KIAA1549

Gene Summary

Gene:KIAA1549; KIAA1549
Location:7q34
Summary:The protein encoded by this gene belongs to the UPF0606 family. This gene has been found to be fused to the BRAF oncogene in many cases of pilocytic astrocytoma. The fusion results from 2Mb tandem duplications at 7q34. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2012]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:UPF0606 protein KIAA1549
Source:NCBIAccessed: 15 March, 2017

Ontology:

What does this gene/protein do?
KIAA1549 is implicated in:
- integral to membrane
Data from Gene Ontology via CGAP

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 15 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 15 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: KIAA1549 (cancer-related)

Helfferich J, Nijmeijer R, Brouwer OF, et al.
Neurofibromatosis type 1 associated low grade gliomas: A comparison with sporadic low grade gliomas.
Crit Rev Oncol Hematol. 2016; 104:30-41 [PubMed] Related Publications
Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder, associated with a variable clinical phenotype including café-au-lait spots, intertriginous freckling, Lisch nodules, neurofibromas, optic pathway gliomas and distinctive bony lesions. NF1 is caused by a mutation in the NF1 gene, which codes for neurofibromin, a large protein involved in the MAPK- and the mTOR-pathway through RAS-RAF signalling. NF1 is a known tumour predisposition syndrome, associated with different tumours of the nervous system including low grade gliomas (LGGs) in the paediatric population. The focus of this review is on grade I pilocytic astrocytomas (PAs), the most commonly observed histologic subtype of low grade gliomas in NF1. Clinically, these PAs have a better prognosis and show different localisation patterns than their sporadic counterparts, which are most commonly associated with a KIAA1549:BRAF fusion. In this review, possible mechanisms of tumourigenesis in LGGs with and without NF1 will be discussed, including the contribution of different signalling pathways and tumour microenvironment. Furthermore we will discuss how increased understanding of tumourigenesis may lead to new potential targets for treatment.

Roth JJ, Fierst TM, Waanders AJ, et al.
Whole Chromosome 7 Gain Predicts Higher Risk of Recurrence in Pediatric Pilocytic Astrocytomas Independently From KIAA1549-BRAF Fusion Status.
J Neuropathol Exp Neurol. 2016; 75(4):306-15 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
The most frequent genetic alteration identified in pediatric pilocytic astrocytomas and pilomyxoid variant is the KIAA1549-BRAF fusion, which typically results from a 2.0 Mb tandem duplication in chromosome band 7q34. Less frequent abnormalities include fusion genes,BRAF, FGFR, KRAS, and NF1 point mutations, and whole chromosome gains. To correlate genetic alterations with clinical course data, we retrospectively analyzed the tumors with pilocytic and pilomyxoid histology of a cohort of 116 pediatric patients, aged 5 months to 23 years. Gross total resection was associated with a decreased risk of recurrence (p = 0.001), supporting previous findings that complete tumor excision correlates with long-term and disease-free survival. We found no significant association between recurrence rate and the presence of the KIAA1549-BRAF fusion or BRAF mutation (p = 0.167). Interestingly, gain of whole chromosome 7 (WC7) was associated with a 4.7-fold increased risk of tumor recurrence, even after adjusting for surgical status (p = 0.025), and other genetic alterations. Using fluorescence in situ hybridization, we demonstrated that when WC7 gain accompanies the KIAA1549-BRAF fusion, the fusion likely arises first. This study highlights the utility of genetic studies for risk assessment of pilocytic and pilomyxoid astrocytomas, which may impact treatment selections.

Nikiforova MN, Wald AI, Melan MA, et al.
Targeted next-generation sequencing panel (GlioSeq) provides comprehensive genetic profiling of central nervous system tumors.
Neuro Oncol. 2016; 18(3):379-87 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Identification of genetic changes in CNS tumors is important for the appropriate clinical management of patients. Our objective was to develop a next-generation sequencing (NGS) assay for simultaneously detecting the various types of genetic alterations characteristic for adult and pediatric CNS tumors that can be applied to small brain biopsies.
METHODS: We report an amplification-based targeted NGS assay (GlioSeq) that analyzes 30 genes for single nucleotide variants (SNVs) and indels, 24 genes for copy number variations (CNVs), and 14 types of structural alterations in BRAF, EGFR, and FGFR3 genes in a single workflow. GlioSeq performance was evaluated in 54 adult and pediatric CNS tumors, and the results were compared with fluorescence in-situ hybridization, Sanger sequencing, and reverse transcription PCR.
RESULTS: GlioSeq correctly identified 71/71 (100%) genetic alterations known to be present by conventional techniques, including 56 SNVs/indels, 9 CNVs, 3 EGFRvIII, and 3 KIAA1549-BRAF fusions. Only 20 ng of DNA and 10 ng of RNA were required for successful sequencing of 100% frozen and 96% formalin-fixed, paraffin-embedded tissue specimens. The assay sensitivity was 3%-5% of mutant alleles for SNVs and 1%-5% for gene fusions. The most commonly detected alterations were IDH1, TP53, TERT, ATRX. CDKN2A, and PTEN in high-grade gliomas, followed by BRAF fusions in low-grade gliomas and H3F3A mutations in pediatric gliomas.
CONCLUSIONS: GlioSeq NGS assay offers accurate and sensitive detection of a wide range of genetic alterations in a single workflow. It allows rapid and cost-effective profiling of brain tumor specimens and thus provides valuable information for patient management.

Trabelsi S, Mama N, Ladib M, et al.
Adult recurrent pilocytic astrocytoma: Clinical, histopathological and molecular study.
Neurochirurgie. 2015; 61(6):392-7 [PubMed] Related Publications
BACKGROUND: PA is a grade I glial tumor that mostly occurs in children. However, although apparently similar to paediatric PA, adult PA presents a different clinical follow-up that could arise from specific molecular alterations. A variety of genetic alterations have been identified as diagnostic or prognostic glioma molecular markers.
MATERIAL AND METHODS: We describe a right infratentorial tumor that occurred in a 58-year-old man. Neuroimaging and neuropathological examination suggested PA as an initial diagnosis. The tumor was completely resected. Unexpectedly, two years later, a rapidly growing tumor on the operative site was observed with a second location in the pineal region. Immunohistochemical reactions (IHC), Multiplex ligation probe amplification (MLPA) and fluorescence in situ hybridization (FISH) was performed in both primary and relapse tumor.
RESULTS: Neuroimaging and neuropathological examinations suggested an unusual diagnosis for adult patients: a recurrent PA. Both MLPA and FISH analysis contribute to diagnostic confirmation by KIAA1549: BRAF fusion detection. Additional genetic results revealed interesting findings that justified the tumor aggressivity.
CONCLUSION: Molecular analysis of adult PA cases should be routinely combined with histopathological and neuroimaging examination to further refine prognostic diagnoses.

Fontebasso AM, Shirinian M, Khuong-Quang DA, et al.
Non-random aneuploidy specifies subgroups of pilocytic astrocytoma and correlates with older age.
Oncotarget. 2015; 6(31):31844-56 [PubMed] Free Access to Full Article Related Publications
Pilocytic astrocytoma (PA) is the most common brain tumor in children but is rare in adults, and hence poorly studied in this age group. We investigated 222 PA and report increased aneuploidy in older patients. Aneuploid genomes were identified in 45% of adult compared with 17% of pediatric PA. Gains were non-random, favoring chromosomes 5, 7, 6 and 11 in order of frequency, and preferentially affecting non-cerebellar PA and tumors with BRAF V600E mutations and not with KIAA1549-BRAF fusions or FGFR1 mutations. Aneuploid PA differentially expressed genes involved in CNS development, the unfolded protein response, and regulators of genomic stability and the cell cycle (MDM2, PLK2),whose correlated programs were overexpressed specifically in aneuploid PA compared to other glial tumors. Thus, convergence of pathways affecting the cell cycle and genomic stability may favor aneuploidy in PA, possibly representing an additional molecular driver in older patients with this brain tumor.

Bidinotto LT, Scapulatempo-Neto C, Mackay A, et al.
Molecular Profiling of a Rare Rosette-Forming Glioneuronal Tumor Arising in the Spinal Cord.
PLoS One. 2015; 10(9):e0137690 [PubMed] Free Access to Full Article Related Publications
Rosette-forming glioneuronal tumor (RGNT) of the IV ventricle is a rare and recently recognized brain tumor entity. It is histologically composed by two distinct features: a glial component, resembling pilocytic astrocytoma, and a component forming neurocytic rosettes and/or perivascular rosettes. Herein, we describe a 33-year-old man with RGNT arising in the spinal cord. Following an immunohistochemistry validation, we further performed an extensive genomic analysis, using array-CGH (aCGH), whole exome and cancer-related hotspot sequencing, in order to better understand its underlying biology. We observed the loss of 1p and gain of 1q, as well as gain of the whole chromosomes 7, 9 and 16. Local amplifications in 9q34.2 and 19p13.3 (encompassing the gene SBNO2) were identified. Moreover, we observed focal gains/losses in several chromosomes. Additionally, on chromosome 7, we identified the presence of the KIAA1549:BRAF gene fusion, which was further validated by RT-PCR and FISH. Across all mutational analyses, we detected and validated the somatic mutations of the genes MLL2, CNNM3, PCDHGC4 and SCN1A. Our comprehensive molecular profiling of this RGNT suggests that MAPK pathway and methylome changes, driven by KIAA1549:BRAF fusion and MLL2 mutation, respectively, could be associated with the development of this rare tumor entity.

Faulkner C, Ellis HP, Shaw A, et al.
BRAF Fusion Analysis in Pilocytic Astrocytomas: KIAA1549-BRAF 15-9 Fusions Are More Frequent in the Midline Than Within the Cerebellum.
J Neuropathol Exp Neurol. 2015; 74(9):867-72 [PubMed] Free Access to Full Article Related Publications
Pilocytic astrocytomas (PAs) are increasingly tested for KIAA1549-BRAF fusions. We used reverse transcription polymerase chain reaction for the 3 most common KIAA1549-BRAF fusions, together with BRAF V600E and histone H3.3 K27M analyses to identify relationships of these molecular characteristics with clinical features in a cohort of 32 PA patients. In this group, the overall BRAF fusion detection rate was 24 (75%). Ten (42%) of the 24 had the 16-9 fusion, 8 (33%) had only the 15-9 fusion, and 1 (4%) of the patients had only the 16-11 fusion. In the PAs with only the 15-9 fusion, 1 PA was in the cerebellum and 7 were centered in the midline outside of the cerebellum, that is, in the hypothalamus (n = 4), optic pathways (n = 2), and brainstem (n = 1). Tumors within the cerebellum were negatively associated with fusion 15-9. Seven (22%) of the 32 patients had tumor-related deaths and 25 of the patients (78%) were alive between 2 and 14 years after initial biopsy. Age, sex, tumor location, 16-9 fusion, and 15-9 fusion were not associated with overall survival. Thus, in this small cohort, 15-9 KIAA1549-BRAF fusion was associated with midline PAs located outside of the cerebellum; these tumors, which are generally difficult to resect, are prone to recurrence.

Gierke M, Sperveslage J, Schwab D, et al.
Analysis of IDH1-R132 mutation, BRAF V600 mutation and KIAA1549-BRAF fusion transcript status in central nervous system tumors supports pediatric tumor classification.
J Cancer Res Clin Oncol. 2016; 142(1):89-100 [PubMed] Related Publications
OBJECTIVE: Gliomas are the leading cause of cancer-related morbidity in children and comprise a clinical, histological and molecular heterogenous group of CNS tumors. Appropriate treatment of these tumors relies on correct classification into tumor types and malignancy grades.
METHODS: We examined 170 (0-18 years) pediatric and 131 (19-35 years) young adult brain tumors including pilocytic astrocytomas (PAs), pilomyxoid astrocytomas (PMAs), diffuse astrocytomas (DAs), gangliogliomas, dysembryoplastic neuroepithelial tumors (DNTs) and pleomorphic xanthoastrocytomas (PXAs) for IDH1 and BRAF mutation/BRAF fusion gene status. The obtained data were compared to results in 464 (<35 years) adult brain tumors. In 32 tumors with an oligodendroglial or mixed glioma differentiation, additionally the LOH1p/19q status was determined.
RESULTS: By combining immunohistochemistry and molecular methods, IDH1/2 mutations were observed in 6 pediatric, 35 young adult and 43 adult tumors of the astrocytic/oligodendroglial lineage. BRAF V600E mutations (20 pediatric, 7 young adults and 2 adults) were found mostly in gangliogliomas, PXAs, few astrocytomas and few DNTs. Except for one DA case, BRAF fusions (35 pediatric, 8 young adults and 2 adults) were restricted to PA and PMA and associated with age and infratentorial location. All mutations were mutually exclusive and always present in the primary tumor. Two-thirds of all pediatric samples harbored one of the three examined mutations.
CONCLUSION: Combination of IDH1-R132, BRAF V600 and KIAA1549-BRAF fusion analysis is therefore a useful tool to increase diagnostic accuracy in pediatric gliomas.

Gessi M, Engels AC, Lambert S, et al.
Molecular characterization of disseminated pilocytic astrocytomas.
Neuropathol Appl Neurobiol. 2016; 42(3):273-8 [PubMed] Related Publications
AIM: Pilocytic astrocytomas represent the most common paediatric tumours of the central nervous system. Dissemination through the ventricular system occurs rarely in patients with pilocytic astrocytomas; however, it is more common in infants with diencephalic tumours, and is associated with a poor outcome. Despite histological similarities with classic pilocytic astrocytomas, it is still unclear whether disseminated pilocytic astrocytomas may have specific molecular features.
METHODS: Seventeen disseminated pilocytic astrocytomas were investigated using the molecular inversion probe array and screened for the presence of gene fusions (KIAA1549-BRAF) and mutations (BRAF, RAS and FGFR1).
RESULTS: Along with evidence of a constitutive MAPK activation in all cases, the molecular inversion probe array, fluorescence in situ hybridization analysis and mutational study revealed KIAA1549-BRAF fusions in 66% and BRAF(V600E) mutations in 5% of cases. No KRAS, HRAS, NRAS or FGFR1 mutations were found.
CONCLUSIONS: disseminated pilocytic astrocytomas showed genetic features similar to classic pilocytic astrocytoma, including a similar incidence of KIAA1549-BRAF fusions, BRAF mutations and a stable genetic profile. Given common activation of the MAPK pathway, the use of specific inhibitors can be hypothesized for the treatment of disseminated pilocytic astrocytomas, along with standard chemo- and/or radiotherapy.

Becker AP, Scapulatempo-Neto C, Carloni AC, et al.
KIAA1549: BRAF Gene Fusion and FGFR1 Hotspot Mutations Are Prognostic Factors in Pilocytic Astrocytomas.
J Neuropathol Exp Neurol. 2015; 74(7):743-54 [PubMed] Free Access to Full Article Related Publications
Up to 20% of patients with pilocytic astrocytoma (PA) experience a poor outcome. BRAF alterations and Fibroblast growth factor receptor 1 (FGFR1) point mutations are key molecular alterations in Pas, but their clinical implications are not established. We aimed to determine the frequency and prognostic role of these alterations in a cohort of 69 patients with PAs. We assessed KIAA1549:BRAF fusion by fluorescence in situ hybridization and BRAF (exon 15) mutations by capillary sequencing. In addition, FGFR1 expression was analyzed using immunohistochemistry, and this was compared with gene amplification and hotspot mutations (exons 12 and 14) assessed by fluorescence in situ hybridization and capillary sequencing. KIAA1549:BRAF fusion was identified in almost 60% of cases. Two tumors harbored mutated BRAF. Despite high FGFR1 expression overall, no cases had FGFR1 amplifications. Three cases harbored a FGFR1 p.K656E point mutation. No correlation was observed between BRAF and FGFR1 alterations. The cases were predominantly pediatric (87%), and no statistical differences were observed in molecular alterations-related patient ages. In summary, we confirmed the high frequency of KIAA1549:BRAF fusion in PAs and its association with a better outcome. Oncogenic mutations of FGFR1, although rare, occurred in a subset of patients with worse outcome. These molecular alterations may constitute alternative targets for novel clinical approaches, when radical surgical resection is unachievable.

Kumar A, Pathak P, Purkait S, et al.
Oncogenic KIAA1549-BRAF fusion with activation of the MAPK/ERK pathway in pediatric oligodendrogliomas.
Cancer Genet. 2015; 208(3):91-5 [PubMed] Related Publications
Pediatric oligodendrogliomas (pODGs) are rare central nervous system tumors, and comparatively little is known about their molecular pathogenesis. Co-deletion of 1p/19q; and IDH1, CIC, and FUBP1 mutations, which are molecular signatures of adult oligodendrogliomas, are extremely rare in pODGs. In this report, two pODGs, one each of grade II and grade III, were evaluated using clinical, radiological, histopathologic, and follow-up methods. IDH1, TP53, CIC, H3F3A, and BRAF-V600 E mutations were analyzed by Sanger sequencing and immunohistochemical methods, and 1p/19q co-deletion was analyzed by fluorescence in situ hybridization. PDGFRA amplification, BRAF gain, intragenic duplication of FGFR-TKD, and KIAA1549-BRAF fusion (validated by Sanger sequencing) were analyzed by real-time reverse transcription PCR. Notably, both cases showed the oncogenic KIAA1549_Ex15-BRAF_Ex9 fusion transcript. Further, immunohistochemical analysis showed activation of the MAPK/ERK pathway in both of these cases. However, neither 1p/19q co-deletion; IDH1, TP53, CIC, H3F3A, nor BRAF-V600 E mutation; PDGFRA amplification; BRAF gain; nor duplication of FGFR-TKD was identified. Overall, this study highlights that pODGs can harbor the KIAA1549-BRAF fusion with aberrant MAPK/ERK signaling, and there exists an option of targeting these pathways in such patients. These results indicate that pODGs with the KIAA1549-BRAF fusion may represent a subset of this rare tumor that shares molecular and genetic features of pilocytic astrocytomas. These findings will increase our understanding of pODGs and may have clinical implications.

Collins VP, Jones DT, Giannini C
Pilocytic astrocytoma: pathology, molecular mechanisms and markers.
Acta Neuropathol. 2015; 129(6):775-88 [PubMed] Free Access to Full Article Related Publications
Pilocytic astrocytomas (PAs) were recognized as a discrete clinical entity over 70 years ago. They are relatively benign (WHO grade I) and have, as a group, a 10-year survival of over 90%. Many require merely surgical removal and only very infrequently do they progress to more malignant gliomas. While most show classical morphology, they may present a spectrum of morphological patterns, and there are difficult cases that show similarities to other gliomas, some of which are malignant and require aggressive treatment. Until recently, almost nothing was known about the molecular mechanisms involved in their development. The use of high-throughput sequencing techniques interrogating the whole genome has shown that single abnormalities of the mitogen-activating protein kinase (MAPK) pathway are exclusively found in almost all cases, indicating that PA represents a one-pathway disease. The most common mechanism is a tandem duplication of a ≈2 Mb-fragment of #7q, giving rise to a fusion between two genes, resulting in a transforming fusion protein, consisting of the N-terminus of KIAA1549 and the kinase domain of BRAF. Additional infrequent fusion partners have been identified, along with other abnormalities of the MAP-K pathway, affecting tyrosine kinase growth factor receptors at the cell surface (e.g., FGFR1) as well as BRAF V600E, KRAS, and NF1 mutations among others. However, while the KIAA1549-BRAF fusion occurs in all areas, the incidence of the various other mutations identified differs in PAs that develop in different regions of the brain. Unfortunately, from a diagnostic standpoint, almost all mutations found have been reported in other brain tumor types, although some retain considerable utility. These molecular abnormalities will be reviewed, and the difficulties in their potential use in supporting a diagnosis of PA, when the histopathological findings are equivocal or in the choice of individualized therapy, will be discussed.

Mistry M, Zhukova N, Merico D, et al.
BRAF mutation and CDKN2A deletion define a clinically distinct subgroup of childhood secondary high-grade glioma.
J Clin Oncol. 2015; 33(9):1015-22 [PubMed] Free Access to Full Article Related Publications
PURPOSE: To uncover the genetic events leading to transformation of pediatric low-grade glioma (PLGG) to secondary high-grade glioma (sHGG).
PATIENTS AND METHODS: We retrospectively identified patients with sHGG from a population-based cohort of 886 patients with PLGG with long clinical follow-up. Exome sequencing and array CGH were performed on available samples followed by detailed genetic analysis of the entire sHGG cohort. Clinical and outcome data of genetically distinct subgroups were obtained.
RESULTS: sHGG was observed in 2.9% of PLGGs (26 of 886 patients). Patients with sHGG had a high frequency of nonsilent somatic mutations compared with patients with primary pediatric high-grade glioma (HGG; median, 25 mutations per exome; P = .0042). Alterations in chromatin-modifying genes and telomere-maintenance pathways were commonly observed, whereas no sHGG harbored the BRAF-KIAA1549 fusion. The most recurrent alterations were BRAF V600E and CDKN2A deletion in 39% and 57% of sHGGs, respectively. Importantly, all BRAF V600E and 80% of CDKN2A alterations could be traced back to their PLGG counterparts. BRAF V600E distinguished sHGG from primary HGG (P = .0023), whereas BRAF and CDKN2A alterations were less commonly observed in PLGG that did not transform (P < .001 and P < .001 respectively). PLGGs with BRAF mutations had longer latency to transformation than wild-type PLGG (median, 6.65 years [range, 3.5 to 20.3 years] v 1.59 years [range, 0.32 to 15.9 years], respectively; P = .0389). Furthermore, 5-year overall survival was 75% ± 15% and 29% ± 12% for children with BRAF mutant and wild-type tumors, respectively (P = .024).
CONCLUSION: BRAF V600E mutations and CDKN2A deletions constitute a clinically distinct subtype of sHGG. The prolonged course to transformation for BRAF V600E PLGGs provides an opportunity for surgical interventions, surveillance, and targeted therapies to mitigate the outcome of sHGG.

Antonelli M, Badiali M, Moi L, et al.
KIAA1549:BRAF fusion gene in pediatric brain tumors of various histogenesis.
Pediatr Blood Cancer. 2015; 62(4):724-7 [PubMed] Related Publications
The KIAA1549:BRAF fusion gene is considered a driver genetic event in pilocytic astrocytoma. We investigated a series of 69 pediatric brain neoplasms of diverse histogenesis and grade using the RT-PCR and sequencing. We detected the KIAA1549:BRAF fusion gene in five of 34 non-PA tumors (14.7%), that is, one glioblastoma, one anaplastic astrocytoma, one anaplastic pleomorphic xanthoastrocytoma, 1 ependymoma, and 1 Atypical Teratoid Rhabdoid Tumor. Our study showed that the K-B, although uncommon, it can be detected in non-PA tumors of various histogenesis and grading.

Cruz GR, Dias Oliveira I, Moraes L, et al.
Analysis of KIAA1549-BRAF fusion gene expression and IDH1/IDH2 mutations in low grade pediatric astrocytomas.
J Neurooncol. 2014; 117(2):235-42 [PubMed] Related Publications
Low-grade astrocytomas comprise about 30 % of the central nervous system tumors in children. Several investigations have searched a correlation between the BRAF gene fusions alterations and mutations at IDH1 and IDH2 genes in low grade pediatric astrocytomas. This study identified the expression of KIAA1549-BRAF fusion gene and BRAF V600E mutation, mutations at exon 4 of the IDH1 and IDH2 genes in samples of pilocytic astrocytomas (PA) and grade-II astrocytomas (A-II) pediatric patients. The correlation between these alterations and the clinical profile of the patients was also evaluated. Eighty-two samples of low-grade astrocytomas (65 PA and 17 A-II) were analyzed by PCR and sequencing for each of the targets identified. We identified the KIAA1549-BRAF fusion transcript in 45 % of the samples. BRAF V600E and BRAFins598T mutations were detected in 7 and 1 % of the samples, respectively. Mutations in the R132/R172 residues of the IDH1/IDH2 genes were detected in only two samples, and the G105G polymorphism (rs11554137:C>T) was identified in ten patients. Additionally, we observed two mutations out of the usual hotspots at IDH1 and IDH2 genes. We observed a smaller frequency of mutations in IDHs genes than previously described, but since the prior studies were composed of adult or mixed (adults and children) samples, we believe that our results represent a relevant contribution to the growing knowledge in low grade childhood astrocytomas.

Gupta K, Orisme W, Harreld JH, et al.
Posterior fossa and spinal gangliogliomas form two distinct clinicopathologic and molecular subgroups.
Acta Neuropathol Commun. 2014; 2:18 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Gangliogliomas are low-grade glioneuronal tumors of the central nervous system and the commonest cause of chronic intractable epilepsy. Most gangliogliomas (>70%) arise in the temporal lobe, and infratentorial tumors account for less than 10%. Posterior fossa gangliogliomas can have the features of a classic supratentorial tumor or a pilocytic astrocytoma with focal gangliocytic differentiation, and this observation led to the hypothesis tested in this study - gangliogliomas of the posterior fossa and spinal cord consist of two morphologic types that can be distinguished by specific genetic alterations.
RESULTS: Histological review of 27 pediatric gangliogliomas from the posterior fossa and spinal cord indicated that they could be readily placed into two groups: classic gangliogliomas (group I; n = 16) and tumors that appeared largely as a pilocytic astrocytoma, but with foci of gangliocytic differentiation (group II; n = 11). Detailed radiological review, which was blind to morphologic assignment, identified a triad of features, hemorrhage, midline location, and the presence of cysts or necrosis, that distinguished the two morphological groups with a sensitivity of 91% and specificity of 100%. Molecular genetic analysis revealed BRAF duplication and a KIAA1549-BRAF fusion gene in 82% of group II tumors, but in none of the group I tumors, and a BRAF:p.V600E mutation in 43% of group I tumors, but in none of the group II tumors.
CONCLUSIONS: Our study provides support for a classification that would divide infratentorial gangliogliomas into two categories, (classic) gangliogliomas and pilocytic astrocytomas with gangliocytic differentiation, which have distinct morphological, radiological, and molecular characteristics.

Subbiah V, Westin SN, Wang K, et al.
Targeted therapy by combined inhibition of the RAF and mTOR kinases in malignant spindle cell neoplasm harboring the KIAA1549-BRAF fusion protein.
J Hematol Oncol. 2014; 7:8 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Oncologic patients who are extreme responders to molecularly targeted therapy provide an important opportunity to better understand the biologic basis of response and, in turn, inform clinical decision making. Malignant neoplasms with an uncertain histologic and immunohistochemical characterization present challenges both on initial diagnostic workups and then later in management, as current treatment algorithms are based on a morphologic diagnosis. Herein, we report a case of a difficult to characterize sarcoma-like lesion for which genomic profiling with clinical next generation sequencing (NGS) identified the molecular underpinnings of arrested progression(stable disease) under combination targeted therapy within a phase I clinical trial.
METHODS: Genomic profiling with clinical next generation sequencing was performed on the FoundationOne™ platform (Foundation Medicine, Cambridge MA). Histopathology and immunohistochemical studies were performed in the Department of Pathology, MD Anderson Cancer Center (Houston, TX). Treatment was administered in the context of a phase I clinical trial ClinicalTrials.gov Identifier: (NCT01187199).
RESULTS: The histology of the tumor was that of a spindle cell neoplasm, grade 2 by FNCLCC standards. Immunohistochemical staining was positive for S100 and CD34. Genomic profiling identified the following alterations: a KIAA1549-BRAF gene fusion resulting from a tandem duplication event, a homozygous deletion of PTEN, and frameshift insertion/deletions in CDKN2A A68fs*51, SUFU E283fs*3, and MAP3K1 N325fs*3. The patient had a 25% reduction in tumor (RECIST v1.1) following combination therapy consisting of sorafenib, temsirolimus, and bevazicumab within a phase I clinical trial.
CONCLUSIONS: The patient responded to combination targeted therapy that fortuitously targeted KIAA1549-BRAF and PTEN loss within a spindle cell neoplasm, as revealed by genomic profiling based on NGS. This is the first report of a tumor driven by a KIAA1549-BRAF fusion responding to sorafenib-based combination therapy.

Kaul A, Chen YH, Emnett RJ, et al.
Conditional KIAA1549:BRAF mice reveal brain region- and cell type-specific effects.
Genesis. 2013; 51(10):708-16 [PubMed] Free Access to Full Article Related Publications
Low-grade brain tumors (pilocytic astrocytomas) that result from a genomic rearrangement in which the BRAF kinase domain is fused to the amino terminal of the KIAA1549 gene (KIAA1549:BRAF fusion; f-BRAF) commonly arise in the cerebellum of young children. To model this temporal and spatial specificity in mice, we generated conditional KIAA1549:BRAF strains that coexpresses green fluorescent protein (GFP). Although both primary astrocytes and neural stem cells (NSCs) from these mice express f-BRAF and GFP as well as exhibit increased MEK activity, only f-BRAF-expressing NSCs exhibit increased proliferation in vitro. Using Cre driver lines in which KIAA1549:BRAF expression was directed to NSCs (f-BRAF; BLBP-Cre mice), astrocytes (f-BRAF; GFAP-Cre mice), and NG2 progenitor cells (f-BRAF; NG2-Cre mice), increased glial cell numbers were observed only in the cerebellum of f-BRAF; BLBP-Cre mice in vivo. The availability of this unique KIAA1549:BRAF conditional transgenic mouse strain will enable future mechanistic studies aimed at defining the developmentally-regulated temporal and spatial determinants that underlie low-grade astrocytoma formation in children.

Reis GF, Bloomer MM, Perry A, et al.
Pilocytic astrocytomas of the optic nerve and their relation to pilocytic astrocytomas elsewhere in the central nervous system.
Mod Pathol. 2013; 26(10):1279-87 [PubMed] Related Publications
Pilocytic astrocytoma is a low-grade glioma that affects mostly children and young adults and can occur anywhere in the central nervous system. Pilocytic astrocytoma of the optic nerve is an equally indolent subtype that is occasionally associated with neurofibromatosis type 1. In earlier studies, this subtype was considered within the larger category of 'optic pathway glioma,' which included infiltrating astrocytomas and other hypothalamic tumors. However, there have been suggestions that gliomas in the optic nerve, and especially pilocytic astrocytoma of the optic nerve, are biologically different from tumors within the hypothalamus and other parts of the optic tract. Furthermore, the recent discovery of BRAF duplication and fusion with the KIAA1549 gene is reported to be more typical for posterior fossa tumors, and the rate of this aberration is not well known in pilocytic astrocytoma of the optic nerve. To determine the distinction of pilocytic astrocytoma of the optic nerve from pilocytic astrocytoma of the posterior fossa and to investigate the prevalence of BRAF aberrations, we reviewed the clinicopathological and molecular features of all such patients in our institution. Our study demonstrates that BRAF duplication is more frequent in posterior fossa tumors compared with pilocytic astrocytoma of the optic nerve (P=0.011). However, the rates of phospho-MAPK1 and CDKN2A expression were high in both pilocytic astrocytoma of the optic nerve and posterior fossa pilocytic astrocytoma, suggesting that the MAPK pathway is active in these tumors. Our study supports the notion that BRAF duplication is more typical of posterior fossa pilocytic astrocytoma and that molecular alterations other than KIAA1549 fusion may underlie MAPK pathway activation in pilocytic astrocytoma of the optic nerve.

Chen YH, Gutmann DH
The molecular and cell biology of pediatric low-grade gliomas.
Oncogene. 2014; 33(16):2019-26 [PubMed] Related Publications
Pilocytic astrocytoma (PA) is the most common glial cell tumor arising in children. Sporadic cases are associated with KIAA1549:BRAF fusion rearrangements, while 15-20% of children develop PA in the context of the neurofibromatosis 1 (NF1) inherited tumor predisposition syndrome. The unique predilection of these tumors to form within the optic pathway and brainstem (NF1-PA) and cerebellum (sporadic PA) raises the possibility that gliomagenesis requires more than biallelic inactivation of the NF1 tumor suppressor gene or expression of the KIAA1549:BRAF transcript. Several etiologic explanations include differential susceptibilities of preneoplastic neuroglial cell types in different brain regions to these glioma-causing genetic changes, contributions from non-neoplastic cells and signals in the tumor microenvironment, and genomic modifiers that confer glioma risk. As clinically-faithful rodent models of sporadic PA are currently under development, Nf1 genetically-engineered mouse (GEM) models have served as tractable systems to study the role of the cell of origin, deregulated intracellular signaling, non-neoplastic cells in the tumor microenvironment and genomic modifiers in gliomagenesis. In this report, we highlight advances in Nf1-GEM modeling and review new experimental evidence that supports the emerging concept that Nf1- and KIAA1549:BRAF-induced gliomas arise from specific cell types in particular brain locations.

Dimitriadis E, Alexiou GA, Tsotsou P, et al.
BRAF alterations in pediatric low grade gliomas and mixed neuronal-glial tumors.
J Neurooncol. 2013; 113(3):353-8 [PubMed] Related Publications
Low grade astrocytomas are the most common brain tumor in children. Recent studies have identified alterations in the BRAF serine/threonine kinase gene that result in mitogen activated protein kinase pathway activation. Herewith, we investigated the genetic changes of BRAF in pediatric low grade gliomas and their relation to pathological findings and Ki-67 proliferation index. The results showed gene fusions between KIAA1549 and BRAF in 66.7 % of tumors. The majority involved the KIAA1549-BRAF exon 16-exon 9 variant. Fusion junction between KIAA1549 exon 15 and BRAF exon 9 was found in five tumors, in which the myxoid component was the predominant. This has not been previously reported. No significant correlation was found between specific KIAA1549 and BRAF fusion junctions and Ki-67 index. All of the samples included in this study were tested for the presence of the BRAF(V600E) mutation, and no positive sample was found.

Sievert AJ, Lang SS, Boucher KL, et al.
Paradoxical activation and RAF inhibitor resistance of BRAF protein kinase fusions characterizing pediatric astrocytomas.
Proc Natl Acad Sci U S A. 2013; 110(15):5957-62 [PubMed] Free Access to Full Article Related Publications
Astrocytomas are the most common type of brain tumors in children. Activated BRAF protein kinase mutations are characteristic of pediatric astrocytomas with KIAA1549-BRAF fusion genes typifying low-grade astrocytomas and (V600E)BRAF alterations characterizing distinct or higher-grade tumors. Recently, BRAF-targeted therapies, such as vemurafenib, have shown great promise in treating V600E-dependent melanomas. Like (V600E)BRAF, BRAF fusion kinases activate MAPK signaling and are sufficient for malignant transformation; however, here we characterized the distinct mechanisms of action of KIAA1549-BRAF and its differential responsiveness to PLX4720, a first-generation BRAF inhibitor and research analog of vemurafenib. We found that in cells expressing KIAA1549-BRAF, the fusion kinase functions as a homodimer that is resistant to PLX4720 and accordingly is associated with CRAF-independent paradoxical activation of MAPK signaling. Mutagenesis studies demonstrated that KIAA1549-BRAF fusion-mediated signaling is diminished with disruption of the BRAF kinase dimer interface. In addition, the KIAA1549-BRAF fusion displays increased binding affinity to kinase suppressor of RAS (KSR), an RAF relative recently demonstrated to facilitate MEK phosphorylation by BRAF. Despite its resistance to PLX4720, the KIAA1549-BRAF fusion is responsive to a second-generation selective BRAF inhibitor that, unlike vemurafenib, does not induce activation of wild-type BRAF. Our data support the development of targeted treatment paradigms for BRAF-altered pediatric astrocytomas and also demonstrate that therapies must be tailored to the specific mutational context and distinct mechanisms of action of the mutant kinase.

Sadighi Z, Slopis J
Pilocytic astrocytoma: a disease with evolving molecular heterogeneity.
J Child Neurol. 2013; 28(5):625-32 [PubMed] Related Publications
Pilocytic astrocytoma, the most common pediatric brain tumor, is a clinically and molecularly heterogeneous disease that occurs most often in the cerebellum and hypothalamic and chiasmatic regions. Classically, pilocytic astrocytomas are driven by the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway. Recently described genetic aberrations involving this pathway are critical for tumorigenesis. Tandem duplication of 7q34 encodes BRAF and produces several KIAA1549-BRAF novel oncogenic fusions. Activating point mutations of BRAF, such as BRAF (V600E), also lead to pilocytic astrocytoma. Loss of the NF1 gene allows hyperactivation of the oncogene KRAS. In this review, we discuss the current understanding of the novel molecular aberrations described in pilocytic astrocytomas and their clinical relevance for prognosis and treatment. The prognostic indications of these aberrations are discussed with regard to tumor location, tumor pathology, and patient age. A better understanding of the evolving molecular heterogeneity of pilocytic astrocytomas offers hope for developing molecularly targeted therapeutic armamentariums.

Poole Perry LJ, Jakobiec FA, Zakka FR, et al.
Reactive retinal astrocytic tumors (so-called vasoproliferative tumors): histopathologic, immunohistochemical, and genetic studies of four cases.
Am J Ophthalmol. 2013; 155(3):593-608.e1 [PubMed] Free Access to Full Article Related Publications
PURPOSE: To evaluate the cellular nature of and diagnostic terminology used in connection with acquired retinal "vasoproliferative tumors."
DESIGN: Retrospective clinicopathologic study.
METHODS: Clinical records and microscopic slides of 4 enucleated globes were reviewed. Special stains and immunohistochemical probes for CD31, CD34, p53, glial fibrillary acidic protein (GFAP), CD163, and Ki67 (cell replication) were employed; ultrastructural and fluorescence in situ hybridization (FISH) analyses were performed.
RESULTS: Tumors were located inferotemporally in middle-aged patients. They were uniformly composed of compacted elongated, GFAP-positive spindle cells (due to intermediate filaments identified ultrastructurally) with a Ki67 index of less than 1%. Rosenthal fibers and eosinophilic granular bodies were observed. Hyalinized periodic acid-Schiff-positive vessels were widely separated. CD31 and CD34 revealed a sparse microvasculature. Tumor-associated exudate spread predominantly subretinally. The retinal pigment epithelium had undergone extensive placoid fibrous metaplasia with focal ossification. P53 upregulation, BRAF-KIAA gene rearrangement, and IDH1R132H mutation typically associated with low-grade astrocytic neoplasms were absent.
CONCLUSIONS: Retinal "vasoproliferative" tumors have been mischaracterized, because they actually display a paucity of microvessels. Proliferating fibrous astrocytes with a very low proliferation index predominate, without immunohistochemical or genetic evidence favoring a neoplasm. Subretinal exudate appeared capable of provoking widespread fibrous metaplasia of the pigment epithelium that was mainly responsible for secondary retinal damage. The term "reactive retinal astrocytic tumor" is proposed as more appropriate for this entity. In carefully selected progressive lesions, consideration should be given to earlier surgical intervention before extensive subretinal exudate accumulates and pigment epithelial proliferation with fibrous metaplasia ensues.

Kaul A, Chen YH, Emnett RJ, et al.
Pediatric glioma-associated KIAA1549:BRAF expression regulates neuroglial cell growth in a cell type-specific and mTOR-dependent manner.
Genes Dev. 2012; 26(23):2561-6 [PubMed] Free Access to Full Article Related Publications
Tandem duplications involving the BRAF kinase gene have recently been identified as the most frequent genetic alteration in sporadic pediatric glioma, creating a novel fusion protein (f-BRAF) with increased BRAF activity. To define the role of f-BRAF in gliomagenesis, we demonstrate that f-BRAF regulates neural stem cell (NSC), but not astrocyte, proliferation and is sufficient to induce glioma-like lesions in mice. Moreover, f-BRAF-driven NSC proliferation results from tuberin/Rheb-mediated mammalian target of rapamycin (mTOR) hyperactivation, leading to S6-kinase-dependent degradation of p27. Collectively, these results establish mTOR pathway activation as a key growth regulatory mechanism common to both sporadic and familial low-grade gliomas in children.

Ichimura K, Nishikawa R, Matsutani M
Molecular markers in pediatric neuro-oncology.
Neuro Oncol. 2012; 14 Suppl 4:iv90-9 [PubMed] Free Access to Full Article Related Publications
Pediatric molecular neuro-oncology is a fast developing field. A multitude of molecular profiling studies in recent years has unveiled a number of genetic abnormalities unique to pediatric brain tumors. It has now become clear that brain tumors that arise in children have distinct pathogenesis and biology, compared with their adult counterparts, even for those with indistinguishable histopathology. Some of the molecular features are so specific to a particular type of tumors, such as the presence of the KIAA1549-BRAF fusion gene for pilocytic astrocytomas or SMARCB1 mutations for atypical teratoid/rhabdoid tumors, that they could practically serve as a diagnostic marker on their own. Expression profiling has resolved the existence of 4 molecular subgroups in medulloblastomas, which positively translated into improved prognostication for the patients. The currently available molecular markers, however, do not cover all tumors even within a single tumor entity. The molecular pathogenesis of a large number of pediatric brain tumors is still unaccounted for, and the hierarchy of tumors is likely to be more complex and intricate than currently acknowledged. One of the main tasks of future molecular analyses in pediatric neuro-oncology, including the ongoing genome sequencing efforts, is to elucidate the biological basis of those orphan tumors. The ultimate goal of molecular diagnostics is to accurately predict the clinical and biological behavior of any tumor by means of their molecular characteristics, which is hoped to eventually pave the way for individualized treatment.

Gessi M, Lambert SR, Lauriola L, et al.
Absence of KIAA1549-BRAF fusion in rosette-forming glioneuronal tumors of the fourth ventricle (RGNT).
J Neurooncol. 2012; 110(1):21-5 [PubMed] Related Publications
Rosette-forming glioneuronal tumors (RGNT) of the fourth ventricle are rare mixed glioneuronal tumors included in the revised WHO classification of central nervous system tumors, showing partial histological similarities to pilocytic astrocytomas. To evaluate potential similarities at the molecular level between these tumors, we analysed a series of 10 RGNT for the presence of KIAA1549-BRAF fusions using interphase fluorescence in situ hybridisation. However, we found no cases showing KIAA1549-BRAF gene fusion or BRAF (V600E) mutation. Our data support the hypothesis that RGNT may represent a distinct entity among the glioneuronal tumors of the central nervous system, with molecular features different from pilocytic astrocytomas.

Ida CM, Lambert SR, Rodriguez FJ, et al.
BRAF alterations are frequent in cerebellar low-grade astrocytomas with diffuse growth pattern.
J Neuropathol Exp Neurol. 2012; 71(7):631-9 [PubMed] Related Publications
Cerebellar low-grade astrocytomas with a diffuse pattern of growth are uncommon, comprising World Health Organization (WHO) grade II diffuse astrocytomas (DA) and a minority of WHO grade I pilocytic astrocytomas (PA), so-called PA, "diffuse variant." Among 106 cerebellar low-grade astrocytomas (WHO grade I and II) operated on at the Mayo Clinic (1984-2010), we identified 19 such cases: 8 PA, "diffuse variant," 5 DA, and 6 that we were unable to classify further (low-grade astrocytomas, subtype indeterminate). We characterized these tumors using immunohistochemistry and currently available molecular markers (IDH1/2 mutations and BRAF mutation/fusion gene status) and investigated whether the markers could be used to aid the diagnostic process in combination with the clinical and pathologic features. KIAA1549-BRAF fusion was detected in 4 PA, "diffuse variant," 2 DA, and 2 low-grade astrocytomas, subtype indeterminate, indicating that these tumors were molecularly consistent with PA, the most common subtype of the series. A BRAF V600E mutation was detected in 1 PA, "diffuse variant" case; an IDH1 R132G mutation was found in 1 DA case. These results suggest that KIAA1549-BRAF fusion status and IDH1/2 and BRAF V600E mutational analyses may assist in the histologic classification of this diagnostically challenging group of tumors and result in a more accurate and objective combined molecular and histologic classification.

Badiali M, Gleize V, Paris S, et al.
KIAA1549-BRAF fusions and IDH mutations can coexist in diffuse gliomas of adults.
Brain Pathol. 2012; 22(6):841-7 [PubMed] Related Publications
KIAA1549-BRAF fusion gene and isocitrate dehydrogenase (IDH) mutations are considered two mutually exclusive genetic events in pilocytic astrocytomas and diffuse gliomas, respectively. We investigated the presence of the KIAA1549-BRAF fusion gene in conjunction with IDH mutations and 1p/19q loss in 185 adult diffuse gliomas. Moreover BRAF(v600E) mutation was also screened. The KIAA1549-BRAF fusion gene was evaluated by reverse-transcription polymerase chain reaction (RT-PCR) and sequencing. We found IDH mutations in 125 out 175 cases (71.4%). There were KIAA1549-BRAF fusion gene in 17 out of 180 (9.4%) cases and BRAF(v600E) in 2 out of 133 (1.5%) cases. In 11 of these 17 cases, both IDH mutations and the KIAA1549-BRAF fusion were present, as independent molecular events. Moreover, 6 of 17 cases showed co-presence of 1p/19q loss, IDH mutations and KIAA1549-BRAF fusion. Among the 17 cases with KIAA1549-BRAF fusion gene 15 (88.2%) were oligodendroglial neoplasms. Similarly, the two cases with BRAF(v600E) mutation were both oligodendroglioma and one had IDH mutations and 1p/19q co-deletion. Our results suggest that in a small fraction of diffuse gliomas, KIAA1549-BRAF fusion gene and BRAF(v600E) mutation may be responsible for deregulation of the Ras-RAF-ERK signaling pathway. Such alterations are more frequent in oligodendroglial neoplasm and may be co-present with IDH mutations and 1p/19q loss.

Lin A, Rodriguez FJ, Karajannis MA, et al.
BRAF alterations in primary glial and glioneuronal neoplasms of the central nervous system with identification of 2 novel KIAA1549:BRAF fusion variants.
J Neuropathol Exp Neurol. 2012; 71(1):66-72 [PubMed] Free Access to Full Article Related Publications
Recent studies highlight the importance of BRAF alterations resulting in mitogen activated protein kinase (MAK/ERK) pathway activation in low-grade CNS tumors. We studied 106 low-grade CNS neoplasms in a cohort of primarily pediatric patients to identify the prevalence and clinicopathologic significance of these alterations. Polymerase chain reaction testing identified KIAA1549:BRAF fusions in 51 (48%) tumors overall, including 42 (60%) pilocytic astrocytomas, 4 (17%) unclassifiable low-grade gliomas, 4 (36%) low-grade glioneuronal/neuroepithelial tumors, 0 (of 5) pleomorphic xanthoastrocytomas, 0 (of 4) diffuse astrocytomas (World Health Organization grade II), and 1 (of 3, 33%) pilomyxoid astrocytoma. KIAA1549:BRAF gene fusions confirmed by sequencing included the previously reported ones involving exons 1-16/9-18 (49%), 1-15/9-18 (35%), and 1-16/11-18 (8%) and 2 fusions with novel breakpoints: 1-15/11-18 (6%) and 1-17/10-18 (1%). DNA sequencing identified BRAF mutations in 8% of tumors. BRAF mutations were absent. KIAA1549:BRAF fusions were significantly more frequent in infratentorial (57%) and optic pathway (59%) tumors versus supratentorial (19%) tumors (p = 0.001). We did not identify significantly improved progression-free survival in tumors with fusions. In summary, KIAA1549:BRAF fusions predominate in pilocytic astrocytomas but are also present in some low-grade unclassifiable gliomas and glioneuronal tumors. The prognostic and therapeutic significance of this alteration is unclear and merits further study.

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