The genomic landscape of dysembryoplastic neuroepithelial tumours and a comprehensive analysis of recurrent cases

• Published in: Neuropathology and applied neurobiology 2022-10, Vol.48 (6), p.e12834-n/a
• Main Authors: Pagès, Mélanie, Debily, Marie‐Anne, Fina, Frédéric, Jones, David T. W., Saffroy, Raphael, Castel, David, Blauwblomme, Thomas, Métais, Alice, Bourgeois, Marie, Lechapt‐Zalcman, Emmanuèle, Tauziède‐Espariat, Arnault, Andreiuolo, Felipe, Chrétien, Fabrice, Grill, Jacques, Boddaert, Nathalie, Figarella‐Branger, Dominique, Beroukhim, Rameen, Varlet, Pascale
• Format: Article
• Language: English
• Subjects: Astrocytoma; Brain; Brain Neoplasms; Brain Neoplasms - pathology; Cancer; DNA fingerprinting; DNA methylation; DNA methylation profiling; dysembryoplastic neuroepithelial tumours; FGFR1; Fibroblast growth factor receptor 1; Genomics; Genotypes; Glioma; glioneuronal tumours; Humans; Hybridization; Immunohistochemistry; Life Sciences; MAP kinase; molecular pathology; Neoplasms, Neuroepithelial; Neoplasms, Neuroepithelial - genetics; Neoplasms, Neuroepithelial - pathology; paediatric low‐grade gliomas; Phenotypes; Retrospective Studies; Signal transduction; Spinal cord; Tumors
• ISSN: 0305-1846; 1365-2990; 1365-2990
• DOI: 10.1111/nan.12834

Aims Dysembryoplastic neuroepithelial tumour (DNT) is a glioneuronal tumour that is challenging to diagnose, with a wide spectrum of histological features. Three histopathological patterns have been described: specific DNTs (both the simple form and the complex form) comprising the specific glioneuronal element, and also the non‐specific/diffuse form which lacks it, and has unclear phenotype–genotype correlations with numerous differential diagnoses. Methods We used targeted methods (immunohistochemistry, fluorescence in situ hybridisation and targeted sequencing) and large‐scale genomic methodologies including DNA methylation profiling to perform an integrative analysis to better characterise a large retrospective cohort of 82 DNTs, enriched for tumours that showed progression on imaging. Results We confirmed that specific DNTs are characterised by a single driver event with a high frequency of FGFR1 variants. However, a subset of DNA methylation‐confirmed DNTs harbour alternative genomic alterations to FGFR1 duplication/mutation. We also demonstrated that a subset of DNTs sharing the same FGFR1 alterations can show in situ progression. In contrast to the specific forms, “non‐specific/diffuse DNTs” corresponded to a heterogeneous molecular group encompassing diverse, newly‐described, molecularly distinct entities. Conclusions Specific DNT is a homogeneous group of tumours sharing characteristics of paediatric low‐grade gliomas: a quiet genome with a recurrent genomic alteration in the RAS‐MAPK signalling pathway, a distinct DNA methylation profile and a good prognosis but showing progression in some cases. The “non‐specific/diffuse DNTs” subgroup encompasses various recently described histomolecular entities, such as PLNTY and diffuse astrocytoma, MYB or MYBL1 altered. Specific DNTs are characterized by a single driver event with a high frequency of FGFR1 duplication/mutation, but alternative genomic alterations could be observed. A subset of DNTs sharing the same FGFR1 alterations can show in situ progression. DNA methylation profiling could convey prognostic information as DNT‐MC‐1 is enriched with progressive form of DNT. Contrarily to specific forms, “non‐specific/diffuse DNTs” corresponded to a heterogeneous molecular group encompassing newly described distinct histo‐molecular tumours as PLNTY or diffuse astrocytoma, MYB or MYBL1‐altered.