BACKGROUND: Childhood CNS primitive neuro-ectodermal brain tumours (PNETs) are very aggressive brain tumours for which the molecular features and best treatment approaches are unknown. We assessed a large cohort of these rare tumours to identify molecular markers to enhance clinical management of this disease. METHODS: We obtained 142 primary hemispheric CNS PNET samples from 20 institutions in nine countries and examined transcriptional profiles for a subset of 51 samples and copy number profiles for a subset of 77 samples. We used clustering, gene, and pathway enrichment analyses to identify tumour subgroups and group-specific molecular markers, and applied immunohistochemical and gene-expression analyses to validate and assess the clinical significance of the subgroup markers. FINDINGS: We identified three molecular subgroups of CNS PNETs that were distinguished by primitive neural (group 1), oligoneural (group 2), and mesenchymal lineage (group 3) gene-expression signatures with differential expression of cell-lineage markers LIN28 and OLIG2. Patients with group 1 tumours were most often female (male:female ratio 0.61 for group 1 vs 1.25 for group 2 and 1.63 for group 3; p=0.043 [group 1 vs groups 2 and 3]), youngest (median age at diagnosis 2.9 years [95% CI 2.4-5.2] for group 1 vs 7.9 years [6.0-9.7] for group 2 and 5.9 years [4.9-7.8] for group 3; p=0.005), and had poorest survival (median survival 0.8 years [95% CI 0.5-1.2] in group 1, 1.8 years [1.4-2.3] in group 2 and 4.3 years [0.8-7.8] in group 3; p=0.019). Patients with group 3 tumours had the highest incidence of metastases at diagnosis (no distant metastasis:metastasis ratio 0.90 for group 3 vs 2.80 for group 1 and 5.67 for group 2; p=0.037). INTERPRETATION: LIN28 and OLIG2 are promising diagnostic and prognostic molecular markers for CNS PNET that warrant further assessment in prospective clinical trials. FUNDING: Canadian Institute of Health Research, Brainchild/SickKids Foundation, and the Samantha Dickson Brain Tumour Trust.
Type of Publication:
Journal article published