Genome sequencing identifies somatic BRAF duplication c.1794_1796dupTAC;p.Thr599dup in pediatric patient with low-grade ganglioglioma

Gangliogliomas (WHO grade I) are rare tumors affecting the central nervous system and are most frequently observed in children. Next-generation sequencing of tumors is being utilized at an increasing rate in both research and clinical settings to characterize the genetic factors that drive tumorigenesis. Here, we report a rare BRAF somatic mutation (NM_004333.4:c.1794_1796dupTAC; p.Thr599dup) in the tumor genome from a pediatric patient in her late teens, who was initially diagnosed with low-grade ganglioglioma at age 13. This duplication of 3 nt introduces a second threonine residue at amino acid 599 of the BRAF protein. Based on previous studies, this variant is likely to increase kinase activity, similar to the well-characterized BRAF p.Val600Glu (V600E) pathogenic variant. In addition, although the p.T599dup somatic mutation has been documented rarely in human cancers, the variant has not been previously reported in ganglioglioma. The identification of this variant presents an opportunity to consider targeted therapy (e.g., BRAF inhibitor) for this patient.

[1]  P. Poulikakos,et al.  New perspectives for targeting RAF kinase in human cancer , 2017, Nature Reviews Cancer.

[2]  Marilyn M. Li,et al.  Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. , 2017, The Journal of molecular diagnostics : JMD.

[3]  Yufei Shi,et al.  Classical V600E and other non-hotspot BRAF mutations in adult differentiated thyroid cancer , 2016, Journal of Translational Medicine.

[4]  Heather L. Mulder,et al.  Genetic alterations in uncommon low-grade neuroepithelial tumors: BRAF, FGFR1, and MYB mutations occur at high frequency and align with morphology , 2016, Acta Neuropathologica.

[5]  James Y. Zou Analysis of protein-coding genetic variation in 60,706 humans , 2015, Nature.

[6]  Li Ding,et al.  Germline Mutations in Predisposition Genes in Pediatric Cancer. , 2015, The New England journal of medicine.

[7]  J. Blay,et al.  Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations. , 2015, The New England journal of medicine.

[8]  J. Biegel,et al.  Chromosome Band 7q34 Deletions Resulting in KIAA1549‐BRAF and FAM131B‐BRAF Fusions in Pediatric Low‐Grade Gliomas , 2015, Brain pathology.

[9]  Peter White,et al.  Churchill: an ultra-fast, deterministic, highly scalable and balanced parallelization strategy for the discovery of human genetic variation in clinical and population-scale genomics , 2015, Genome Biology.

[10]  D. Ellison,et al.  Posterior fossa and spinal gangliogliomas form two distinct clinicopathologic and molecular subgroups , 2014, Acta Neuropathologica Communications.

[11]  P. A. Futreal,et al.  Emerging patterns of somatic mutations in cancer , 2013, Nature Reviews Genetics.

[12]  N. Pandis,et al.  BRAF alterations in pediatric low grade gliomas and mixed neuronal–glial tumors , 2013, Journal of Neuro-Oncology.

[13]  A. Sivachenko,et al.  Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples , 2013, Nature Biotechnology.

[14]  J. Utikal,et al.  Improved survival with MEK inhibition in BRAF-mutated melanoma. , 2012, The New England journal of medicine.

[15]  Dirk Schadendorf,et al.  Improved survival with MEK Inhibition in BRAF-mutated melanoma for the METRIC Study Group , 2012 .

[16]  Lauren E Haydu,et al.  Distinguishing Clinicopathologic Features of Patients with V600E and V600K BRAF-Mutant Metastatic Melanoma , 2012, Clinical Cancer Research.

[17]  Pablo Cingolani,et al.  © 2012 Landes Bioscience. Do not distribute. , 2022 .

[18]  S. Pfister,et al.  Functional characterization of a BRAF insertion mutant associated with pilocytic astrocytoma , 2011, International journal of cancer.

[19]  S. Lacomme,et al.  BRAF, p53 and SOX2 in anaplastic thyroid carcinoma: evidence for multistep carcinogenesis , 2011, Pathology.

[20]  Kirsten Schmieder,et al.  Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma , 2011, Acta Neuropathologica.

[21]  Andrew Collins,et al.  TFG, a target of chromosome translocations in lymphoma and soft tissue tumors, fuses to GPR128 in healthy individuals , 2010, Haematologica.

[22]  G. Rao This week in Neurology® , 2009, Neurology.

[23]  D. Pearson,et al.  Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549:BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma , 2009, Oncogene.

[24]  J. Fridlyand,et al.  Distinct sets of genetic alterations in melanoma. , 2005, The New England journal of medicine.

[25]  M. Stratton,et al.  The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website , 2004, British Journal of Cancer.

[26]  D. Barford,et al.  Mechanism of Activation of the RAF-ERK Signaling Pathway by Oncogenic Mutations of B-RAF , 2004, Cell.

[27]  A. Nicholson,et al.  Mutations of the BRAF gene in human cancer , 2002, Nature.