Mpth-15molecular Reclassification of Cns-primitive Neuroectodermal Tumors Into Well-known and Novel Tumor Entities
Year: 2015
Type: article
Study design: Observational Study
Abstract: CNS-primitive neuroectodermal tumors (CNS-PNETs) are poorly differentiated embryonal tumors with early onset and aggressive clinical behavior. Histological diagnosis is complicated by morphological heterogeneity and divergent differentiation. Recent studies suggest the existence of molecular subgroups of CNS-PNETs sharing biological characteristics with other CNS tumors. To investigate this we have analyzed 301 fresh-frozen or paraffin-embedded CNS-PNET samples using DNA methylation (n = 301) and expression (n = 76) arrays. (Epi-)genetic profiles of CNS-PNETs were compared to >200 reference cases of other pediatric and adult brain tumors representing more than 20 well-known entities. DNA methylation and gene expression patterns segregated brain tumors by histological entities and molecular subgroups. Solely, CNS-PNET profiles showed a significant overlap with various well-defined entities, including AT/RT, ETMR, high-grade glioma, medulloblastoma, ependymoma, and others. When screening CNS-PNETs with profiles highly resembling other entities, hallmark genetic alterations of these, such as amplification of 19q13.42, mutations in IDH1 or H3F3A, or mutations/deletions of the SMARCB1 locus, were frequently detected. Also, established protein markers, such as INI-1, LIN28A, and OLIG2, confirmed the reclassification of these CNS-PNETs. Strikingly, a subset (∼25%) of CNS-PNETs, which could not be reclassified, segregated into at least five distinct molecular subgroups, each with its own characteristic pattern of DNA-methylation, copy number aberrations, gene expression, and recurrent mutations. Extending our clustering cohort to include larger series of non CNS PNET tumours, we identified additional brain tumors from various entities to resemble DNA methylation and mutation patterns of these five new molecular subgroups. The correct classification of CNS-PNETs based solely on histology remains challenging. The majority of cases can reliably be reclassified using molecular markers, indicating that a significant proportion of CNS-PNETs represents a variety of other brain tumor subtypes. The remaining CNS PNETs comprise five novel tumour groups with distinct molecular features that overlap with tumors previously diagnosed as non PNETs.
Source: Neuro-Oncology
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2561914539