scholarly journals Recurrent copy number alterations in low-grade and anaplastic pleomorphic xanthoastrocytoma with and without BRAF V600E mutation

2017 ◽  
Vol 28 (2) ◽  
pp. 172-182 ◽  
Author(s):  
Rachael A. Vaubel ◽  
Alissa A. Caron ◽  
Seiji Yamada ◽  
Paul A. Decker ◽  
Jeanette E. Eckel Passow ◽  
...  
Keyword(s):  
Copy Number ◽  
Pleomorphic Xanthoastrocytoma ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Low Grade ◽  
Copy Number Alterations

Polymorphous Low-Grade Neuroepithelial Tumor of the Young (PLNTY): Molecular Profiling Confirms Frequent MAPK Pathway Activation

2021 ◽  
Author(s):  
Cristiane M Ida ◽  
Derek R Johnson ◽  
Asha A Nair ◽  
Jaime Davila ◽  
Thomas M Kollmeyer ◽  
...  
Keyword(s):  
Copy Number ◽  
Mapk Pathway ◽  
Braf V600e Mutation ◽  
Mitogen Activated Protein Kinase ◽  
Braf V600e ◽  
Low Grade ◽  
Pathway Activation ◽  
Mitogen Activated Protein ◽  
Copy Number Changes ◽  
Cd34 Expression

Abstract Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently described epileptogenic tumor characterized by oligodendroglioma-like components, aberrant CD34 expression, and frequent mitogen-activated protein kinase (MAPK) pathway activation. We molecularly profiled 13 cases with diagnostic histopathological features of PLNTY (10 female; median age, 16 years; range, 5–52). Patients frequently presented with seizures (9 of 12 with available history) and temporal lobe tumors (9 of 13). MAPK pathway activating alterations were identified in all 13 cases. Fusions were present in the 7 youngest patients: FGFR2-CTNNA3 (n = 2), FGFR2-KIAA1598 (FGFR2-SHTN1) (n = 1), FGFR2-INA (n = 1), FGFR2-MPRIP (n = 1), QKI-NTRK2 (n = 1), and KIAA1549-BRAF (n = 1). BRAF V600E mutation was present in 6 patients (17 years or older). Two fusion-positive cases additionally harbored TP53/RB1 abnormalities suggesting biallelic inactivation. Copy number changes predominantly involving whole chromosomes were observed in all 10 evaluated cases, with losses of chromosome 10q occurring with FGFR2-KIAA1598 (SHTN1)/CTNNA3 fusions. The KIAA1549-BRAF and QKI-NTRK2 fusions were associated respectively with a 7q34 deletion and 9q21 duplication. This study shows that despite its name, PLNTY also occurs in older adults, who frequently show BRAF V600E mutation. It also expands the spectrum of the MAPK pathway activating alterations associated with PLNTY and demonstrates recurrent chromosomal copy number changes consistent with chromosomal instability.

scholarly journals Rapid, Robust and Accessible Molecular Profiling of Biologically and Clinically Relevant Copy Number Alterations in Multiple Myeloma from Small Amounts of Tumor DNA

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5168-5168
Author(s):  
Martin F Kaiser ◽  
Paula Proszek ◽  
Dil Begum ◽  
Nasrin Dahir ◽  
Brian A Walker ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Copy Number ◽  
Mutant Allele ◽  
Molecular Profiling ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Copy Number Alterations ◽  
Allele Ratio ◽  
Input Material ◽  
Tumor Dna

Abstract Background Structural aberrations like copy number alterations (CNA) and translocations play a central role in multiple myeloma tumor biology. The analysis of CNA for complete molecular profiling of myeloma retains clinical significance in the context of recent next-generation sequencing (NGS) results which highlight the highly heterogeneous landscape of single nucleotide mutations, which are often sub-clonal. Detection of CNAs remains the domain of array-based technologies, as demonstrated by the use of copy number arrays by the TCGA consortium and others for CNA detection in NGS projects. High cost and infrastructure attached to CNA analysis by array limit access to this technology in many molecular diagnostic laboratories. We present here a robust and accessible method that combines two multiplex ligation-dependent probe amplification (MLPA) assays for the relevant CNAs in myeloma using low input amounts of purified tumor DNA. Methods Bone marrow myeloma cells from patients at presentation and at relapse from the Myeloma IX and Myeloma XI trials were purified to >95% purity by immunomagnetic separation (Miltenyi Biotech) and DNA was extracted using AllPrep columns (QIAGEN) for analysis by MLPA. A novel myeloma specific probemix was designed and technically validated by MRC-Holland (Amsterdam, The Netherlands), complementing the established myeloma specific probemix P425 (Alpar et al., Gen Chrom Cancer 2013). Results In total 130 purified myeloma cell DNA samples were successfully analyzed by MLPA, interrogating 43 different loci in the following regions: 6p22 - 6p12 [incl. CDKN1A]; 6q12 - 6q26 [incl. TNFAIP3, WTAP, PARK2]; 8p23 – 8p11 [incl. TNFRSF10A/B]; 8q12 – 8q24 [incl. MYC]; 11q13 – 11q25 [incl. CCND1, BIRC2, BIRC3]; 17p [all exons of TP53]; 22q11 – 22q13 [incl. HIRA, EP300]. The assay contains one probe for the detection of BRAF V600E, including determination of mutant allele ratio. This probemix complements another MLPA assay [P425] which interrogates prognostically and biologically relevant regions such as 1p32, 1q21-1q23, 13q14, 16q12-16q23, 17p13 and chr 5, 9 and 15 for detection of hyperdiploidy (HRD). The assay returned good quality results using as little as 25 ng DNA input material without modification of assay conditions. In this group of cases which were enriched with cases known to carry specific CNAs and mutations, frequent copy number aberrations encompassed loss of chr(6q), in the majority of cases (16%) affecting all genes investigated in the region 6q23 – 6q26. In addition, five cases (4%) with an isolated heterozygous deletion of TNFAIP3 at 6q23 and two cases with deletion of TNFAIP3 and WTAP were detected. Gains of MYC at 8q24 were observed in 13 cases (10%) of which 5 showed gains of other regions on 8q as well. BIRC3 and BIRC2 were both lost in 4 cases, including 1 homozygous deletion of both genes. All coding exons of TP53 were heterozygously deleted in 16% of cases in this group containing specifically selected relapsed cases. Gain of chromosome 11 was frequent (29%) and mostly associated with HRD, but gain(11q) without HRD was observed, including 3 cases with isolated gain of the CCND1locus at 11q13.3. Of 11 cases with a known BRAF V600E mutation identified by SSCA, 10 (91%) were detected by MLPA with the remaining mutation showing a signal just above detection limit by SSCA. Calculated median V600E mutant allele ratio in comparison to an artificial plasmid mix mimicking a heterozygous mutation was 39% (range 9%-77%), confirming our previous observation that this mutation is mostly heterozygous and sub-clonal in myeloma. Further cases at presentation from the Myeloma XI trial are currently being analyzed by MLPA and results will be presented at the meeting, including a comparison with matched CNA array data for a selection of cases as well as correlation with clinical data for trial cases. Discussion The combination of this panel with another MLPA probemix [P425], which has been extensively validated in over 1200 myeloma cases by our group, allows assaying of biologically and clinically relevant CNAs in myeloma as well as BRAF V600E mutation status. The tests can be run on standard laboratory equipment and require 25 ng of DNA as input material, making this method suitable for exploring the clinical impact of myeloma specific CNAs in large clinical trials with a potential of transferring the method to the routine diagnostic setting. Disclosures Walker: Onyx: Consultancy. Savola:MRC-Holland: Employment.

scholarly journals LGG-23. EXCELLENT CLINICAL / RADIOLOGICAL RESPONSE TO BRAF INHIBITION IN A YOUNG CHILD WITH IN-OPERABLE SUPRA-SELLAR PILOCYTIC ASTROCYTOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii370-iii371
Author(s):  
Stacy Chapman ◽  
Demitre Serletis ◽  
Colin Kazina ◽  
Mubeen Rafay ◽  
Sherry Krawitz ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Pilocytic Astrocytoma ◽  
Clinical Symptoms ◽  
Obstructive Hydrocephalus ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Low Grade ◽  
Dramatic Improvement ◽  
Chemotherapeutic Regimen ◽  
Response To Chemotherapy

Abstract In-operable low grade gliomas (LGG) in the pediatric population continue to present a treatment dilemma. Due to the low-grade nature of these tumors, and variable response to chemotherapy / radiation, the choice of adjuvant treatment is difficult. Overall survival is directly related to the degree of surgical resection, adding complexity to these inoperable tumors. Current chemotherapeutic regimen for these inoperable tumors includes vincristine (VCR) and carboplatin (Carbo). With advancements in the molecular characterization of gliomas, the role of targeted therapy has come into question. We present a 2-year-old female with biopsy proven Pilocytic Astrocytoma (positive BRAF-V600E mutation) involving the hypothalamic/optic chiasm region. She presented with ataxic gait, bi-temporal hemianopia, obstructive hydrocephalus and central hypothyroidism, which progressed to altered consciousness, and right hemiparesis due to location/mass effect of the tumor. She was initially treated with chemotherapy (VCR/Carbo) but her tumor progressed at 6 weeks of treatment. As her tumor was positive for BRAF-V600E mutation, she was started on Dabrafenib monotherapy, resulting in dramatic improvement in her clinical symptoms (able to stand, improved vision), and a 60% reduction in tumor size at 3-months. At 6-months, follow up MRI showed slight increase in the solid portion of the tumor, with no clinical symptoms. We plan to add MEK inhibitor (Trametinib) and continue with Dabrafenib. Our experience and literature review suggests that LGG with BRAF-V600E mutations may benefit from upfront targeted therapy. Prospective clinical trials comparing the efficacy of BRAF inhibitors versus standard chemotherapy in LGG with BRAF mutations are urgently needed.

scholarly journals HGG-02. ADOLESCENT AND YOUNG ADULT (AYA) GLIOMA WITH BRAF V600E-MUTANTATION

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii344-iii344
Author(s):  
Yui Kimura ◽  
Yukitomo Ishi ◽  
Yuko Watanabe ◽  
Yoshiko Nakano ◽  
Shigeru Yamaguchi ◽  
...  
Keyword(s):  
Braf Inhibitor ◽  
Clinical Information ◽  
Early Recurrence ◽  
Pleomorphic Xanthoastrocytoma ◽  
Adolescent And Young Adult ◽  
Braf V600e ◽  
Low Grade ◽  
Diffuse Astrocytoma ◽  
Genetic Features ◽  
Epithelioid Glioblastoma

Abstract BACKGROUND Biological features of pediatric glioma differ significantly from those of adult glioma, and limited data are available on those of AYA patients. Here, we focused on AYA patients with glioma, especially those harboring BRAF V600E mutation, and investigated their clinical and genetic features. METHOD: We retrospectively analyzed AYA patients with brain tumors harboring BRAF V600E, who were treated in two hospitals in Japan. RESULTS Clinical information was available for 14 patients. The median age at diagnosis was 25 years (range: 15–38). Five patients were diagnosed with glioblastoma (GBM), including one epithelioid type. These patients were over 25. Although one patient with GBM died of the disease 6.9 years after initial diagnosis, the remaining patients were alive. Two patients were alive without recurrence at 38 and 51 months after the treatment. The patient with epithelioid glioblastoma experienced early recurrence. The remaining nine patients (64%) were diagnosed with low-grade glioma, including ganglioglioma, pilocytic astrocytoma, diffuse astrocytoma, oligodendroglioma, pleomorphic xanthoastrocytoma, and polymorphous low-grade neuroepithelial tumor of the young. No patients died of the disease, and four patients are alive without recurrence after initial operation without adjuvant treatment. Two patients are (epithelioid glioblastoma and ganglioglioma) currently undergoing treatment with a BRAF inhibitor for recurrent tumors. DISCUSSION Although the number of this study is limited, our study suggested that the prognosis of AYA patients with BRAF-V600E positive GBM may not be as dismal as that of children or adults.

scholarly journals MPTH-40. COPY NUMBER ALTERATIONS IN PLEOMORPHIC XANTHOASTROCYTOMA AND ANAPLASTIC PLEOMORPHIC XANTHOASTROCYTOMA: CHARACTERIZATION OF 40 CASES BY SNP ARRAY

2016 ◽  
Vol 18 (suppl_6) ◽  
pp. vi114-vi115
Author(s):  
Rachael Vaubel ◽  
Alissa Caron ◽  
Paul Decker ◽  
Seiji Yamada ◽  
Jeanette Eckel-Passow ◽  
...  
Keyword(s):  
Copy Number ◽  
Snp Array ◽  
Pleomorphic Xanthoastrocytoma ◽  
Copy Number Alterations

scholarly journals Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant IDH1

2017 ◽  
Vol 114 (40) ◽  
pp. 10743-10748 ◽  
Author(s):  
Tali Mazor ◽  
Charles Chesnelong ◽  
Aleksandr Pankov ◽  
Llewellyn E. Jalbert ◽  
Chibo Hong ◽  
...  
Keyword(s):  
Copy Number ◽  
Cpg Island ◽  
Clonal Expansion ◽  
Low Grade ◽  
Copy Number Alterations ◽  
Wild Type ◽  
Mutant Idh1

IDH1 mutation is the earliest genetic alteration in low-grade gliomas (LGGs), but its role in tumor recurrence is unclear. Mutant IDH1 drives overproduction of the oncometabolite d-2-hydroxyglutarate (2HG) and a CpG island (CGI) hypermethylation phenotype (G-CIMP). To investigate the role of mutant IDH1 at recurrence, we performed a longitudinal analysis of 50 IDH1 mutant LGGs. We discovered six cases with copy number alterations (CNAs) at the IDH1 locus at recurrence. Deletion or amplification of IDH1 was followed by clonal expansion and recurrence at a higher grade. Successful cultures derived from IDH1 mutant, but not IDH1 wild type, gliomas systematically deleted IDH1 in vitro and in vivo, further suggestive of selection against the heterozygous mutant state as tumors progress. Tumors and cultures with IDH1 CNA had decreased 2HG, maintenance of G-CIMP, and DNA methylation reprogramming outside CGI. Thus, while IDH1 mutation initiates gliomagenesis, in some patients mutant IDH1 and 2HG are not required for later clonal expansions.

scholarly journals Genome-Wide Somatic Copy Number Alterations in Low-Grade PanINs and IPMNs from Individuals with a Family History of Pancreatic Cancer

2012 ◽  
Vol 18 (16) ◽  
pp. 4303-4312 ◽  
Author(s):  
Seung-Mo Hong ◽  
Audrey Vincent ◽  
Mitsuro Kanda ◽  
Julie Leclerc ◽  
Noriyuki Omura ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Family History ◽  
Copy Number ◽  
Low Grade ◽  
Copy Number Alterations ◽  
Genome Wide ◽  
History Of ◽  
Somatic Copy Number Alterations

Use of DNA copy number analysis of grade 2-4 gliomas to reveal differences in molecular ontogeny associated with IDH mutation status.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2026-2026
Author(s):  
Mariko Sato ◽  
Kenneth D. Aldape ◽  
Clinton C Mason ◽  
Kristin Diefes ◽  
Lindsey Heathcock ◽  
...  
Keyword(s):  
Copy Number ◽  
Genetic Alterations ◽  
Idh1 Mutation ◽  
Low Grade ◽  
Copy Number Alterations ◽  
Copy Number Analysis ◽  
Mutation Status ◽  
Younger Age ◽  
Ffpe Samples ◽  
Molecular Inversion Probes

2026 Background: The genetic alterations of glioma have been studied extensively. IDH1 mutation is associated with younger age and better survival. However, differences in molecular ontogeny within glioma related to IDH1 mutation remain unknown. Here we describe a detailed analysis of copy number alterations (CNA) between IDH1mut vs IDH1wt gliomas of grade 2-3 and 4. Methods: CNA were detected by molecular inversion probes (Affymetrix) and analyzed with Nexus Copy Number Software (BioDiscovery). DNA was extracted from 94 patient FFPE samples including grade 2-3: IDH1wt (n = 17) and IDH1mut (n = 28), and grade IV: IDH1wt ( n = 25) and IDH1mut(n = 24). Chromothripsis was detected using a stringent criteria of at least ten switches of CNA in individual chromosomes. Results: We validated prior findings that IDH1wt GBM have higher frequency of Chr7 amplification (including EGFR) and loss of Chr10 (including PTEN). Other CNA across all grades were: gain of 19q12 and loss of 14q11 in IDH1wt, and gain of 11q21, 10p11, 8q21 and loss of 11p15, 19q13 in IDH1mut. Within grade 2-3 samples, few CNA were associated with mutation status: 2-3wt demonstrated higher frequencies of gain of 7q and loss of 10q, 14q11, and 22q13, while 2-3mut demonstrated higher frequencies of 11q21 gain and 19q13 loss. Grade 4 tumors demonstrated more CNA that differed by mutation status, with 4wt tumors demonstrating gain of 7 and loss of 10 and 14q11, while 4mut demonstrated gains of 8q, 10p, 12p13, 1q23, and loss of 11p15, 3p, 19q13, among others. Comparison of grade 2-3mut vs grade 4mut tumors demonstrated larger number of CNA in the grade 4mut tumors including gain of 1p, 14q, 13q33, 9p, 8q and loss of 22q, 11p15, 10q, and 3p, among others. A significantly higher incidence of chromothripsis events was observed in grade 4mut compared to grade 4wt (p = 0.0374). Conclusions: CNA analysis showed significant differences in molecular ontogeny between IDH1wt and IDH1mut, some of which may further elucidate pathogenesis. Significant CNA increases and increased chromthripsis in grade 4mut support malignant transformation of low grade gliomas through accumulation of genomic instability and genomic catastrophe.

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