Detection of BRAF V600E mutation by immunohistochemistry and PCR-RFLP in Moroccan patients with Pediatric Low-Grade Gliomas

The main pathogenetic mechanism of the development of pediatric low grade gliomas (pLGGs) is genetic aberrations in BRAF gene. This study is supported by the Independent Ethics Committee and approved by the Academic Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology. We analyzed the clinical and molecular characteristics of 69 patients with LGGs. Molecular genetic testing for BRAF V600E mutation was performed by allele-specific real-time PCR and Sanger sequencing. BRAF V600E mutation was detected in 15 (21.7%) patients with LGG. The majority of BRAF-mutated cases of LGGs had the midline location: OPG – 7, subcortical ganglia – 1, brainstem – 2. The 2-year PFS was much worse in patients with BRAF V600E compared to patients without this mutation – 30% and 66.2%, respectively. The median time to progression for patients with BRAF V600E mutation was 9.5 months compared to 3.1 years for patients without indicated substitution. 5 patients with BRAF V600E-mutated LGGs who experienced progression after the conventional treatment, received targeted therapy (BRAF-inhibitor-3, BRAF + MEK inhibitors – 2) with good response (complete response – 2, partial response – 3). BRAF V600E mutation contributes to poor outcome in patients with LGGs Targeted therapy could be effective in this cohort of patients.

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LG-46INFERIOR OUTCOME AND POOR RESPONSE TO CONVENTIONAL THERAPIES IN PEDIATRIC LOW-GRADE GLIOMAS HARBORING THE BRAF V600E MUTATION

Neuro-Oncology ◽

10.1093/neuonc/now075.46 ◽

2016 ◽

Vol 18 (suppl 3) ◽

pp. iii89.1-iii89

Author(s):

Alvaro Lassaletta ◽

Matthew Mistry ◽

Anthony Arnaldo ◽

Scott Ryall ◽

Ana Guerreiro-Stucklin ◽

...

Keyword(s):

Poor Response ◽

Braf V600e Mutation ◽

Braf V600e ◽

Low Grade ◽

Low Grade Gliomas

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

Neuro-Oncology ◽

10.1093/neuonc/noaa222.405 ◽

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.

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Molecular Alterations in Pediatric Low-Grade Gliomas That Led to Death

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlab097 ◽

2021 ◽

Author(s):

Jared T Ahrendsen ◽

Claire Sinai ◽

David M Meredith ◽

Seth W Malinowski ◽

Tabitha M Cooney ◽

...

Keyword(s):

Braf V600e ◽

Molecular Characteristics ◽

Low Grade ◽

Diffuse Astrocytoma ◽

Term Survival ◽

Pten Loss ◽

Low Grade Gliomas ◽

Molecular Alterations ◽

Idh1 R132h ◽

Poor Outcomes

Abstract Pediatric low-grade gliomas (PLGGs) have excellent long-term survival, but death can occasionally occur. We reviewed all PLGG-related deaths between 1975 and 2019 at our institution: 48 patients were identified; clinical data and histology were reviewed; targeted exome sequencing was performed on available material. The median age at diagnosis was 5.2 years (0.4–23.4 years), at death was 13.0 years (1.9–43.2 years), and the overall survival was 7.2 years (0.0–33.3 years). Tumors were located throughout CNS, but predominantly in the diencephalon. Diagnoses included low-grade glioma, not otherwise specified (n = 25), pilocytic astrocytoma (n = 15), diffuse astrocytoma (n = 3), ganglioglioma (n = 3), and pilomyxoid astrocytoma (n = 2). Recurrence occurred in 42/48 cases, whereas progression occurred in 10. The cause of death was direct tumor involvement in 31/48 cases. Recurrent drivers included KIAA1549-BRAF (n = 13), BRAF(V600E) (n = 3), NF1 mutation (n = 3), EGFR mutation (n = 3), and FGFR1-TACC1 fusion (n = 2). Single cases were identified with IDH1(R132H), FGFR1(K656E), FGFR1 ITD, FGFR3 gain, PDGFRA amplification, and mismatch repair alteration. CDKN2A/B, CDKN2C, and PTEN loss was recurrent. Patients who received only chemotherapy had worse survival compared with patients who received radiation and chemotherapy. This study demonstrates that PLGG that led to death have diverse molecular characteristics. Location and co-occurring molecular alterations with malignant potential can predict poor outcomes.

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

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlab075 ◽

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.

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Therapeutic and Prognostic Implications of BRAF V600E in Pediatric Low-Grade Gliomas

Journal of Clinical Oncology ◽

10.1200/jco.2016.71.8726 ◽

2017 ◽

Vol 35 (25) ◽

pp. 2934-2941 ◽

Cited By ~ 106

Author(s):

Alvaro Lassaletta ◽

Michal Zapotocky ◽

Matthew Mistry ◽

Vijay Ramaswamy ◽

Marion Honnorat ◽

...

Keyword(s):

Quantitative Imaging ◽

Progression Free Survival ◽

Extent Of Resection ◽

Braf V600e ◽

Low Grade ◽

Low Grade Gliomas ◽

Molecular Stratification ◽

Treatment Data ◽

Poor Outcomes ◽

Independent Cohort

Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180). Results BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively ( P < .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. Conclusion BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy.

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BRAF G469A, BRAF L597V, FGFR1 N546K, FGFR1 K656E and P53 R273H mutations: How are they distributed in Moroccan patients with pediatric Low-Grade Gliomas?

Gene Reports ◽

10.1016/j.genrep.2020.100885 ◽

2020 ◽

Vol 21 ◽

pp. 100885

Author(s):

S. Hennani ◽

H. Dehbi ◽

S. Nadifi ◽

M. Karkouri

Keyword(s):

Low Grade ◽

Low Grade Gliomas ◽

Moroccan Patients

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A phase II prospective study of selumetinib in children with recurrent or refractory low-grade glioma (LGG): A Pediatric Brain Tumor Consortium (PBTC) study.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.10504 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 10504-10504 ◽

Cited By ~ 7

Author(s):

Jason R. Fangusaro ◽

Arzu Onar-Thomas ◽

Tina Young-Poussaint ◽

Shengjie Wu ◽

Azra H Ligon ◽

...

Keyword(s):

Phase Ii ◽

Pediatric Brain Tumor ◽

Braf V600e Mutation ◽

Low Grade Glioma ◽

Braf V600e ◽

Low Grade ◽

Optic Pathway ◽

Grade 3 ◽

Molecular Aberrations

10504 Background: A greater understanding of the Ras-MAP kinase-signaling pathway in pediatric low-grade glioma (LGG) paired with the availability of potent selective inhibitors has enhanced the ability to target this pathway with therapeutic intent. Methods: The PBTC conducted a multi-institutional phase II study (NCT01089101) evaluating selumetinib (AZD6244, ARRY-142886), a MEK I/II inhibitor, in children with recurrent/refractory LGG assigned to 6 strata and treated at 25 mg/m2/dose PO BID for up to two years. Here we present the data from three of these strata. The remaining strata are still accruing patients. Results: Stratum I included children with non-NF-1 and non-optic pathway recurrent/refractory pilocytic astrocytoma (PA) harboring BRAF aberrations (BRAF V600e mutation or the BRAF-KIAA 1549 fusion). Eight of 25 (32%) patients achieved a partial response (PR) with 2-year PFS of 66+/-11%. Two of 7 (29%) patient tumors with a BRAF V600e mutation and 6/18 (33%) with a BRAF KIAA-1549 fusion had a PR. Stratum 3 enrolled NF-1-associated LGG. Tissue for tumor BRAF evaluation was not required for eligibility. Ten of 25 (40%) achieved PR with a 2-year PFS of 96+/-4%. Only one patient progressed while on treatment. Stratum 4 included children with non-NF-1 optic pathway/hypothalamic LGG. Tissue for tumor BRAF evaluation was not required for eligibility. Two of 16 (12.5%) had a PR with a 2-year PFS of 65+/-13%. The BRAF aberration status of the responders in strata 3 and 4 is mostly unknown. All responses were confirmed centrally and seven patients remain on treatment. The most common toxicities were grade 1/2 CPK elevation, diarrhea, hypoalbuminemia, elevated AST and rash. Rare grade 3/4 toxicities included elevated CPK, rash, neutropenia, emesis and paronychia. Conclusions: Selumetinib was effective in treating children with recurrent/refractory LGG, including those with NF-1 associated LGG and PA harboring BRAF V600e mutation or BRAF-KIAA 1549 fusion. Larger prospective studies are necessary to determine the future, specific role of this agent in treating children with LGG harboring specific molecular aberrations. Clinical trial information: NCT01089101.

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