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Clinical outcome in pediatric glial and embryonal brain tumors correlates with in vitro multi-passageable neurosphere formation.

ABSTRACT: Cultured brain tumors can form neurospheres harboring tumorigenic cells with self renewal and differentiation capacities. Renewable neurosphere formation has clinical predictive value in adult malignant gliomas, yet its prognostic role for pediatric brain tumors is unknown.Established neurosphere conditions were used for culturing samples from glial, embryonal and mixed glioneuronal tumors from 56 pediatric patients. Potential associations between neurosphere formation and clinical outcome were analyzed retrospectively.Thirty-seven percent of all samples formed renewable neurospheres. Analysis of available clinical outcome data from 51 patients demonstrated significantly increased hazard ratios (HR) for both disease progression (HR = 9.9, P < 0.001) and death (HR = 16.6, P < 0.01) in the neurosphere forming group. Furthermore, neurosphere formation correlated with adverse progression free survival (PFS) in glial and embryonal tumors, but not in mixed glioneuronal tumors. Overall survival (OS) was significantly worse for neurosphere-forming patients with embryonal tumors, as a group and amongst the subgroup with medulloblastoma, but not in the glial group. Multivariate analysis showed that neurosphere formation was associated with diminished PFS and OS independent of age, gender, or treatment. Neurosphere formation was an independent predictor of diminished PFS of glial tumors after adjusting for grade. Multivariate analysis, adjusting for both Ki67 staining and neurosphere formation, demonstrated that neurosphere formation remained predictive of progression whereas Ki67 did not.Neurosphere formation is more predictive of pediatric brain tumor progression than semi-quantitative Ki67 staining. Pediatric brain tumor derived neurospheres may provide a predictive model for preclinical explorations.

SUBMITTER: Panosyan EH

PROVIDER: S-EPMC4017922 | biostudies-other | 2010 Oct

REPOSITORIES: biostudies-other

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Clinical outcome in pediatric glial and embryonal brain tumors correlates with in vitro multi-passageable neurosphere formation.

Panosyan Eduard H EH Laks Dan R DR Masterman-Smith Michael M Mottahedeh Jack J Yong William H WH Cloughesy Timothy F TF Lazareff Jorge A JA Mischel Paul S PS Moore Theodore B TB Kornblum Harley I HI

Pediatric blood & cancer 20101001 4

<h4>Background</h4>Cultured brain tumors can form neurospheres harboring tumorigenic cells with self renewal and differentiation capacities. Renewable neurosphere formation has clinical predictive value in adult malignant gliomas, yet its prognostic role for pediatric brain tumors is unknown.<h4>Methods</h4>Established neurosphere conditions were used for culturing samples from glial, embryonal and mixed glioneuronal tumors from 56 pediatric patients. Potential associations between neurosphere f ...[more]

PMID: 20589659

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Project description:Tremendous progress has recently been made in both molecular subgrouping, and the establishment of prognostic biomarkers for embryonal brain tumors, particularly medulloblastoma. Several prognostic biomarkers that were initially identified in retrospective cohorts of medulloblastoma, including MYC and MYCN amplification, nuclear ?-catenin accumulation, and chromosome 17 aberrations have now been validated in clinical trials. Moreover, molecular subgroups based on distinct transcriptome profiles have been consistently reported from various groups on different platforms demonstrating that the concept of distinct medulloblastoma subgroups is very robust. Well-described subgroups of medulloblastomas include tumors showing wingless signaling pathway (Wnt) activation, and another characterized by sonic hedgehog pathway activity. Two or more additional subgroups were consistently reported to contain the vast majority of high-risk tumors, including most tumors with metastatic disease at diagnosis and/or large cell/anaplastic histology. Several years ago, atypical teratoid rhabdoid tumor (AT/RT) was recognized as a separate entity based on its distinct biology and particularly aggressive clinical behavior. These tumors may occur supra or infratentorially and are usually found to have genetic alterations of SMARCB1 (INI1/hSNF5), a tumor suppressor gene located on chromosome 22q. Subsequent loss of SMARCB1 protein expression comprises a relatively specific and sensitive diagnostic marker for AT/RT. For CNS primitive neuroectodermal tumors (CNS PNETs), a consistent finding has been that they are molecularly distinct from medulloblastoma. Furthermore, a distinct fraction of CNS PNETs with particularly poor prognosis only occurring in young children was delineated, which was previously labeled ependymoblastoma or embryonal tumor with abundant neuropil and true rosettes (ETANTR) and which is morphologically characterized by the presence of multilayered "ependymoblastic" rosettes. This group of tumors shows a unique cytogenetic abnormality not seen in other brain tumors: focal amplification of a micro-RNA cluster at chromosome 19q13.42, which has never been found to be amplified in other CNS PNETs, medulloblastoma or AT/RT. In summary, these consistent findings have significantly contributed to our ability to sub-classify embryonal brain tumors into clinically and biologically meaningful strata and, for some of the subgroups, have led to the identification of specific targets for future development of molecularly targeted therapies.

Dataset Information

Clinical outcome in pediatric glial and embryonal brain tumors correlates with in vitro multi-passageable neurosphere formation.

Publications

Clinical outcome in pediatric glial and embryonal brain tumors correlates with in vitro multi-passageable neurosphere formation.

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