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Diffuse leptomeningeal glioneuronal tumour (DLGNT) in children: the emerging role of genomic analysis

Diffuse leptomeningeal glioneuronal tumour (DLGNT) in children: the emerging role of genomic... Diffuse leptomeningeal glioneuronal tumours (DLGNT ) represent rare enigmatic CNS tumours of childhood. Most patients with this disease share common radiological and histopathological features but the clinical course of this disease is variable. A radiological hallmark of this disease is widespread leptomeningeal enhancement that may involve the entire neuroaxis with predilection for the posterior fossa and spine. The classic pathologic features include low- to moderate-density cellular lesions with OLIG2 expression and evidence of ‘oligodendroglioma-like’ appearance. The MAPK/ERK signaling pathway has recently been reported as a potential driver of tumourigenesis in up to 80% of DLGNT with KIAA1549:BRAF fusions being the most common event seen. Until now, limited analysis of the biological drivers of tumourigenesis has been undertaken via targeted profiling, chromosomal analysis and immunohistochem- istry. Our study represents the first examples of comprehensive genomic sequencing in DLGNT and shows that it is not only feasible but crucial to our understanding of this rare disease. Moreover, we demonstrate that DLGNT may be more genomically complex than single-event MAPK/ERK signaling pathway tumours. Keywords: Diffuse leptomeningeal glioneuronal tumour, Paediatrics, Brain tumour, Childhood malignancy Introduction Epic 850  K array) [8]. These cases emphasise the impor - Diffuse leptomeningeal glioneuronal tumours (DLGNT) tance of identifying the genomic and epigenomic driv- are rare central nervous system (CNS) tumours defined ers of tumourigenesis in DLGNT and other rare CNS in the 2016 World Health Organisation (WHO) classifi - tumours of childhood [14, 16, 49]. cation of CNS neoplasms [39]. We report on two molec- ularly-distinct cases of DLGNT that represent the only Case presentation patients in the literature to our knowledge whom have Case 1 been sequenced using a comprehensive molecular profil - A 13-year-old boy presented with a one-week history of ing platform including whole genome sequencing (WGS) lethargy, headaches and nausea. At presentation he was of germline and tumour DNA, transcriptome analysis noted to be drowsy and had a left sided facial droop, left (RNAseq) and DNA methylation profiling (based on the sided weakness and dysarthria. An MRI showed mul- tiple foci of abnormal T2 hyperintensity in the anterior spinal cord at C2 and large areas of abnormal T2 hyper- *Correspondence: d.ziegler@unsw.edu.au intensity within the cord at T7-9, all of which were con- Paul G. Ekert and David S. Ziegler have contributed equally to this trast-enhancing (Fig.  1a, b). Although there were no risk publication Kids Cancer Centre, Sydney Children’s Hospital, Randwick, NSW 2031, factors for tuberculosis and CSF, serum and urine were Australia negative for acid fast bacilli and mycobacteria, anti-TB, Full list of author information is available at the end of the article © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. 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Manoharan et al. acta neuropathol commun (2021) 9:147 Page 2 of 11 Fig. 1 Radiological features of DLGNT on sagittal, T2-weighted images (a, c), T1 post-gadolinium imaged (b, d) and histopathological features of DLGNT (e, f, g): Radiology demonstrating a intramedullary C1-2 and T7-9 lesions. b ‘sugar coating’ leptomeningeal spread with nodular disease at cavernous sinus. c Intramedullary C2-T1 lesion with solid and cystic components. d ‘sugar coating’ leptomeningeal spread. Pathology of intramedullary tumour of case 2 demonstrating e. high power of H&E sections (400×) of dysplastic ganglionic type neurons with admixed neoplastic glial cells, f Neu-N positive dysplastic ganglionic type neurons, g diffuse positive staining of GFAP anti-bacteria and antiviral treatments were commenced showed small ovoid OLIG-2 positive cells with hyper- based on the MRI findings. CSF cytology was negative for chromatic nuclei in prominent myxoid stroma. There was tumour cells and had negative tumour markers. insufficient material for flow cytometry. FISH was nega - Biopsy of a cavernous sinus lesion was performed and tive for 1p and 19q loss. Ultimately the histopathology the post-operative course was complicated by recurrence was inconclusive and a definitive diagnosis could not be of hydrocephalus requiring an additional external ven- determined. tricular drain and ultimately the insertion of a ventricu- A sample was submitted for molecular profiling to the loperitoneal shunt. The biopsy was small and crushed but Zero Childhood Cancer (ZERO) national personalised M anoharan et al. acta neuropathol commun (2021) 9:147 Page 3 of 11 medicine program to assist with the diagnostic process the importance of exploring the genomic landscape of and clinical management [58]. Samples enrolled into the these rare tumours with NGS. ZERO national trial (PRecISion Medicine for Children Analysis of copy number variants revealed a 1p/19q co- with Cancer study—PRISM) require both tumour and deletion and 1q gain which is in keeping with a subclass matching germline samples from patients with high-risk of DLGNTs (Fig. 2b). Additional copy number changes of paediatric cancer. Due to diagnostic uncertainty, and per- unclear significance were gain of chromosome 7 and focal sisting MRI changes 1  month after initial presentation, losses in the 9p arm (Additional file  1: Tables 1 and 2). A consideration was given to further biopsy. However, the KIAA1549-BRAF fusion was also identified (Fig.  2c). A genomic analysis from the PRISM study resulted in the methylation array is part of the ZERO profiling of CNS diagnosis of DLGNT and prevented the need for further tumours, and is primarily used as an orthogonal diagnos- invasive surgical intervention. tic technique. Raw IDAT files were processed through the Molecular profiling of the cavernous sinus biopsy DKFZ Molecular Neuropathology (MNP) 2.0 classifier demonstrated multiple somatic genetic findings and and the sample was a match with diffuse leptomeningeal no reportable germline findings (summarized in glioneuronal tumour (probability = 0.97). The combina - Table  1). A somatic pathogenic nonsense BCOR vari- tion of the copy number changes, the KIAA1549-BRAF ant (p.Glu519Ter) was identified in the tumour. BCOR fusion and methylation classifier result aided in resolving is a transcriptional repressor that plays a role in chro- this clinical diagnostic dilemma. matin remodeling and acts as a tumour suppressor gene Treatment was commenced with a combination regi- [5]. The p.Glu519Ter variant is a truncating mutation in men of vincristine and carboplatin. After 6  months of exon 4/15 creating a premature stop codon predicted to treatment there was reduction in size of the intramedul- result in an absence of protein due to nonsense mediated lary lesions and stabilisation of the leptomeningeal dis- decay or complete loss of function due to an aberrant ease. However, the patient experienced an anaphylactic protein product. BCOR is situated on the X chromo- reaction to carboplatin and was subsequently treated some and being that this is a male patient, the hemizy- with 6  months of TPCV (thioguanine, procarbazine, gous mutation would result in no functional copies. The lomustine and vincristine) and achieved disease stability p.Glu519Ter variant is not present in population data- throughout treatment. The patient has now completed bases and in silico tools predict the mutation to be dam- treatment and has no clinical or radiological evidence of aging. Furthermore, most pathogenic/likely pathogenic disease progression 16 months from diagnosis. mutations in the BCOR gene within the ClinVar and PeCan database are loss of function mutations, provid- Case 2 ing additional support to the pathogenicity of this variant An 8-year-old girl presented with acute disorienta- [18, 60] (Fig.  2a). Interestingly, the study by Deng et  al. tion with associated vomiting and headache. There was examining histopathological and molecular alterations in a background history of intermittent, self-resolving a DLGNT cohort also identified a loss of function BCOR headaches over the prior 3–4  months. She was noted to variant [14]. Molecular findings such as these emphasise have moderate to severe papilloedema with associated Table 1 Molecular profiling of DLGNT cases from the PRISM clinical trial Case 1 Case 2 Tumour purity % 71 79 Ploidy Diploid Diploid Tumour mutational burden (mutations/Mb) 0.68 (low) 0.98 (low) Mutational signatures NIL NIL Somatic mutations BCOR:c.1555G > T (p.Glu519Ter) RET:c.2755G > C (p.Ala919Pro) Fusions KIAA1549-BRAF KIAA1549-BRAF Reportable copy number alterations 1p/19q loss, 1q gain 1p loss, 1q gain, chr8 gain Germline mutations NIL NIL RNA Expression Degraded sample Insufficient sample Methylation Match: methylation class diffuse leptomeningeal No match: methylation class glioneuronal tumor (0.97) family Glioblastoma, IDH wildtype (0.78) Molecular alterations from WGS, RNAseq and methylome data as curated and discussed at a Multidisciplinary Tumour Board Manoharan et al. acta neuropathol commun (2021) 9:147 Page 4 of 11 haemorrhages, engorged vessels and decreased visual confirmation, the RET mutation remains a variant of acuity. MRI brain and spine demonstrated a mass in the unknown significance in this tumour. spinal cord extending from C3 to T2, filling most of the Copy number analysis revealed an aneuploid tumour spinal canal. There was some associated T2 hyperinten - with multiple alterations of unknown significance sity with several areas of cyst formation or necrosis and (Fig. 3b, Additional file  1: Tables 3 and 4). However, a loss an enhancing nodule at the cervicothoracic junction of chromosome 1p and a gain of chromosome 1q and (Fig. 1c, d). chromosome 8 were also detected, which are in keep- The initial biopsy of a meningeal deposit was incon - ing with a subclass of DLGNT [14]. This tumour also clusive. A second biopsy of the intramedullary tumour contained a KIAA1549-BRAF fusion with an unknown was performed. Histopathology showed features of a highly repetitive DNA fragment inserted within the low grade tumour with both glial and neuronal differen - duplication (Fig.  3c). BLAT analysis of the repetitive tiation (Fig.  1e–g). There were neoplastic glial cells and sequence could not identify with high certainty the origin dysplastic neuronal cells with a ganglionic appearance. of this fragment. This can be visualised with the LINX Immunohistochemistry staining for BRAF V600E muta- plot in Fig. 3c with single end breakends (the purple lines tion was negative. Chromosome microarray detected a with open unshaded circles) bookending the KIAA1549- 1p deletion, 1q gain, chromosome 17 gain and indicated BRAF duplication as the other breakend match within a KIAA1549-BRAF fusion. A histopathological diagnosis the genome of the tumour could not be established. of DLGNT was made based on the above findings. This adds to the complexity of the formation of the Molecular profiling of a lesional biopsy sample through KIAA1549-BRAF fusion within this tumour which also PRISM identified a somatic RET variant of unknown sig - has 1 copy loss of the 7q arm where the KIAA1549 and nificance (p.Ala919Pro). RET is a receptor tyrosine kinase BRAF genes reside. This emphasizes that very complex that is an upstream member of the MAPK pathway [33]. genomic rearrangements may underlie the expression of This missense variant is situated in an ATP binding site even common fusion drivers. The combination of whole and the protein tyrosine kinase domain 2 and in silico genome and RNA sequencing often helps resolve such models have predicted this variant to be damaging. It is complexity [58]. Methylation studies processed through adjacent to a well-studied pathogenic gain of function the DKFZ CNS classifier found that the patient’s sam - mutation Met918Thr [27, 53] (Fig. 3a). Functional studies ple was not a strong match to any particular entity. The on the RET A919P variant suggest that this variant has an closest match was glioblastoma, subclass midline, IDH additive effect but may require a second hit in the RET wildtype (0.78). gene to be a tumourigenic driver [27]. The RET A919P Treatment with vincristine and carboplatin was com- variant along with the inclusion of a downstream path- menced but ceased after 3 cycles due to moderate to way member such as the KIAA1549-BRAF fusion (iden- severe drug reactions to carboplatin (fever, tachycar- tified in this tumour) may have an amplificative effect dia and hypotension). The patient was subsequently on the MAPK pathway. However, without biological treated with trametinib, based on the presence of the (See figure on next page.) Fig. 2 Molecular alterations within DLGNT case 1. a Schematic of the BCOR gene demonstrating protein domains and the location of the E519* variant. Synonymous mutations have been excluded and data from PeCan incorporated. b CIRCOS plot illustrating the somatic alterations in the tumour and labelling of common tumour suppressor genes (brown) and oncogenes (black) in the MAPK pathway. The CIRCOS plot can be interpreted as follows: The outer first circle demonstrates the 22 autosomal chromosomes and the sex chromosomes. The dark band within the chromosome represents the centrosomes with the p arm to the left of the band and the q arm to the right. The dark bands can also be representative of heterochromatin or missing p arms. The following circle (light purple) illustrates the somatic single nucleotide variants with each dot representing a missense change (C > A blue, C > G black, C > T red, T > A grey, T > A grey, T > C green, T > G pink) and the location of the dot within the circle is associated with its corrected allele frequency (0% at the bottom edge of the ring to 100% at the top edge of the ring). The next ring consists of short insertions and deletions (yellow and red, respectively). The third circle consisting of red and green shading shows the copy number alterations in the tumour with red indicating loss and green indicating gains/amplifications (with the scale ranging from a complete loss of 0 up to gains and above of 6). The fourth circle (orange and blue shading) demonstrates the ‘minor allele copy numbers’ ranging from 0 to 3. Loss of heterozygosity is indicated in orange and is for values below 1, whereas amplification of both alleles is shown in blue and it will be any value above 1. The innermost circle represents different types of structural variants in the tumour (translocations (blue), deletions (red), insertions (yellow), tandem duplications (green) and inversions (black). c LINX plot demonstrating the KIAA1549-BRAF dup in this case. The outer edge shows the chromosomes affected by structural variants (SVs) in the tumour and the position of their breakends. The KIAA1549 and BRAF genes are shown in blue and brown, respectively with their exons numbered. The internal circle shows the derivative chromosome segments with breakends shown as shaded circles and the same event united with the same coloured line. The inner green and pink circles show copy number gain or loss, respectively and the inner blue and orange circles show the minor allele ploidy. The innermost circle demonstrates the break junctions of the SVs M anoharan et al. acta neuropathol commun (2021) 9:147 Page 5 of 11 Fig. 2 (See legend on previous page.) KIAA1549-BRAF duplication, with early evidence of Discussion minor response on surveillance MRI. Subsequently, Diffuse leptomeningeal glioneuronal tumours are a rare the patient had disease progression after 6  months on group of central nervous system (CNS) tumours, with trametinib. Further treatment options are currently being less than 100 cases reported in the literature [1, 4, 7, 9, explored. 11, 13, 14, 16, 17, 23–25, 34, 42–47, 49–51]. The major - ity of cases are reported in children but adult cases have Manoharan et al. acta neuropathol commun (2021) 9:147 Page 6 of 11 Fig. 3 Molecular alterations within DLGNT case 2. a Schematic of the RET gene demonstrating protein domains and the location of the A919P variant in this tumour along with the most commonly seen missense variant M918T (COSMIC) and mutations from PeCan. b CIRCOS plot indicating various copy number alterations from the tumour in case 2. c LINX plot demonstrating the complex KIAA1549-BRAF dup in case 2 also been described [11, 13, 45]. Although defined in childhood’ [45] and ‘Superficially disseminated glioma 2016, DLGNT is likely synonymous with other histori- of children’ [1]. These tumours are characterized radio - cal entities variably described in the literature prior to logically by widespread leptomeningeal enhancement the 2016 classification as ‘Primary diffuse leptomenin - on MRI and histologically by low to moderate-density geal oligodendroglioma’ [24], ‘Diffuse leptomeningeal with cellular features that are akin to oligodendroglio- oligodendrogliomatosis’ [4, 7, 9], ‘Primary dissemi- mas [1, 4, 22, 25, 45]. Attempts to classify this group of nated leptomeningeal oligodendroglioma’ [7], ‘Dissemi- tumours as a single pathologic entity were buoyed by nated oligodendroglial-like leptomeningeal tumour of Rodriguez et  al.’s publication of the largest case series M anoharan et al. acta neuropathol commun (2021) 9:147 Page 7 of 11 of 36 cases and description of common radiological, anaplastic changes, focally elevated proliferative index histopathological and chromosomal abnormalities (up to 53% in some cases) and glomeruloid microvascular demonstrated on FISH and SNP array [45]. Here we changes [34, 41, 45, 50]. demonstrate the findings of the first comprehensive The clinical course for the majority of patients with genomic profiling of two cases of DLGNT that further DLGNT is indolent with some patients displaying slow our understanding of this rare and enigmatic disease. asymptomatic progression without therapy for over The clinical presentation of patients with DLGNT are 18  months [16, 45, 50]. Unfortunately, for a subset of varied, dependent on area(s) of disease involvement and patients, the clinical course is more aggressive and relent- range from paraesthesia and seizures to symptoms of less and results in patients dying of their disease [16, 22, hydrocephalus, such as headache and vomiting [1, 11, 16, 45]. Due to the rarity of this disease and lack of estab- 45, 49]. The diagnosis of DLGNT can be complicated by lished treatment protocols, comparison of clinical out- the wide range of differential diagnoses for leptomenin - comes for patients on different therapies is not possible geal enhancement on MRI scans including infection and [2, 16]. Treatment strategies employed for patients with subarachnoid haemorrhage and difficulties in obtaining a this disease range from observation only, to chemother- histopathological diagnosis due to small biopsy samples apy, to craniospinal radiation. Multiple paediatric low [54, 56]. grade glioma (pLGG) chemotherapy protocols have been Radiologically, the classic MRI findings in DLGNT administered in this patient population including combi- include leptomeningeal enhancement involving the brain nations of vincristine and carboplatin (VCR/carboplatin); and spine associated with cystic T2 hyperintense lesions carboplatin monotherapy; vinblastine monotherapy; that may not enhance. The intracranial disease is typi - bevacizumab; temozolomide, cisplatin/etoposide and cally most evident in the basal cisterns, Sylvian fissures, combination therapy with thioguanine, procarbazine, brainstem and cerebellar folia. Discrete parenchymal lomustine and vincristine (TPCV) [6, 12, 15, 26, 38, 40]. abnormalities are described in the spine and can be asso- These treatment protocols have resulted in some patients ciated with thickening of nerve roots [16, 45, 48, 49, 55, achieving a partial response (PR) and others achieving 56]. Although multiple cases of DLGNT display this clas- long-term stable disease (SD), suggesting a role for pLGG sical appearance on MRI, others are atypical in radiologi- chemotherapy in DLGNT [2, 16, 45, 57]. Other reports cal appearance but consistent with the histopathological have described clear clinical improvement and radiologi- and/or molecular diagnosis [47, 50]. cal stability after craniospinal irradiation in a subset of The histopathologic diagnosis of DLGNT is often patients with DLGNT [16, 22, 45]. The rarity of DLGNT elusive due to limited tumour material from biopsies has precluded the development of randomized clinical of sparse leptomeningeal disease and as a result, multi- trials to determine the optimal treatment of this disease. ple patients have non-diagnostic initial biopsies [2, 49]. Recent advances in genomic analyses of childhood As in Case 1, patients may be empirically commenced CNS tumours have resulted in an improved understand- on treatment for another condition such as tubercu- ing of key genetic alterations in multiple types of brain lous meningitis or subarachnoid haemorrhage based tumours. In DLGNT, these analyses have highlighted the on radiological and clinical features [50, 51, 54]. As a sentinel role of activation of the mitogen-activated pro- result, diagnostic workup can be prolonged and treat- tein kinase/extracellular signal regulated kinase (MAPK/ ment for DLGNT delayed. Patients with cerebrospinal ERK) pathway in tumourigenesis [10, 11, 14, 16, 46]. The fluid (CSF) sent for cytology typically  show no evidence pivotal role of aberrant MAPK/ERK pathway activa- of tumour cells despite extensive leptomeningeal disease tion has been well described as a crucial driver in pLGG radiologically [1, 45, 49]. The classic histopathologic fea - and targeting this pathway is now the focus of multiple tures of DLGNT are that of a low- to moderate-cellular- paediatric clinical trials [20, 28, 29, 35–37]. The most ity tumour with monomorphic oligodendroglioma-like frequent alteration described in pLGG is BRAF dupli- cells surrounded by dense collagen. The monomorphic cation with KIAA1549 being the most common fusion intermediate-sized cells typically have low mitotic activ- partner [59]. Recent publications have highlighted the ity (median 0–4 mitoses per high power field) and low role of the MAPK/ERK pathway alterations in DLGNT Ki-67 labelling-index (< 5%) and the majority of patients with KIAA1549:BRAF fusions being the most common displayed desmoplastic stroma [45]. OLIG2 expression genomic event seen with deletion of chromosomal arm on IHC is classic with more variable expression of GFAP 1p or 1p/19q co-deletion [11, 14, 16, 46]. Despite the oli- or synaptophysin [11, 45, 49]. Although the majority of godendroglioma-like appearance of DLGNT on histopa- patients have histopathologic features consistent with thology, IDH mutations are not apparent in this disease a low-grade glioneuronal tumour, a small subset have [14, 16]. Other alterations described in DLGNT include concerning high-grade pathologic features including BRAF V600E mutation and fusions of NTRK1/2/3 and Manoharan et al. acta neuropathol commun (2021) 9:147 Page 8 of 11 TRIM33:RAF1, which are known to result in activation of with a poorer prognosis and clinical outcome [8, 14]. The the MAPK/ERK pathway [3, 14, 16, 30, 31, 59]. detailed copy number analysis from our study allowed us Our work and others describe MAPK/ERK pathway to segregate the two DLGNT tumours based on the sug- alterations as the dominant pathway alteration, identified gested molecular profiles from Deng et  al. The genomic in up to 66–80% of DLGNT [11, 14, 16, 46]. Despite mul- profile from case 1 matches well with the DLGNT- tiple recent publications highlighting the potential role of MC-1 subclass due to the 1p loss and 7q34 gain associ- MAPK/ERK pathway alterations in DLGNT, many have ated with both classes, but more specifically the 1p/19q limited their analysis to targeted profiling of BRAF altera- co-deletion observed in 47% of DLGNT-MC-1 vs 15% tions, and FISH and SNP arrays as methods of detecting in DLNT-MC-2. In contrast, case 2 closely resembles MAPK/ERK pathway alterations [11, 16, 46]. Through DLGNT-MC-2, specifically with the 1q gain (100% of PRISM, we were able to undertake comprehensive profil - DLGNT-MC-2 vs. 35% DLGNT-MC-1), chromosome ing of the cancer genome of DLGNT to interrogate the 8 gain (54% of DLGNT-MC-2 vs 6% in DLGNT-MC-1) genomics of this rare disease to a depth that has not pre- and absence of 1p/19q co-deletion. Furthermore, case 2 viously been described in the literature [58]. The PRISM contains a focal 7q34 gain (where the KIAA1549-BRAF program resulted in a patient receiving a diagnosis when fusion resides), but equates to a balanced ploidy in a histopathological review alone was unable to diagnose region of copy number loss as the entirety of 7q is hap- DLGNT and in this patient further pursuit of high-risk loid. We postulate that potentially the loss of identifiable surgical biopsy was avoided by comprehensive genomic methylation probes in this region along with the unusual analysis (Case 1). fragment within the KIAA1549-BRAF fusion of probable Although the comprehensive profiling performed in retrotransposon origin has led to the poor methylation PRISM is not universally accessible, it has the potential match within the DKFZ CNS classifier for this case. to identify novel drivers of tumourigenesis, which will be Our work will contribute to the genomic analysis of crucial in our understanding of this rare disease. In par- DLGNT and the ability of future profiling studies to iden - ticular, this will be crucial for the 20–30% of patients with tify alterations to the epigenome as a feature of DLGNT DLGNT for whom MAPK/ERK pathway alterations are tumours along with the MAPK pathway. Furthermore, not found and the oncogenic driver(s) remain elusive. we were able to exclude underlying germline mutations With limited tumour material, we were able to under- which have not been well studied in this disease and only take comprehensive profiling including WGS, methyla - identified in two previous patients, one with a germline tion and germline testing. This allowed for detection of TP53 variant and another with germline RAF1 mutation the KIAA1549:BRAF fusion in both patients as well as a and cardio-facio-cutaneous syndrome [16, 52]. pathogenic somatic BCOR variant in case 1 and a somatic The divergent clinical outcomes of patients with RET variant in case 2, along with numerous copy number DLGNT remain perplexing, with some patients expe- variations that we have not reported on due to uncertain riencing indolent chronic disease and others having an diagnostic and prognostic significance. Intriguingly, the aggressive relentless clinical trajectory [16, 21, 45, 49]. recent publication by Deng et  al. study also identified Establishing a link between the clinical paradigm and somatic variants in the BCOR and ATRX genes, which the genomics in these patients, remains an area of sig- are known in the literature to be epigenetic regulators [5, nificant interest. We reported on two cases with genetic 14]. profiles most resembling DLGNT-MC-1 (case 1) and Targeting the MAPK/ERK pathway in paediatric CNS DLGNT-MC-2 (case 2), despite both cases displaying tumours has been an area of significant progress in the the KIAA1549-:BRAF fusion. In addition, our identifica - last decade [32, 35]. With the advent of inhibitors of tion of a pathogenic BCOR variant (case 1) and somatic MEK and BRAF, targeted therapeutic options have been RET variant (case 2) suggests a wider genetic profile for shown in clinical trials to have a role in relapsed/refrac- this disease and evidence of intra-tumoral molecular het- tory pLGG and paediatric high grade glioma (pHGG) erogeneity that may contribute to variations in clinical [19, 36]. Although the use of targeted inhibitors of MEK outcomes. and BRAF have not yet been well described in DLGNT, demonstrating the sentinel role of the MAPK/ERK path- way will potentially allow these therapeutic options to be Conclusions used in paediatric patients with DLGNT (eg. case 2) in Diffuse leptomeningeal glioneuronal tumours (DLGNT) the future [35–37]. are an enigmatic and heterogeneous group of rare CNS Deng et al. described two separate methylation classes tumours that are an indolent disease for some patients of DLGNT (DLGNT-MC-1 and DLGNT-MC-2) with and an aggressive fatal tumour for others. With emerg- suggestion that DLGNT-MC-2 encompasses the patients ing knowledge about the role of MAPK/ERK pathway M anoharan et al. acta neuropathol commun (2021) 9:147 Page 9 of 11 Childhood Cancer is a joint initiative led by the Children’s Cancer Institute and aberrations in the majority of children with this disease, Sydney Children’s Hospital, Randwick. we highlight the value of comprehensive profiling of can - cer genomes in these patients. This profiling assists in Availability of data and materials WGS, RNAseq and methylation data generated by this study are available diagnosis, allows for detection of other novel genomic from the European Genome-phenome Archive under accession num- alterations that may be oncogenic drivers, and may con- ber EGAS00001004572. Databases used to help filter, prioritize and interpret tribute towards our understanding of the divergent clini- variants are available online, including COSMIC (https:// cancer. sanger. ac. uk/ cosmic), Cancer Gene Census (https:// cancer. sanger. ac. uk/ census), Pecan cal outcomes in this disease. (https:// pecan. stjude. cloud/), dbscSNV (http:// www. liulab. scien ce/ dbscs nv. html), dbNSFP (https:// sites. google. com/ site/ jpopg en/ dbNSFP), ExAC (http:// exac. broad insti tute. org/), gnomAD (https:// gnomad. broad insti tute. org/), Abbreviations MGRB (https:// sgc. garvan. org. au/), GIAB (https:// jimb. stanf ord. edu/ giab- resou BCOR: BCL6 corepressor; CSF: Cerebrospinal fluid; CNS: Central nervous rces), Platinum Genomes (https:// github. com/ Illum ina/ Plati numGe nomes), system; DLGNT: Diffuse leptomeningeal glioneuronal tumor; FISH: Fluores- ClinVar (https:// www. ncbi. nlm. nih. gov/ clinv ar/), ESP (https:// evs. gs. washi cence in situ hybridization; HTS: High-throughput drug screen; IDH: Isocitrate ngton. edu/ EVS/) and 1000 Genomes (https:// www. inter natio nalge nome. org/ dehydrogenase; IHC: Immunohistochemistry; MAPK/ERK: Mitogen-activated data). protein kinase/ extracellular signal regulated kinase; MRI: Magnetic resonance imaging; OLIG2: Oligodendrocyte transcription factor 2; PDX: Patient-derived xenograft; pHGG: Pediatric high-grade glioma; pLGG: Pediatric low-grade Declarations glioma; PR: Partial response; RET: Rearranged during transfection protoon- cogene; SD: Stable disease; WGS: Whole genome sequencing; WHO: World Ethics approval and consent to participate Health Organisation. Ethics approval was provided by the Hunter New England Human Research Ethics Committee of Hunter New England Local Health District in New South Wales, Australia (Reference No: 17/02/15/4.06) and New South Wales Human Supplementary Information Research Ethics Committee (Reference No: HREC/17/HNE/29) for the PRISM The online version contains supplementary material available at https:// doi. study. Informed consent for each participant was provided by parents/legal org/ 10. 1186/ s40478- 021- 01248-w. guardian for participants under the age of 18 years and by the participants who were over the age of 18 years. Additional file 1. Supplementary Tables 1 & 2: Single Nucleotide Variants Consent for publication (SNVs) and Copy Number Variants (CNVs) identified in case 1 from WGS, Not applicable. Supplementary Tables 3 & 4: SNVs and CNVs identified in case 2 from WGS Competing interests Additional file 2: Supplementary Figure 1: Histopathology images from The authors declare no relevant conflicts of interest. case 1 demonstrating: a. high power (×400) H&E staining demonstrating tumour cells embedded in fibromyxoid stroma, b. OLIG2 stain (×200), c. Author details synaptophysin stain (×400), CD56 stain (×400) Kids Cancer Centre, Sydney Children’s Hospital, Randwick, NSW 2031, Australia. Children’s Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Authors’ contributions Kensington, NSW, Australia. Cancer Centre for Children, The Children’s Hos- Conceptualization, NM, PE and DSZ; data curation, PA and MW; writing—origi- pital Westmead, Westmead, NSW 2145, Australia. Department of Anatomical nal draft preparation, NM, PA and AS; histopathology image curation and pho- Pathology, NSW Health Pathology, Prince of Wales Hospital, Randwick, NSW tography, MR and HD; review and editing, all authors; supervision, PE and DSZ. 2031, Australia. Department of Histopathology, The Children’s Hospital At All authors have read and agreed to the published version of the manuscript. Westmead, Westmead, NSW 2145, Australia. Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, VIC 3052, Australia. School Funding of Women’s and Children’s Health, UNSW Sydney, Kensington, NSW, Australia. We thank the Australian Federal Government Department of Health, the New Cancer Immunology Program, Peter MacCallum Cancer Centre, Mel- South Wales State Government and the Australian Cancer Research Founda- bourne 3000, Australia. Sir Peter MacCallum Department of Oncology, The tion for funding to establish infrastructure to support the Zero Childhood University of Melbourne, Parkville 3052, Australia. Cancer personalized medicine program. We thank the Kids Cancer Alliance, Cancer Therapeutics Cooperative Research Centre, for supporting the devel- Received: 23 July 2021 Accepted: 23 August 2021 opment of a personalized medicine program; Tour de Cure for supporting tumor biobank personnel; The Steven Walter Children’s Cancer Foundation and The Hyundai Help 4 Kids Foundation for supporting P.G.E.; and the Lions Kids Cancer Genome Project, a joint initiative of Lions International Founda- tion, the Australian Lions Children’s Cancer Research Foundation (ALCCRF), References the Garvan Institute of Medical Research, the Children’s Cancer Institute and 1. Agamanolis DP, Katsetos CD, Klonk CJ, Bartkowski HM, Ganapathy S, the Kids Cancer Centre, Sydney Children’s Hospital. 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Diffuse leptomeningeal glioneuronal tumour (DLGNT) in children: the emerging role of genomic analysis

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Abstract

Diffuse leptomeningeal glioneuronal tumours (DLGNT ) represent rare enigmatic CNS tumours of childhood. Most patients with this disease share common radiological and histopathological features but the clinical course of this disease is variable. A radiological hallmark of this disease is widespread leptomeningeal enhancement that may involve the entire neuroaxis with predilection for the posterior fossa and spine. The classic pathologic features include low- to moderate-density cellular lesions with OLIG2 expression and evidence of ‘oligodendroglioma-like’ appearance. The MAPK/ERK signaling pathway has recently been reported as a potential driver of tumourigenesis in up to 80% of DLGNT with KIAA1549:BRAF fusions being the most common event seen. Until now, limited analysis of the biological drivers of tumourigenesis has been undertaken via targeted profiling, chromosomal analysis and immunohistochem- istry. Our study represents the first examples of comprehensive genomic sequencing in DLGNT and shows that it is not only feasible but crucial to our understanding of this rare disease. Moreover, we demonstrate that DLGNT may be more genomically complex than single-event MAPK/ERK signaling pathway tumours. Keywords: Diffuse leptomeningeal glioneuronal tumour, Paediatrics, Brain tumour, Childhood malignancy Introduction Epic 850  K array) [8]. These cases emphasise the impor - Diffuse leptomeningeal glioneuronal tumours (DLGNT) tance of identifying the genomic and epigenomic driv- are rare central nervous system (CNS) tumours defined ers of tumourigenesis in DLGNT and other rare CNS in the 2016 World Health Organisation (WHO) classifi - tumours of childhood [14, 16, 49]. cation of CNS neoplasms [39]. We report on two molec- ularly-distinct cases of DLGNT that represent the only Case presentation patients in the literature to our knowledge whom have Case 1 been sequenced using a comprehensive molecular profil - A 13-year-old boy presented with a one-week history of ing platform including whole genome sequencing (WGS) lethargy, headaches and nausea. At presentation he was of germline and tumour DNA, transcriptome analysis noted to be drowsy and had a left sided facial droop, left (RNAseq) and DNA methylation profiling (based on the sided weakness and dysarthria. An MRI showed mul- tiple foci of abnormal T2 hyperintensity in the anterior spinal cord at C2 and large areas of abnormal T2 hyper- *Correspondence: d.ziegler@unsw.edu.au intensity within the cord at T7-9, all of which were con- Paul G. Ekert and David S. Ziegler have contributed equally to this trast-enhancing (Fig.  1a, b). Although there were no risk publication Kids Cancer Centre, Sydney Children’s Hospital, Randwick, NSW 2031, factors for tuberculosis and CSF, serum and urine were Australia negative for acid fast bacilli and mycobacteria, anti-TB, Full list of author information is available at the end of the article © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Manoharan et al. acta neuropathol commun (2021) 9:147 Page 2 of 11 Fig. 1 Radiological features of DLGNT on sagittal, T2-weighted images (a, c), T1 post-gadolinium imaged (b, d) and histopathological features of DLGNT (e, f, g): Radiology demonstrating a intramedullary C1-2 and T7-9 lesions. b ‘sugar coating’ leptomeningeal spread with nodular disease at cavernous sinus. c Intramedullary C2-T1 lesion with solid and cystic components. d ‘sugar coating’ leptomeningeal spread. Pathology of intramedullary tumour of case 2 demonstrating e. high power of H&E sections (400×) of dysplastic ganglionic type neurons with admixed neoplastic glial cells, f Neu-N positive dysplastic ganglionic type neurons, g diffuse positive staining of GFAP anti-bacteria and antiviral treatments were commenced showed small ovoid OLIG-2 positive cells with hyper- based on the MRI findings. CSF cytology was negative for chromatic nuclei in prominent myxoid stroma. There was tumour cells and had negative tumour markers. insufficient material for flow cytometry. FISH was nega - Biopsy of a cavernous sinus lesion was performed and tive for 1p and 19q loss. Ultimately the histopathology the post-operative course was complicated by recurrence was inconclusive and a definitive diagnosis could not be of hydrocephalus requiring an additional external ven- determined. tricular drain and ultimately the insertion of a ventricu- A sample was submitted for molecular profiling to the loperitoneal shunt. The biopsy was small and crushed but Zero Childhood Cancer (ZERO) national personalised M anoharan et al. acta neuropathol commun (2021) 9:147 Page 3 of 11 medicine program to assist with the diagnostic process the importance of exploring the genomic landscape of and clinical management [58]. Samples enrolled into the these rare tumours with NGS. ZERO national trial (PRecISion Medicine for Children Analysis of copy number variants revealed a 1p/19q co- with Cancer study—PRISM) require both tumour and deletion and 1q gain which is in keeping with a subclass matching germline samples from patients with high-risk of DLGNTs (Fig. 2b). Additional copy number changes of paediatric cancer. Due to diagnostic uncertainty, and per- unclear significance were gain of chromosome 7 and focal sisting MRI changes 1  month after initial presentation, losses in the 9p arm (Additional file  1: Tables 1 and 2). A consideration was given to further biopsy. However, the KIAA1549-BRAF fusion was also identified (Fig.  2c). A genomic analysis from the PRISM study resulted in the methylation array is part of the ZERO profiling of CNS diagnosis of DLGNT and prevented the need for further tumours, and is primarily used as an orthogonal diagnos- invasive surgical intervention. tic technique. Raw IDAT files were processed through the Molecular profiling of the cavernous sinus biopsy DKFZ Molecular Neuropathology (MNP) 2.0 classifier demonstrated multiple somatic genetic findings and and the sample was a match with diffuse leptomeningeal no reportable germline findings (summarized in glioneuronal tumour (probability = 0.97). The combina - Table  1). A somatic pathogenic nonsense BCOR vari- tion of the copy number changes, the KIAA1549-BRAF ant (p.Glu519Ter) was identified in the tumour. BCOR fusion and methylation classifier result aided in resolving is a transcriptional repressor that plays a role in chro- this clinical diagnostic dilemma. matin remodeling and acts as a tumour suppressor gene Treatment was commenced with a combination regi- [5]. The p.Glu519Ter variant is a truncating mutation in men of vincristine and carboplatin. After 6  months of exon 4/15 creating a premature stop codon predicted to treatment there was reduction in size of the intramedul- result in an absence of protein due to nonsense mediated lary lesions and stabilisation of the leptomeningeal dis- decay or complete loss of function due to an aberrant ease. However, the patient experienced an anaphylactic protein product. BCOR is situated on the X chromo- reaction to carboplatin and was subsequently treated some and being that this is a male patient, the hemizy- with 6  months of TPCV (thioguanine, procarbazine, gous mutation would result in no functional copies. The lomustine and vincristine) and achieved disease stability p.Glu519Ter variant is not present in population data- throughout treatment. The patient has now completed bases and in silico tools predict the mutation to be dam- treatment and has no clinical or radiological evidence of aging. Furthermore, most pathogenic/likely pathogenic disease progression 16 months from diagnosis. mutations in the BCOR gene within the ClinVar and PeCan database are loss of function mutations, provid- Case 2 ing additional support to the pathogenicity of this variant An 8-year-old girl presented with acute disorienta- [18, 60] (Fig.  2a). Interestingly, the study by Deng et  al. tion with associated vomiting and headache. There was examining histopathological and molecular alterations in a background history of intermittent, self-resolving a DLGNT cohort also identified a loss of function BCOR headaches over the prior 3–4  months. She was noted to variant [14]. Molecular findings such as these emphasise have moderate to severe papilloedema with associated Table 1 Molecular profiling of DLGNT cases from the PRISM clinical trial Case 1 Case 2 Tumour purity % 71 79 Ploidy Diploid Diploid Tumour mutational burden (mutations/Mb) 0.68 (low) 0.98 (low) Mutational signatures NIL NIL Somatic mutations BCOR:c.1555G > T (p.Glu519Ter) RET:c.2755G > C (p.Ala919Pro) Fusions KIAA1549-BRAF KIAA1549-BRAF Reportable copy number alterations 1p/19q loss, 1q gain 1p loss, 1q gain, chr8 gain Germline mutations NIL NIL RNA Expression Degraded sample Insufficient sample Methylation Match: methylation class diffuse leptomeningeal No match: methylation class glioneuronal tumor (0.97) family Glioblastoma, IDH wildtype (0.78) Molecular alterations from WGS, RNAseq and methylome data as curated and discussed at a Multidisciplinary Tumour Board Manoharan et al. acta neuropathol commun (2021) 9:147 Page 4 of 11 haemorrhages, engorged vessels and decreased visual confirmation, the RET mutation remains a variant of acuity. MRI brain and spine demonstrated a mass in the unknown significance in this tumour. spinal cord extending from C3 to T2, filling most of the Copy number analysis revealed an aneuploid tumour spinal canal. There was some associated T2 hyperinten - with multiple alterations of unknown significance sity with several areas of cyst formation or necrosis and (Fig. 3b, Additional file  1: Tables 3 and 4). However, a loss an enhancing nodule at the cervicothoracic junction of chromosome 1p and a gain of chromosome 1q and (Fig. 1c, d). chromosome 8 were also detected, which are in keep- The initial biopsy of a meningeal deposit was incon - ing with a subclass of DLGNT [14]. This tumour also clusive. A second biopsy of the intramedullary tumour contained a KIAA1549-BRAF fusion with an unknown was performed. Histopathology showed features of a highly repetitive DNA fragment inserted within the low grade tumour with both glial and neuronal differen - duplication (Fig.  3c). BLAT analysis of the repetitive tiation (Fig.  1e–g). There were neoplastic glial cells and sequence could not identify with high certainty the origin dysplastic neuronal cells with a ganglionic appearance. of this fragment. This can be visualised with the LINX Immunohistochemistry staining for BRAF V600E muta- plot in Fig. 3c with single end breakends (the purple lines tion was negative. Chromosome microarray detected a with open unshaded circles) bookending the KIAA1549- 1p deletion, 1q gain, chromosome 17 gain and indicated BRAF duplication as the other breakend match within a KIAA1549-BRAF fusion. A histopathological diagnosis the genome of the tumour could not be established. of DLGNT was made based on the above findings. This adds to the complexity of the formation of the Molecular profiling of a lesional biopsy sample through KIAA1549-BRAF fusion within this tumour which also PRISM identified a somatic RET variant of unknown sig - has 1 copy loss of the 7q arm where the KIAA1549 and nificance (p.Ala919Pro). RET is a receptor tyrosine kinase BRAF genes reside. This emphasizes that very complex that is an upstream member of the MAPK pathway [33]. genomic rearrangements may underlie the expression of This missense variant is situated in an ATP binding site even common fusion drivers. The combination of whole and the protein tyrosine kinase domain 2 and in silico genome and RNA sequencing often helps resolve such models have predicted this variant to be damaging. It is complexity [58]. Methylation studies processed through adjacent to a well-studied pathogenic gain of function the DKFZ CNS classifier found that the patient’s sam - mutation Met918Thr [27, 53] (Fig. 3a). Functional studies ple was not a strong match to any particular entity. The on the RET A919P variant suggest that this variant has an closest match was glioblastoma, subclass midline, IDH additive effect but may require a second hit in the RET wildtype (0.78). gene to be a tumourigenic driver [27]. The RET A919P Treatment with vincristine and carboplatin was com- variant along with the inclusion of a downstream path- menced but ceased after 3 cycles due to moderate to way member such as the KIAA1549-BRAF fusion (iden- severe drug reactions to carboplatin (fever, tachycar- tified in this tumour) may have an amplificative effect dia and hypotension). The patient was subsequently on the MAPK pathway. However, without biological treated with trametinib, based on the presence of the (See figure on next page.) Fig. 2 Molecular alterations within DLGNT case 1. a Schematic of the BCOR gene demonstrating protein domains and the location of the E519* variant. Synonymous mutations have been excluded and data from PeCan incorporated. b CIRCOS plot illustrating the somatic alterations in the tumour and labelling of common tumour suppressor genes (brown) and oncogenes (black) in the MAPK pathway. The CIRCOS plot can be interpreted as follows: The outer first circle demonstrates the 22 autosomal chromosomes and the sex chromosomes. The dark band within the chromosome represents the centrosomes with the p arm to the left of the band and the q arm to the right. The dark bands can also be representative of heterochromatin or missing p arms. The following circle (light purple) illustrates the somatic single nucleotide variants with each dot representing a missense change (C > A blue, C > G black, C > T red, T > A grey, T > A grey, T > C green, T > G pink) and the location of the dot within the circle is associated with its corrected allele frequency (0% at the bottom edge of the ring to 100% at the top edge of the ring). The next ring consists of short insertions and deletions (yellow and red, respectively). The third circle consisting of red and green shading shows the copy number alterations in the tumour with red indicating loss and green indicating gains/amplifications (with the scale ranging from a complete loss of 0 up to gains and above of 6). The fourth circle (orange and blue shading) demonstrates the ‘minor allele copy numbers’ ranging from 0 to 3. Loss of heterozygosity is indicated in orange and is for values below 1, whereas amplification of both alleles is shown in blue and it will be any value above 1. The innermost circle represents different types of structural variants in the tumour (translocations (blue), deletions (red), insertions (yellow), tandem duplications (green) and inversions (black). c LINX plot demonstrating the KIAA1549-BRAF dup in this case. The outer edge shows the chromosomes affected by structural variants (SVs) in the tumour and the position of their breakends. The KIAA1549 and BRAF genes are shown in blue and brown, respectively with their exons numbered. The internal circle shows the derivative chromosome segments with breakends shown as shaded circles and the same event united with the same coloured line. The inner green and pink circles show copy number gain or loss, respectively and the inner blue and orange circles show the minor allele ploidy. The innermost circle demonstrates the break junctions of the SVs M anoharan et al. acta neuropathol commun (2021) 9:147 Page 5 of 11 Fig. 2 (See legend on previous page.) KIAA1549-BRAF duplication, with early evidence of Discussion minor response on surveillance MRI. Subsequently, Diffuse leptomeningeal glioneuronal tumours are a rare the patient had disease progression after 6  months on group of central nervous system (CNS) tumours, with trametinib. Further treatment options are currently being less than 100 cases reported in the literature [1, 4, 7, 9, explored. 11, 13, 14, 16, 17, 23–25, 34, 42–47, 49–51]. The major - ity of cases are reported in children but adult cases have Manoharan et al. acta neuropathol commun (2021) 9:147 Page 6 of 11 Fig. 3 Molecular alterations within DLGNT case 2. a Schematic of the RET gene demonstrating protein domains and the location of the A919P variant in this tumour along with the most commonly seen missense variant M918T (COSMIC) and mutations from PeCan. b CIRCOS plot indicating various copy number alterations from the tumour in case 2. c LINX plot demonstrating the complex KIAA1549-BRAF dup in case 2 also been described [11, 13, 45]. Although defined in childhood’ [45] and ‘Superficially disseminated glioma 2016, DLGNT is likely synonymous with other histori- of children’ [1]. These tumours are characterized radio - cal entities variably described in the literature prior to logically by widespread leptomeningeal enhancement the 2016 classification as ‘Primary diffuse leptomenin - on MRI and histologically by low to moderate-density geal oligodendroglioma’ [24], ‘Diffuse leptomeningeal with cellular features that are akin to oligodendroglio- oligodendrogliomatosis’ [4, 7, 9], ‘Primary dissemi- mas [1, 4, 22, 25, 45]. Attempts to classify this group of nated leptomeningeal oligodendroglioma’ [7], ‘Dissemi- tumours as a single pathologic entity were buoyed by nated oligodendroglial-like leptomeningeal tumour of Rodriguez et  al.’s publication of the largest case series M anoharan et al. acta neuropathol commun (2021) 9:147 Page 7 of 11 of 36 cases and description of common radiological, anaplastic changes, focally elevated proliferative index histopathological and chromosomal abnormalities (up to 53% in some cases) and glomeruloid microvascular demonstrated on FISH and SNP array [45]. Here we changes [34, 41, 45, 50]. demonstrate the findings of the first comprehensive The clinical course for the majority of patients with genomic profiling of two cases of DLGNT that further DLGNT is indolent with some patients displaying slow our understanding of this rare and enigmatic disease. asymptomatic progression without therapy for over The clinical presentation of patients with DLGNT are 18  months [16, 45, 50]. Unfortunately, for a subset of varied, dependent on area(s) of disease involvement and patients, the clinical course is more aggressive and relent- range from paraesthesia and seizures to symptoms of less and results in patients dying of their disease [16, 22, hydrocephalus, such as headache and vomiting [1, 11, 16, 45]. Due to the rarity of this disease and lack of estab- 45, 49]. The diagnosis of DLGNT can be complicated by lished treatment protocols, comparison of clinical out- the wide range of differential diagnoses for leptomenin - comes for patients on different therapies is not possible geal enhancement on MRI scans including infection and [2, 16]. Treatment strategies employed for patients with subarachnoid haemorrhage and difficulties in obtaining a this disease range from observation only, to chemother- histopathological diagnosis due to small biopsy samples apy, to craniospinal radiation. Multiple paediatric low [54, 56]. grade glioma (pLGG) chemotherapy protocols have been Radiologically, the classic MRI findings in DLGNT administered in this patient population including combi- include leptomeningeal enhancement involving the brain nations of vincristine and carboplatin (VCR/carboplatin); and spine associated with cystic T2 hyperintense lesions carboplatin monotherapy; vinblastine monotherapy; that may not enhance. The intracranial disease is typi - bevacizumab; temozolomide, cisplatin/etoposide and cally most evident in the basal cisterns, Sylvian fissures, combination therapy with thioguanine, procarbazine, brainstem and cerebellar folia. Discrete parenchymal lomustine and vincristine (TPCV) [6, 12, 15, 26, 38, 40]. abnormalities are described in the spine and can be asso- These treatment protocols have resulted in some patients ciated with thickening of nerve roots [16, 45, 48, 49, 55, achieving a partial response (PR) and others achieving 56]. Although multiple cases of DLGNT display this clas- long-term stable disease (SD), suggesting a role for pLGG sical appearance on MRI, others are atypical in radiologi- chemotherapy in DLGNT [2, 16, 45, 57]. Other reports cal appearance but consistent with the histopathological have described clear clinical improvement and radiologi- and/or molecular diagnosis [47, 50]. cal stability after craniospinal irradiation in a subset of The histopathologic diagnosis of DLGNT is often patients with DLGNT [16, 22, 45]. The rarity of DLGNT elusive due to limited tumour material from biopsies has precluded the development of randomized clinical of sparse leptomeningeal disease and as a result, multi- trials to determine the optimal treatment of this disease. ple patients have non-diagnostic initial biopsies [2, 49]. Recent advances in genomic analyses of childhood As in Case 1, patients may be empirically commenced CNS tumours have resulted in an improved understand- on treatment for another condition such as tubercu- ing of key genetic alterations in multiple types of brain lous meningitis or subarachnoid haemorrhage based tumours. In DLGNT, these analyses have highlighted the on radiological and clinical features [50, 51, 54]. As a sentinel role of activation of the mitogen-activated pro- result, diagnostic workup can be prolonged and treat- tein kinase/extracellular signal regulated kinase (MAPK/ ment for DLGNT delayed. Patients with cerebrospinal ERK) pathway in tumourigenesis [10, 11, 14, 16, 46]. The fluid (CSF) sent for cytology typically  show no evidence pivotal role of aberrant MAPK/ERK pathway activa- of tumour cells despite extensive leptomeningeal disease tion has been well described as a crucial driver in pLGG radiologically [1, 45, 49]. The classic histopathologic fea - and targeting this pathway is now the focus of multiple tures of DLGNT are that of a low- to moderate-cellular- paediatric clinical trials [20, 28, 29, 35–37]. The most ity tumour with monomorphic oligodendroglioma-like frequent alteration described in pLGG is BRAF dupli- cells surrounded by dense collagen. The monomorphic cation with KIAA1549 being the most common fusion intermediate-sized cells typically have low mitotic activ- partner [59]. Recent publications have highlighted the ity (median 0–4 mitoses per high power field) and low role of the MAPK/ERK pathway alterations in DLGNT Ki-67 labelling-index (< 5%) and the majority of patients with KIAA1549:BRAF fusions being the most common displayed desmoplastic stroma [45]. OLIG2 expression genomic event seen with deletion of chromosomal arm on IHC is classic with more variable expression of GFAP 1p or 1p/19q co-deletion [11, 14, 16, 46]. Despite the oli- or synaptophysin [11, 45, 49]. Although the majority of godendroglioma-like appearance of DLGNT on histopa- patients have histopathologic features consistent with thology, IDH mutations are not apparent in this disease a low-grade glioneuronal tumour, a small subset have [14, 16]. Other alterations described in DLGNT include concerning high-grade pathologic features including BRAF V600E mutation and fusions of NTRK1/2/3 and Manoharan et al. acta neuropathol commun (2021) 9:147 Page 8 of 11 TRIM33:RAF1, which are known to result in activation of with a poorer prognosis and clinical outcome [8, 14]. The the MAPK/ERK pathway [3, 14, 16, 30, 31, 59]. detailed copy number analysis from our study allowed us Our work and others describe MAPK/ERK pathway to segregate the two DLGNT tumours based on the sug- alterations as the dominant pathway alteration, identified gested molecular profiles from Deng et  al. The genomic in up to 66–80% of DLGNT [11, 14, 16, 46]. Despite mul- profile from case 1 matches well with the DLGNT- tiple recent publications highlighting the potential role of MC-1 subclass due to the 1p loss and 7q34 gain associ- MAPK/ERK pathway alterations in DLGNT, many have ated with both classes, but more specifically the 1p/19q limited their analysis to targeted profiling of BRAF altera- co-deletion observed in 47% of DLGNT-MC-1 vs 15% tions, and FISH and SNP arrays as methods of detecting in DLNT-MC-2. In contrast, case 2 closely resembles MAPK/ERK pathway alterations [11, 16, 46]. Through DLGNT-MC-2, specifically with the 1q gain (100% of PRISM, we were able to undertake comprehensive profil - DLGNT-MC-2 vs. 35% DLGNT-MC-1), chromosome ing of the cancer genome of DLGNT to interrogate the 8 gain (54% of DLGNT-MC-2 vs 6% in DLGNT-MC-1) genomics of this rare disease to a depth that has not pre- and absence of 1p/19q co-deletion. Furthermore, case 2 viously been described in the literature [58]. The PRISM contains a focal 7q34 gain (where the KIAA1549-BRAF program resulted in a patient receiving a diagnosis when fusion resides), but equates to a balanced ploidy in a histopathological review alone was unable to diagnose region of copy number loss as the entirety of 7q is hap- DLGNT and in this patient further pursuit of high-risk loid. We postulate that potentially the loss of identifiable surgical biopsy was avoided by comprehensive genomic methylation probes in this region along with the unusual analysis (Case 1). fragment within the KIAA1549-BRAF fusion of probable Although the comprehensive profiling performed in retrotransposon origin has led to the poor methylation PRISM is not universally accessible, it has the potential match within the DKFZ CNS classifier for this case. to identify novel drivers of tumourigenesis, which will be Our work will contribute to the genomic analysis of crucial in our understanding of this rare disease. In par- DLGNT and the ability of future profiling studies to iden - ticular, this will be crucial for the 20–30% of patients with tify alterations to the epigenome as a feature of DLGNT DLGNT for whom MAPK/ERK pathway alterations are tumours along with the MAPK pathway. Furthermore, not found and the oncogenic driver(s) remain elusive. we were able to exclude underlying germline mutations With limited tumour material, we were able to under- which have not been well studied in this disease and only take comprehensive profiling including WGS, methyla - identified in two previous patients, one with a germline tion and germline testing. This allowed for detection of TP53 variant and another with germline RAF1 mutation the KIAA1549:BRAF fusion in both patients as well as a and cardio-facio-cutaneous syndrome [16, 52]. pathogenic somatic BCOR variant in case 1 and a somatic The divergent clinical outcomes of patients with RET variant in case 2, along with numerous copy number DLGNT remain perplexing, with some patients expe- variations that we have not reported on due to uncertain riencing indolent chronic disease and others having an diagnostic and prognostic significance. Intriguingly, the aggressive relentless clinical trajectory [16, 21, 45, 49]. recent publication by Deng et  al. study also identified Establishing a link between the clinical paradigm and somatic variants in the BCOR and ATRX genes, which the genomics in these patients, remains an area of sig- are known in the literature to be epigenetic regulators [5, nificant interest. We reported on two cases with genetic 14]. profiles most resembling DLGNT-MC-1 (case 1) and Targeting the MAPK/ERK pathway in paediatric CNS DLGNT-MC-2 (case 2), despite both cases displaying tumours has been an area of significant progress in the the KIAA1549-:BRAF fusion. In addition, our identifica - last decade [32, 35]. With the advent of inhibitors of tion of a pathogenic BCOR variant (case 1) and somatic MEK and BRAF, targeted therapeutic options have been RET variant (case 2) suggests a wider genetic profile for shown in clinical trials to have a role in relapsed/refrac- this disease and evidence of intra-tumoral molecular het- tory pLGG and paediatric high grade glioma (pHGG) erogeneity that may contribute to variations in clinical [19, 36]. Although the use of targeted inhibitors of MEK outcomes. and BRAF have not yet been well described in DLGNT, demonstrating the sentinel role of the MAPK/ERK path- way will potentially allow these therapeutic options to be Conclusions used in paediatric patients with DLGNT (eg. case 2) in Diffuse leptomeningeal glioneuronal tumours (DLGNT) the future [35–37]. are an enigmatic and heterogeneous group of rare CNS Deng et al. described two separate methylation classes tumours that are an indolent disease for some patients of DLGNT (DLGNT-MC-1 and DLGNT-MC-2) with and an aggressive fatal tumour for others. With emerg- suggestion that DLGNT-MC-2 encompasses the patients ing knowledge about the role of MAPK/ERK pathway M anoharan et al. acta neuropathol commun (2021) 9:147 Page 9 of 11 Childhood Cancer is a joint initiative led by the Children’s Cancer Institute and aberrations in the majority of children with this disease, Sydney Children’s Hospital, Randwick. we highlight the value of comprehensive profiling of can - cer genomes in these patients. This profiling assists in Availability of data and materials WGS, RNAseq and methylation data generated by this study are available diagnosis, allows for detection of other novel genomic from the European Genome-phenome Archive under accession num- alterations that may be oncogenic drivers, and may con- ber EGAS00001004572. Databases used to help filter, prioritize and interpret tribute towards our understanding of the divergent clini- variants are available online, including COSMIC (https:// cancer. sanger. ac. uk/ cosmic), Cancer Gene Census (https:// cancer. sanger. ac. uk/ census), Pecan cal outcomes in this disease. (https:// pecan. stjude. cloud/), dbscSNV (http:// www. liulab. scien ce/ dbscs nv. html), dbNSFP (https:// sites. google. com/ site/ jpopg en/ dbNSFP), ExAC (http:// exac. broad insti tute. org/), gnomAD (https:// gnomad. broad insti tute. org/), Abbreviations MGRB (https:// sgc. garvan. org. au/), GIAB (https:// jimb. stanf ord. edu/ giab- resou BCOR: BCL6 corepressor; CSF: Cerebrospinal fluid; CNS: Central nervous rces), Platinum Genomes (https:// github. com/ Illum ina/ Plati numGe nomes), system; DLGNT: Diffuse leptomeningeal glioneuronal tumor; FISH: Fluores- ClinVar (https:// www. ncbi. nlm. nih. gov/ clinv ar/), ESP (https:// evs. gs. washi cence in situ hybridization; HTS: High-throughput drug screen; IDH: Isocitrate ngton. edu/ EVS/) and 1000 Genomes (https:// www. inter natio nalge nome. org/ dehydrogenase; IHC: Immunohistochemistry; MAPK/ERK: Mitogen-activated data). protein kinase/ extracellular signal regulated kinase; MRI: Magnetic resonance imaging; OLIG2: Oligodendrocyte transcription factor 2; PDX: Patient-derived xenograft; pHGG: Pediatric high-grade glioma; pLGG: Pediatric low-grade Declarations glioma; PR: Partial response; RET: Rearranged during transfection protoon- cogene; SD: Stable disease; WGS: Whole genome sequencing; WHO: World Ethics approval and consent to participate Health Organisation. Ethics approval was provided by the Hunter New England Human Research Ethics Committee of Hunter New England Local Health District in New South Wales, Australia (Reference No: 17/02/15/4.06) and New South Wales Human Supplementary Information Research Ethics Committee (Reference No: HREC/17/HNE/29) for the PRISM The online version contains supplementary material available at https:// doi. study. Informed consent for each participant was provided by parents/legal org/ 10. 1186/ s40478- 021- 01248-w. guardian for participants under the age of 18 years and by the participants who were over the age of 18 years. Additional file 1. Supplementary Tables 1 & 2: Single Nucleotide Variants Consent for publication (SNVs) and Copy Number Variants (CNVs) identified in case 1 from WGS, Not applicable. Supplementary Tables 3 & 4: SNVs and CNVs identified in case 2 from WGS Competing interests Additional file 2: Supplementary Figure 1: Histopathology images from The authors declare no relevant conflicts of interest. case 1 demonstrating: a. high power (×400) H&E staining demonstrating tumour cells embedded in fibromyxoid stroma, b. OLIG2 stain (×200), c. Author details synaptophysin stain (×400), CD56 stain (×400) Kids Cancer Centre, Sydney Children’s Hospital, Randwick, NSW 2031, Australia. Children’s Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Authors’ contributions Kensington, NSW, Australia. Cancer Centre for Children, The Children’s Hos- Conceptualization, NM, PE and DSZ; data curation, PA and MW; writing—origi- pital Westmead, Westmead, NSW 2145, Australia. Department of Anatomical nal draft preparation, NM, PA and AS; histopathology image curation and pho- Pathology, NSW Health Pathology, Prince of Wales Hospital, Randwick, NSW tography, MR and HD; review and editing, all authors; supervision, PE and DSZ. 2031, Australia. Department of Histopathology, The Children’s Hospital At All authors have read and agreed to the published version of the manuscript. Westmead, Westmead, NSW 2145, Australia. Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, VIC 3052, Australia. School Funding of Women’s and Children’s Health, UNSW Sydney, Kensington, NSW, Australia. We thank the Australian Federal Government Department of Health, the New Cancer Immunology Program, Peter MacCallum Cancer Centre, Mel- South Wales State Government and the Australian Cancer Research Founda- bourne 3000, Australia. Sir Peter MacCallum Department of Oncology, The tion for funding to establish infrastructure to support the Zero Childhood University of Melbourne, Parkville 3052, Australia. Cancer personalized medicine program. We thank the Kids Cancer Alliance, Cancer Therapeutics Cooperative Research Centre, for supporting the devel- Received: 23 July 2021 Accepted: 23 August 2021 opment of a personalized medicine program; Tour de Cure for supporting tumor biobank personnel; The Steven Walter Children’s Cancer Foundation and The Hyundai Help 4 Kids Foundation for supporting P.G.E.; and the Lions Kids Cancer Genome Project, a joint initiative of Lions International Founda- tion, the Australian Lions Children’s Cancer Research Foundation (ALCCRF), References the Garvan Institute of Medical Research, the Children’s Cancer Institute and 1. Agamanolis DP, Katsetos CD, Klonk CJ, Bartkowski HM, Ganapathy S, the Kids Cancer Centre, Sydney Children’s Hospital. Lions International and Staugaitis SM, Kuerbitz SJ, Patton DF, Talaizadeh A, Cohen BH (2012) An ALCCRF provided funding to perform WGS. We thank the Cure Brain Cancer unusual form of superficially disseminated glioma in children: report of Foundation for supporting RNA sequencing of patients with brain tumors; 3 cases. J Child Neurol 27:727–733. https:// doi. org/ 10. 1177/ 08830 73811 the Kids Cancer Project for supporting molecular profiling and molecular and clinical trial personnel; and the University of New South Wales, W. Peters and 2. Aguilera D, Castellino RC, Janss A, Schniederjan M, McNall R, MacDon- the Australian Genomics Health Alliance for providing personnel funding ald T, Mazewski C (2018) Clinical responses of patients with diffuse support. The New South Wales Ministry of Health-funded Luminesce Alliance leptomeningeal glioneuronal tumors to chemotherapy. Childs Nerv Syst provided funding support for computational personnel and infrastructure. 34:329–334. https:// doi. org/ 10. 1007/ s00381- 017- 3584-x The Medical Research Future Fund, the Australian Brain Cancer Mission, the 3. Amatu A, Sartore-Bianchi A, Siena S (2016) NTRK gene fusions as novel Minderoo Foundation’s Collaborate Against Cancer Initiative and funds raised targets of cancer therapy across multiple tumour types. ESMO Open through the Zero Childhood Cancer Capacity Campaign, a joint initiative of 1:e000023. https:// doi. org/ 10. 1136/ esmoo pen- 2015- 000023 the Children’s Cancer Institute and the Sydney Children’s Hospital Founda- 4. Armao DM, Stone J, Castillo M, Mitchell KM, Bouldin TW, Suzuki K (2000) tion, supported the national clinical trial and associated clinical and research Diffuse leptomeningeal oligodendrogliomatosis: radiologic/pathologic personnel. We thank the Kinghorn Foundation for personnel support. Zero correlation. 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J Neurooncol 104:529–533. https:// doi. org/ 10. 1007/ Publisher’s Note s11060- 010- 0505-1 Springer Nature remains neutral with regard to jurisdictional claims in pub- 49. Schniederjan MJ, Alghamdi S, Castellano-Sanchez A, Mazewski C, lished maps and institutional affiliations. Brahma B, Brat DJ, Brathwaite CD, Janss AJ (2013) Diffuse leptomeningeal neuroepithelial tumor: 9 pediatric cases with chromosome 1p/19q dele- tion status and IDH1 (R132H) immunohistochemistry. Am J Surg Pathol 37:763–771. https:// doi. org/ 10. 1097/ PAS. 0b013 e3182 7bf4cc Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? 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Acta Neuropathologica Communications – Springer Journals

Published: Sep 7, 2021

Keywords: Diffuse leptomeningeal glioneuronal tumour; Paediatrics; Brain tumour; Childhood malignancy

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