Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2011 Dec;13(12):1296-307.
doi: 10.1093/neuonc/nor140. Epub 2011 Sep 23.

High expression of BMP pathway genes distinguishes a subset of atypical teratoid/rhabdoid tumors associated with shorter survival

Diane K Birks  1 , Andrew M Donson, Purvi R Patel, Christopher Dunham, Andrea Muscat, Elizabeth M Algar, David M Ashley, B K Kleinschmidt-Demasters, Rajeev Vibhakar, Michael H Handler, Nicholas K Foreman
Affiliations

High expression of BMP pathway genes distinguishes a subset of atypical teratoid/rhabdoid tumors associated with shorter survival

Diane K Birks et al. Neuro Oncol. 2011 Dec.

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.

PubMed Disclaimer

Figures

Fig. 1.
Fig. 1.
Hierarchical clustering of AT/RTs. (A) Molecular profiling was performed using gene expression microarrays to measure 19,667 genes in 18 AT/RT tumor samples. The top 10% of genes, as ranked by variance across samples, were used as input to an agglomerative hierarchical clustering algorithm. Four clusters are defined on the resulting dendrogram, marked clusters 1–4. (B) Principal component analysis (PCA) of the AT/RTs in (A) using the same top 10% of high variance genes in (A).
Fig. 2.
Fig. 2.
Survival analysis of AT/RTs based on molecular classification. (A) Kaplan-Meier survival plot of 17 patients with AT/RT, using the clusters identified by hierarchical clustering of 18 patients with AT/RT (see Fig. 1). One patient included in the clustering was lost to follow-up and is not included in the survival analysis. The difference between the 4 clusters was statistically significant (log rank P value <.001). Vertical ticks indicate censored survival observations. (B) Multivariate survival model (Cox regression analysis) was used with the same patients in (A) to assess the importance of cluster membership and diagnostic age in AT/RT survival.
Fig. 3.
Fig. 3.
BMP4 gene expression in AT/RT samples. (A) Expression of BMP4 mRNA in 18 AT/RT samples grouped by the molecular clusters defined in Fig. 1. Gene expression was measured by Affymetrix U133 Plus2 GeneChips. (B) The same BMP4 expression values as (A), plotted against survival time for the 17 patients included in the survival analysis (Fig. 2) (one patient was lost to follow-up).
Fig. 4.
Fig. 4.
Differentially expressed BMP signaling genes. Heatmap of expression data for all genes from BMP signaling geneset #2 that showed differential expression (P < .05) in clusters 3 and 4 (short survival group), compared with clusters 1 and 2 (longer survival group). Eighteen genes were upregulated, and 7 were downregulated. Gene expression was measured by Affymetrix U133 Plus2 GeneChips.
Fig. 5.
Fig. 5.
Top-scoring Ingenuity pathways analysis functional network. The 193 genes differentially expressed between the short survival group (clusters 3 and 4) and the longer survival group (clustera 1 and 2) were input to Ingenuity pathway analysis for functional network generation. The top-scoring network is shown here. The intensity of the node color indicates the degree of upregulation (red) or downregulation (green) of genes differentially expressed in the dataset being examined.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Louis DN. International Agency for Research on Cancer. World Health Organization. WHO classification of tumours of the central nervous system. 4th ed. Lyon: International Agency for Research on Cancer; 2007.
    1. Biegel JA, Tan L, Zhang F, Wainwright L, Russo P, Rorke LB. Alterations of the hSNF5/INI1 gene in central nervous system atypical teratoid/rhabdoid tumors and renal and extrarenal rhabdoid tumors. Clin. Cancer Res. 2002;8(11):3461–3467. - PubMed
    1. Judkins AR, Mauger J, Ht A, Rorke LB, Biegel JA. Immunohistochemical analysis of hSNF5/INI1 in pediatric CNS neoplasms. Am J Surg Pathol. 2004;28(5):644–650. doi:10.1097/00000478-200405000-00013. - DOI - PubMed
    1. Hilden JM, Meerbaum S, Burger P, et al. Central nervous system atypical teratoid/rhabdoid tumor: results of therapy in children enrolled in a registry. J Clin Oncol. 2004;22(14):2877–2884. doi:10.1200/JCO.2004.07.073. - DOI - PubMed
    1. Chen ML, McComb JG, Krieger MD. Atypical teratoid/rhabdoid tumors of the central nervous system: management and outcomes. Neurosurg Focus. 2005;18(6A):E8. - PubMed

Publication types

MeSH terms