Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Case Reports
. 2015 Mar;25(2):182-92.
doi: 10.1111/bpa.12167. Epub 2014 Sep 12.

Chromosome band 7q34 deletions resulting in KIAA1549-BRAF and FAM131B-BRAF fusions in pediatric low-grade Gliomas

Jacquelyn J Roth  1 , Mariarita Santi, Avrum N Pollock, Brian N Harding, Lucy B Rorke-Adams, Laura S Tooke, Jaclyn A Biegel
Affiliations
Case Reports

Chromosome band 7q34 deletions resulting in KIAA1549-BRAF and FAM131B-BRAF fusions in pediatric low-grade Gliomas

Jacquelyn J Roth et al. Brain Pathol. 2015 Mar.

Abstract

The majority of pediatric low-grade gliomas (LGGs) are characterized by constitutive activation of the mitogen-activated protein kinase (MAPK) pathway through various mechanisms including BRAF mutations, inactivation of NF1, and KIAA1549-BRAF and FAM131B-BRAF fusions. The KIAA1549-BRAF fusion typically results from a 2.0 Mb tandem duplication in chromosome band 7q34. In the present study, single nucleotide polymorphism (SNP)-based array analysis of three LGGs demonstrated deletions in 7q34 that resulted in a BRAF fusion. Case 1 was likely a pilocytic astrocytoma (PA) with three deletions in 7q33q34 and an exon 15-9 KIAA1549-BRAF fusion. SNP array analysis of case 2, a possible dysembryoplastic neuroepithelial tumor (DNT), revealed a 2.6 Mb deletion, which included the 5' end of BRAF and extended to the 3' end of FAM131B. In case 3, deletions involving BRAF and FAM131B were observed in both a primary and a recurrent PA. RNA-based sequence analysis of cases 2 and 3 confirmed a fusion between FAM131B exon 2 and BRAF exon 9. The presence of fusion transcripts in these three LGGs highlights the utility of SNP array analysis to identify deletions that are suggestive of fusion proteins. BRAF fusions can result from multiple non-overlapping deletions, suggesting various complex mechanisms of formation.

Keywords: BRAF; FAM131B; KIAA1549; pediatric glioma.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Magnetic resonance imaging (MRI) findings from cases 1, 2 and 3A. A–D. Radiologic findings from case 1. Axial T1 (A), coronal fluid attenuated inversion recovery (FLAIR) (B), axial susceptibility (C) and axial post‐contrast (D) images of the brain. Note the fairly well‐circumscribed lesion in the posterior left temporal lobe which is dark on T1 and bright on FLAIR. Signal drop off on the susceptibility image suggests calcium and/or hemorrhage, with fairly avid contrast enhancement on post‐contrast imaging. E–H. Radiologic findings from case 2. Axial T1 (E), axial FLAIR (F), coronal T2 (G) and axial post‐contrast (H) images of the brain. Note the well‐circumscribed lesion within the medial right temporal lobe, which is dark on T1, moderately bright on FLAIR, bright on T2, and without any appreciable contrast enhancement. I–L. Radiologic findings from case 3A. Sagittal T1 (I), sagittal T2 (J), axial FLAIR (K) and sagittal post‐contrast (L) images of the brain. Note the fairly well‐circumscribed lesion within the pineal/tectal region which is dark on T1, moderately bright on FLAIR and T2, and without any appreciable contrast enhancement. Blue arrow indicates possible brain stem invasion of the tumor (K).
Figure 2
Figure 2
Pathology findings. A–E. Pathology findings from case 1. A. Large areas of tumor demonstrate a loose background with microcystic changes and irregular spaces with faintly bluish/myxoid material [200×; hematoxylin and eosin (H&E)]. B. Some areas of the tumor are more solid with round to ovoid astrocytes (200×; H&E). C. Scattered Rosenthal fibers are visible (400×; H&E). D. Numerous calcifications of different sizes are spread throughout the tumor (200×; H&E). E. Disorganized collections of, most likely entrapped neurons are present (200×; H&E). F–J. Pathology findings from case 2. F and G. The tumor is composed of fibrillary astrocytes in a faintly bluish neuropil without perivascular inflammation or eosinophilic granular bodies (F: 200×, G: 400×; H&E). H. Although classical pools of mucin with floating neurons are not present there are atypical, large neurons (400×; H&E). I and J. The neurons present throughout the tumor are highlighted by neurofilament (NFP) (I: 200×, J: 400X; NFP). K–O. Pathology findings from case 3. K. The first biopsy demonstrates features of a low‐grade astrocytoma with Rosenthal fibers (400×; H&E). L and M. The second resection demonstrates a rather diffuse growth pattern with a hint of focal, biphasic organization (200×; H&E). N. Pathologic findings from the residual/recurrent tumor demonstrate a recurrent low‐grade astrocytoma with radiation induced vascular changes (200×; H&E). O. Numerous Rosenthal fibers are present (400×; H&E).
Figure 3
Figure 3
SNP array findings. A–D. GenomeStudio images of 7q33q34 include the B‐allele frequency (BAF) (top plots) and Log  R ratio (bottom plots). Deletions, numbered from proximal to distal for each case, are marked with red bars below the deleted SNP probes. A. SNP array results from case 1 demonstrating three deletions in 7q33q34. B. SNP array results from case 2 revealing one deletion in 7q34. C. SNP array analysis from case 3B demonstrating four deletions in 7q34. D. SNP array analysis from the recurrent tumor 3C demonstrating four deletions in 7q34. E. Schematic representation of KIAA 1549, BRAF and FAM 131 B. Exon deletions are colored in red for exons which are definitely deleted, in light pink for those that are possibly deleted, and in blue for exons with normal copy number (exon 5 of FAM 131 B in case 3C is potentially only partially deleted). Genes and exons are not drawn to scale and all genes located in 7q33q34 are not pictured.
Figure 4
Figure 4
Sanger sequence analysis of fusion products detected by reverse transcriptase‐polymerase chain reaction (RT‐PCR). Twenty nucleotides surrounding the fusion junction are shown in each chromatogram. A. Sequence chromatogram demonstrates a fusion between KIAA 1549 exon 15 and BRAF exon 9 in case 1. B. A fusion between FAM 131 B exon 2 and BRAF exon 9 was detected by sequence analysis of case 2. C. The same fusion product that was present in case 2 (B) was detected in case 3B.
Figure 5
Figure 5
Models of fusion formation. Illustrations represent possible mechanisms of fusion formation for (B) case 1, (C) case 2 and (D) case 3A/B/C. Fusion transcripts that are produced are labeled in red. Chromosomes, genes and deletions are not drawn to scale. For case 1 (B), two possible insertion mechanisms are labeled as model 1 and model 2. Both mechanisms result in the same chromosomal arrangement. The structure of a normal chromosome 7 is shown in (A). In the cases with multiple deletions, we cannot discount the fact that the deletions may be present on different homologs of chromosome 7.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Bar EE, Lin A, Tihan T, Burger PC, Eberhart CG (2008) Frequent gains at chromosome 7q34 involving BRAF in pilocytic astrocytoma. J Neuropathol Exp Neurol 67:878–887. - PubMed
    1. Ciampi R, Knauf JA, Kerler R, Gandhi M, Zhu Z, Nikiforova MN et al (2005) Oncogenic AKAP9‐BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer. J Clin Invest 115:94–101. - PMC - PubMed
    1. Cin H, Meyer C, Herr R, Janzarik WG, Lambert S, Jones DT et al (2011) Oncogenic FAM131B‐BRAF fusion resulting from 7q34 deletion comprises an alternative mechanism of MAPK pathway activation in pilocytic astrocytoma. Acta Neuropathol 121:763–774. - PubMed
    1. Colin C, Padovani L, Chappe C, Mercurio S, Scavarda D, Loundou A et al (2013) Outcome analysis of childhood pilocytic astrocytomas: a retrospective study of 148 cases at a single institution. Neuropathol Appl Neurobiol 39:693–705. - PubMed
    1. Dahiya S, Yu J, Kaul A, Leonard JR, Gutmann DH (2012) Novel BRAF alteration in a sporadic pilocytic astrocytoma. Case Rep Med 2012:418672. - PMC - PubMed

Publication types

Substances

-