXA and their use should be emphasized.
| S-EPMC4890800 | biostudies-literature
Project description:BackgroundPleomorphic xanthoastrocytoma (PXA) is a rare WHO grade II tumor accounting for less than 1% of all astrocytomas. Malignant transformation into PXA with anaplastic features, is unusual and correlates with poorer outcome of the patients.MethodsUsing a DNA methylation custom array, we have quantified the DNA methylation level on the promoter sequence of 807 cancer-related genes of WHO grade II (n = 11) and III PXA (n = 2) and compared to normal brain tissue (n = 10) and glioblastoma (n = 87) samples. DNA methylation levels were further confirmed on independent samples by pyrosequencing of the promoter sequences.ResultsIncreasing DNA promoter hypermethylation events were observed in anaplastic PXA as compared with grade II samples. We further validated differential hypermethylation of CD81, HCK, HOXA5, ASCL2 and TES on anaplastic PXA and grade II tumors. Moreover, these epigenetic alterations overlap those described in glioblastoma patients, suggesting common mechanisms of tumorigenesis.ConclusionsEven taking into consideration the small size of our patient populations, our data strongly suggest that epigenome-wide profiling of PXA is a valuable tool to identify methylated genes, which may play a role in the malignant progression of PXA. These methylation alterations may provide useful biomarkers for decision-making in those patients with low-grade PXA displaying a high risk of malignant transformation.
| S-EPMC4000050 | biostudies-literature
Project description:Backgroundβ3-αC loop is a highly conserved structural domain across oncogene families, which is a switch for kinase activity. There have been numerous researches on mutations within β3-αC loop in EGFR, but relatively less in ERBB2, BRAF, and MAP2K1. In addition, previous studies mainly focus on β3-αC deletion in EGFR, which is the most common type affecting kinase activity and driving lung cancer. Other mutation types are not well studied.MethodsHere we analyzed the profile of β3-αC loop mutations in a total of 10,000 tumor biopsy and/or ctDNA patient samples using hybridization capture-based next-generation sequencing.ResultsWe identified 1616 mutations within β3-αC loop in this cohort. Most mutations were located in EGFR, with less percentage in ERBB2, BRAF, and MAP2K1. EGFR β3-αC deletions occurred at a high percentage of 96.7% and were all drug-relevant. We also detected rare EGFR β3-αC insertions and point mutations, most of which were related to EGFR TKIs resistance. ERBB2 β3-αC deletions were only found in breast cancers and sensitive to EGFR/ERBB2 inhibitor. Moreover, BRAF and MAP2K1 mutations within β3-αC loop also demonstrated drugs relevance.ConclusionOur study showed that oncogenic mutations within the β3-αC loop of ERBB2, MAP2K1, and BRAF are analogous to that of EGFR, which have profound effect on drug response. Understanding the mutation profile within the β3-αC loop is critical for targeted therapies.
| S-EPMC7549570 | biostudies-literature
Project description:Pleomorphic xanthoastrocytoma (PXA) is a World Health Organization (WHO) Grade II glioma occurring primarily in children and young adults. Most PXAs harbor the known activating mutation BRAF V600E. We report a case of locally recurrent PXA with anaplastic features in a 10-yr-old female. The PXA was negative by immunohistochemical (IHC) staining for BRAF V600E mutation. Whole-exome and transcriptome sequencing of the tumor confirmed the absence of BRAF V600E, but identified copy-number alterations (including loss of the tumor suppressor CDKN2A) and a novel TMEM106B-BRAF fusion. Based on similar BRAF fusion proteins, this novel fusion is predicted to result in activation of BRAF signaling. Demonstration of positive IHC for phospho-ERK1/2 and phospho-MEK1/2 supported this prediction, and implicated MEK inhibitors as a potential therapeutic strategy.
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