Prediction of central nervous system embryonal tumour outcome based on gene expression

Abstract

Embryonal tumours of the central nervous system (CNS) represent a heterogeneous group of tumours about which little is known biologically, and whose diagnosis, on the basis of morphologic appearance alone, is controversial. Medulloblastomas, for example, are the most common malignant brain tumour of childhood, but their pathogenesis is unknown, their relationship to other embryonal CNS tumours is debated, and patients' response to therapy is difficult to predict. We approached these problems by developing a classification system based on DNA microarray gene expression data derived from 99 patient samples. Here we demonstrate that medulloblastomas are molecularly distinct from other brain tumours including primitive neuroectodermal tumours (PNETs), atypical teratoid/rhabdoid tumours (AT/RTs) and malignant gliomas. Previously unrecognized evidence supporting the derivation of medulloblastomas from cerebellar granule cells through activation of the Sonic Hedgehog (SHH) pathway was also revealed. We show further that the clinical outcome of children with medulloblastomas is highly predictable on the basis of the gene expression profiles of their tumours at diagnosis.

Neural development and the ontogeny of central nervous system tumors

“…Tumors with identical histology and presumed state of differentiation might have very different growth characteristics and prognosis, and they apparently arise from different developmental lineages (Pomeroy et al, 2002). This is in agreement with the conclusion that cancer is a primarily a genetic disease.…”

“…Moreover, a small percentage of sporadic medulloblastomas have mutations of Smoothened (SMO), a transmembrane protein that interacts with PTCH and is derepressed when Shh binds to PTCH (Dong et al, 2000;Zurawel et al, 2000;Taylor et al, 2002). Both familial and sporadic medulloblastomas with mutations of molecules in the Shh/PTCH pathway are typically of the desmoplastic histological variant (Hynes et al, 1995;Pietsch et al, 1997;Pomeroy et al, 2002).…”

Advances in treatment of pediatric brain tumors

“…DNA microarray gene expression analyzed in tumor tissue from a large cohort of medulloblastoma patients showed that clinical outcome is predicted by the profile of gene expression, and is a better predictor than the expression or amplification of any single gene or any single gene mutation. 22 The results of the gene expression patterns and other genetic alterations are now being validated in the current Childrens Oncology Group (COG) protocols for medulloblastoma, and may complement clinical and histologic criteria for risk-stratification in future studies.…”

“…Recent significant advances made in identifying key molecular markers/gene expression patterns of theses tumors should help to resolve controversy about PNET classification and better stratify them for future therapy. 22 Medulloblastoma, (infratentorial or cerebellar PNET), accounts for 20-25 % of pediatric brain tumors, making it the most common intracranial tumor of childhood. 49 In children, the tumor typically arises from the cerebellar vermis in the roof of the fourth ventricle into which it grows, filling the cavity and causing obstructive hydrocephalus.…”

“…A pilot study of medulloblastoma DNA microarray gene expression was able to demonstrate that clinical outcomes of children with medulloblastoma was highly predictable on the basis of the gene expression profile of their tumors at diagnosis, and independent of clinical or other criteria. 22 The prognostic accuracy of any of these molecular markers in medulloblastoma is not yet firmly established, as they have all been evaluated in somewhat underpowered studies or have included heterogenous patient groups. However, validation of the most promising of these markers is ongoing in current COG and other international consortia medulloblastoma studies.…”