title: High expression of BMP pathway genes distinguishes a subset of atypical teratoid/rhabdoid tumors associated with shorter survival.
abstract: Molecular profiling of tumors has proven to be a valuable tool for identification of prognostic and diagnostic subgroups in medulloblastomas, glioblastomas, and other cancers. However, the molecular landscape of atypical teratoid/rhabdoid tumors (AT/RTs) remains largely unexplored. To address this issue, we used microarrays to measure the gene expression profiles of 18 AT/RTs and performed unsupervised hierarchical clustering to determine molecularly similar subgroups. Four major subgroups (clusters) were identified. These did not conform to sex, tumor location, or presence of monosomy 22. Clusters showed distinct gene signatures and differences in enriched biological processes, including elevated expression of some genes associated with choroid plexus lineage in cluster 4. In addition, survival differed significantly by cluster, with shortest survival (mean, 4.7 months) in both clusters 3 and 4, compared with clusters 1 and 2 (mean, 28.1 months). Analysis showed that multiple bone morphogenetic protein (BMP) pathway genes were upregulated in the short survival clusters, with BMP4 showing the most significant upregulation (270-fold). Thus, high expression of BMP pathway genes was negatively associated with survival in this dataset. Our study indicates that molecular subgroups exist in AT/RTs and that molecular profiling of these comparatively rare tumors may be of diagnostic, prognostic, and therapeutic value.
authors.affiliation: University of Colorado, Denver-Anschutz Medical Campus, Department of Neurosurgery, Aurora, CO 80045, USA. diane.birks@ucdenver.edu
authors.forename: Diane K
authors.initials: DK
authors.lastname: Birks
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Donson
authors.forename: Purvi R
authors.initials: PR
authors.lastname: Patel
authors.forename: Christopher
authors.initials: C
authors.lastname: Dunham
authors.forename: Andrea
authors.initials: A
authors.lastname: Muscat
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Algar
authors.forename: David M
authors.initials: DM
authors.lastname: Ashley
authors.forename: B K
authors.initials: BK
authors.lastname: Kleinschmidt-Demasters
authors.forename: Rajeev
authors.initials: R
authors.lastname: Vibhakar
authors.forename: Michael H
authors.initials: MH
authors.lastname: Handler
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Foreman
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000235:genetics* / Q000378:metabolism; D002675:Child, Preschool; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018335:Rhabdoid Tumor / Q000145:classification* / Q000235:genetics / Q000401:mortality*; D013724:Teratoma / Q000145:classification* / Q000235:genetics / Q000401:mortality*
chemical_list: D014408:Biomarkers, Tumor; D019485:Bone Morphogenetic Proteins; D012333:RNA, Messenger