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Case Reports
. 2018 Jan 18;8(1):1032.
doi: 10.1038/s41598-018-19389-9.

The ten-year evolutionary trajectory of a highly recurrent paediatric high grade neuroepithelial tumour with MN1:BEND2 fusion

Anna Burford  1   2   3 , Alan Mackay  1   2   3 , Sergey Popov  1   2   3   4 , Maria Vinci  1   2   3   5 , Diana Carvalho  1   2   3 , Matthew Clarke  1   2   3 , Elisa Izquierdo  1   2   3 , Aimee Avery  6 , Thomas S Jacques  6   7 , Wendy J Ingram  8 , Andrew S Moore  9   10   11 , Kieran Frawley  11 , Timothy E Hassall  10 , Thomas Robertson  12 , Chris Jones  13   14   15
Affiliations
Case Reports

The ten-year evolutionary trajectory of a highly recurrent paediatric high grade neuroepithelial tumour with MN1:BEND2 fusion

Anna Burford et al. Sci Rep. .

Abstract

Astroblastomas are rare brain tumours which predominate in children and young adults, and have a controversial claim as a distinct entity, with no established WHO grade. Reports suggest a better outcome than high grade gliomas, though they frequently recur. Recently, they have been described to overlap with a newly-discovered group of tumours described as'high grade neuroepithelial tumour with MN1 alteration' (CNS HGNET-MN1), defined by global methylation patterns and strongly associated with gene fusions targeting MN1. We have studied a unique case of astroblastoma arising in a 6 year-old girl, with multiple recurrences over a period of 10 years, with the pathognomonic MN1:BEND2 fusion. Exome sequencing allowed for a phylogenetic reconstruction of tumour evolution, which when integrated with clinical, pathological and radiological data provide for a detailed understanding of disease progression, with initial treatment driving tumour dissemination along four distinct trajectories. Infiltration of distant sites was associated with a later genome doubling, whilst there was evidence of convergent evolution of different lesions acquiring distinct alterations targeting NF-κB. These data represent an unusual opportunity to understand the evolutionary history of a highly recurrent childhood brain tumour, and provide novel therapeutic targets for astroblastoma/CNS HGNET-MN1.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Histopathological features at presentation. Sample. (A) with haematoxyllin and eosin (H&E) staining, there are areas of multiple perivascular pseudorosettes (inset) as well as areas of necrosis and vascular hyalinisation. Cells are heterogenously positive for EMA, GFAP and S100 by immunohistochemistry. Original magnification x100 (inset, x400).
Figure 2
Figure 2
Clinical timeline. Surgical samples are lablled. (A–K), and annoated by age at resection/biopsy and anatomical location. Points of treatment initiation are indicated in red. RT, radiotherapy; TMZ, temozolomide; CCNU, lomustine.
Figure 3
Figure 3
Post-contrast, T1 weighted axial MRI images of all recurrences. (A–K) representative images prior to 1st to 11th surgical resections respectively. (L), representative image of final tumour progression. (A) age 6.79, underwent surgical resection of left frontal tumour. (B) age 7.33, left frontal craniotomy, partial resection, treated with radiotherapy and temozolomide. (C) age 9.11, left frontal subtotal resection, treated with CCNU and temozolomide. (D) age 11.26, biopsy. (E) age 13.10, resection. (F) age 14.04, resection. (G) age 14.29, right temporal craniotomy, gross total resection. (H) age 14.67, sphenoid tumour, endoscopic endonasal sphenoidectomy. (I) age 14.96, left temporal resection. (J) age 16.05, nasal biopsy. (K) age 16.17, nasal cavity resection. The patient died aged 16.42 years (Final).
Figure 4
Figure 4
Histopathological features of all recurrences. (A) Initial presentation – age 6.79 years (as in Fig. 1). (B) Similar morphology with high focal mitotic activity, fewer perivascular pseudorosettes and sharply demarcated borders. Evidence of calcification. (C) More cellular tumour with only single ribbon-like structures and almost no pseudorosettes seen. (D) Similar morphology to C, with hyalinised vessels. (E) Fewer mitotic figures present, and cells seen with conspicuous nucleoli. (F) Similar to (B), but with no calcification. Increased perivascular ribbons and necrotic foci. (G) Distinct lesion with prominent cellular pleomorphism and large hyperchromatic nuclei. Many cells have an epithelioid appearance. There are papillary structures and numerous pseudorosettes. (H) Tumour is infiltrating the sphenoid bone and sinus and has numerous invasive, pleomorphic cells with hyperchromatic and large nuclei. (I) Well vascularised pleomorphic tumour with several pseudorosettes. (J) Tumour was mostly necrotic tumour but viable tissue. showed pseudorosettes around hyalinised vessels. (K) Tumour was mostly necrotic. but preserved tumour shows numerous pseudorosettes, mostly around hyalinised vessels with thick walls. Original magnification x200.
Figure 5
Figure 5
Identification of MN1:BEND2 fusion. (A) Cartoon of fusion between exon 1 of MN1 (22q12.1, orange) and exons 9–14 of BEND2 (Xp22.13, blue), with spanning reads from RNAseq from sample (F) underneath. (B) Top: RT-PCR using primers designed against MN1, BEND2, and spanning the breakpoint, in samples (E), (F) and (H). KNS42 paediatric glioblastoma cells were used as a fusion-negative control. Beta actin (ACTB) was used as a positive RT-PCR control. Bottom: Sanger sequencing of the fusion band in sample. (E) Showing a sequence spanning the breakpoint. (C) FISH using probes directed against MN1 (green) and BEND2 (red), detecting fusion signals throughout sample (H). (D) RNAseq coverage of BEND2, with high levels of expression of exons 9–14 in sample (E).
Figure 6
Figure 6
Intratumoral heterogeneity and phylogentic reconstruction. (A) Contingency plots for cancer cell fractions (CCF) of somatic mutations identified in specimens (A–K). Key as provided in the figure. (B) Coxcomb plots for number of subclones in each specimen, with the area of each scaled according to the number of variants predicted to be contained within, as calculated by EXPANDS. They are placed along concentric circles according to the sampling time after initial diagnosis, and in distinct anatomical locations. (C) Phylogenetic tree of tumour specimens built using maximum parsimony from exome sequencing data. Blue line represents the ‘trunk’, yellow lines the shared major and minor ‘branches’, red lines the private ‘leaves’. Selected alterations are labelled, those targeting the NF-κB pathway are shaded.
Figure 7
Figure 7
NF-κB pathway activation. Strong cytoplasmic and nuclear expression of RELA/NF-κB-p65 by immunohistochemistry is seen in all later specimens (D–K), and only weakly observed in (A–C). Main image, original magnification x200; inset x400.
Figure 8
Figure 8
Integrated clinical and molecular inference of tumour evolution. Taking all available data, we proposed an evolutionary history along four distinct trajectories over 10 years. Brain diagram modified from Patrick J. Lynch, medical illustrator; C. Carl Jaffe, MD, cardiologist, under Creative Commons Attribution 2.5 License 2006. (https://upload.wikimedia.org/wikipedia/commons/4/44/Brain_human_lateral_view.svg).
See this image and copyright information in PMC

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