Expression profiles of 151 pediatric low-grade gliomas reveal molecular differences associated with location and histological subtype

Bergthold, Guillaume; Bandopadhayay, Pratiti; Hoshida, Yujin; Ramkissoon, Shakti; Ramkissoon, Lori; Rich, Benjamin E.; Maire, Cécile L.; Paolella, Brenton R.; Schumacher, Steven E.; Tabak, Barbara; Ferrer-Luna, Rubén; Özek, M. Memet; Sav, Aydın; Santagata, Sandro; Wen, Patrick Y.; Goumnerova, Liliana; Ligon, Azra H.; Stiles, Charles D.; Segal, Rosalind A.; Golub, Todd R.; Grill, Jacques; Ligon, Keith L.; Chan, Jennifer A.; Kieran, Mark W.; Beroukhim, Rameen

doi:10.1093/neuonc/nov045

Cited by 42 publications

(47 citation statements)

References 45 publications

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“…BRAF mutations have been sparsely seen among adult lowgrade glial-neuronal tumors (49)(50)(51) LGG, a group comprised primarily of gangliogliomas, diffuse astrocytoma, DNET, and a small proportion of pilocytic astrocytomas, also demonstrating that this cluster was significantly enriched for a significant number of gene sets that together suggested a neuronal signature (55). Furthermore, they did not detect any alteration in gene expression profile among BRAF-altered tumors when compared with wild-type BRAF in LGG.…”

Section: Braf Mutations Are Common In Dig/diamentioning

confidence: 99%

Desmoplastic Infantile Ganglioglioma/Astrocytoma (DIG/DIA) Are Distinct Entities with Frequent BRAFV600 Mutations

Wang

Jones

Abecassis

et al. 2018

Molecular Cancer Research

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Desmoplastic infantile ganglioglioma (DIG) and desmoplastic infantile astrocytoma (DIA) are extremely rare tumors that typically arise in infancy; however, these entities have not been well characterized in terms of genetic alterations or clinical outcomes. Here, through a multi-institutional collaboration, the largest cohort of DIG/DIA to date is examined using advanced laboratory and data processing techniques. Targeted DNA exome sequencing and DNA methylation profiling were performed on tumor specimens obtained from different patients ( = 8) diagnosed histologically as DIG/DIGA. Two of these cases clustered with other tumor entities, and were excluded from analysis. The remaining 16 cases were confirmed to be DIG/DIA by histology and by DNA methylation profiling. Somatic gene mutations were discovered in 7 instances (43.8%); 4 were mutations, and 3 were mutations. Three instances of malignant transformation were found, and sequencing of the recurrence demonstrated a new mutation in one case, new deletion in one case, and in the third case, the original tumor harboredan fusion, also present at recurrence. DIG/DIA are distinct pathologic entities that frequently harbor mutations. Complete surgical resection is the ideal treatment, and overall prognosis is excellent. While, the small sample size and incomplete surgical records limit a definitive conclusion about the risk of tumor recurrence, the risk appears quite low. In rare cases with wild-type , malignant progression can be observed, frequently with the acquisition of other genetic alterations. DIG/DIA are a distinct molecular entity, with a subset frequently harboring either or mutations..

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Section: Braf Mutations Are Common In Dig/diamentioning

confidence: 99%

Desmoplastic Infantile Ganglioglioma/Astrocytoma (DIG/DIA) Are Distinct Entities with Frequent BRAFV600 Mutations

Wang

Jones

Abecassis

et al. 2018

Molecular Cancer Research

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“…While the presence of ganglion cells in DIG could suggest some biological overlap with conventional ganglioglioma, the latter lacks the very young patient age, massive size, and rich desmoplastic investiture of DIG. Gangliogliomas in pediatric patients are known to harbor v‐Raf murine sarcoma viral oncogene homolog B ( BRAF ) V600E mutations, variably reported as 35%, 50%, and >60% of cases. This has prompted several previous studies looking for BRAF mutations in DIAs and DIGs.…”

Section: Introductionmentioning

confidence: 99%

Desmoplastic infantile astrocytoma/ganglioglioma with rare BRAF V600D mutation

Greer

Foreman

Donson

et al. 2016

Pediatric Blood & Cancer

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Background Desmoplastic infantile astrocytoma (DIA) and desmoplastic infantile gangliogliomas (DIGs) are rare, massive, cystic and solid tumors of infants usually found in superficial cerebral hemispheres. They manifest prominent desmoplastic stroma, admixed neoplastic astrocytes, primitive-appearing small cells, and additional neoplastic ganglion cells in the case of DIGs. While v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutation is found in up to 50% of pediatric gangliogliomas, two recent studies found that it was rare in DIA/DIGs; we sought to assess BRAF status in DIA/DIGs from our institution. Procedure Departmental files from 2000 to 2016 were reviewed to identify cases. Clinical, neuroimaging, histological, and immunohistochemistry (IHC) features were assessed; the latter included IHC for astrocytic and neuronal markers and BRAF VE1. BRAF mutational assessment by Sanger and next-generation sequencing was attempted in all cases. Results All six identified cases (four males–two females; three DIA–three DIG) occurred in children <1-year old, were large, cerebral-hemispheric, cystic and solid, and enhancing tumors. Only one case, a DIG with prominent aggregates of neoplastic ganglion cells, showed either BRAF VE1 IHC positivity or mutation by Sanger and next-generation sequencing (rare c. 1799_1800delinsAT; p. V600D). Four of six archival cases were BRAF VE1 IHC negative, but failed mutational sequencing. Conclusion Five of six classic DIA/DIGs were negative for BRAF mutation; previous series have identified BRAF mutation in two of 18 and one of 14 cases, although all were the more common BRAF V600E. We were unable to find other examples of glial tumors in public databases with this rare BRAF V600D mutation. Identification of BRAF mutational opens the possibility of BRAF-targeted therapies for the subset of DIA/DIG that clinically progress postresection.

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“…These have shown that histologically identical tumours have different methylation and gene expression profiles depending on their location and that these differences are associated with genes involved in nervous system development pathways (Bergthold et al, 2015;Lambert et al, 2013;Sharma et al, 2007;Tchoghandjian et al, 2009). Here, we have provided further evidence in support of this concept, identifying location-specific differential methylation of genes involved in embryonic nervous system development, several of which have been previously reported, including LHX2, NR2E1, SIX3, PAX3 and IRX2 (Bergthold et al, 2015;Lambert et al, 2013;Sharma et al, 2007;Tchoghandjian et al, 2009). Additionally, our analysis showed that many of the location-specific differences identified in DNA methylation profile were reflected in control adult brain, which supports the concept that tissue of origin is an important driver of DNA methylation profile of histologically similar tumours.…”

Section: Discussionmentioning

confidence: 99%

“…Whilst there is no difference in the frequency of copy number variations according to PA location, there is evidence to show that tumour location is associated with specific MAPK pathway alterations (Jones et al, 2006;Pfister et al, 2008). For example, KIAA1549-BRAF fusions are more common in posterior fossa tumours (up to 90%), compared to supratentorial tumours (33-59%), and BRAF V600E mutations are more frequent in supratentorial tumours (~18%) than those in the posterior fossa (~3%) (Bergthold et al, 2015;Horbinski, 2013;Zhang et al, 2013). These location-specific alterations are also seen in gene expression analyses that show significant differences between supratentorial and infratentorial PAs and between hypothalamic/chiasmatic and posterior fossa PAs (Bergthold et al, 2015;Sharma et al, 2007;Tchoghandjian et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Methylation profiling of paediatric pilocytic astrocytoma reveals variants specifically associated with tumour location and predictive of recurrence

et al. 2018

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Childhood pilocytic astrocytomas (PA) are low‐grade tumours with an excellent prognosis. However, a minority, particularly those in surgically inaccessible locations, have poorer long‐term outcome. At present, it is unclear whether anatomical location in isolation, or in combination with underlying biological variation, determines clinical behaviour. Here, we have tested the utility of DNA methylation profiling to inform tumour biology and to predict behaviour in paediatric PA. Genome‐wide DNA methylation profiles were generated for 117 paediatric PAs. Using a combination of analyses, we identified DNA methylation variants specific to tumour location and predictive of behaviour. Receiver‐operating characteristic analysis was used to test the predictive utility of clinical and/or DNA methylation features to classify tumour behaviour at diagnosis. Unsupervised analysis distinguished three methylation clusters associated with tumour location (cortical, midline and infratentorial). Differential methylation of 5404 sites identified enrichment of genes involved in ‘embryonic nervous system development’. Specific hypermethylation of NEUROG1 and NR2E1 was identified as a feature of cortical tumours. A highly accurate method to classify tumours according to behaviour, which combined three clinical features (age, location and extent of resection) and methylation level at a single site, was identified. Our findings show location‐specific epigenetic profiles for PAs, potentially reflecting their cell type of origin. This may account for differences in clinical behaviour according to location independent of histopathology. We also defined an accurate method to predict tumour behaviour at diagnosis. This warrants further testing in similar patient cohorts.

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Expression profiles of 151 pediatric low-grade gliomas reveal molecular differences associated with location and histological subtype

Abstract: Expression profiling of PLGGs reveals significant differences associated with tumor location, histology, and BRAF genomic status. Supratentorial PAs, in particular, are enriched in inflammatory pathways that appear to be tumor-related.

Cited by 42 publications

References 45 publications

Desmoplastic Infantile Ganglioglioma/Astrocytoma (DIG/DIA) Are Distinct Entities with Frequent BRAFV600 Mutations

Desmoplastic Infantile Ganglioglioma/Astrocytoma (DIG/DIA) Are Distinct Entities with Frequent BRAFV600 Mutations

Desmoplastic infantile astrocytoma/ganglioglioma with rare BRAF V600D mutation

Methylation profiling of paediatric pilocytic astrocytoma reveals variants specifically associated with tumour location and predictive of recurrence

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