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A biology-driven approach identifies the hypoxia gene signature as a predictor of the outcome of neuroblastoma patients.

Fardin P, Barla A, Mosci S, Rosasco L, Verri A, Versteeg R, Caron HN, Molenaar JJ, Ora I, Eva A, Puppo M, Varesio L - Mol. Cancer (2010)

Bottom Line: The NB-hypo successfully stratifies the neuroblastoma patients into good and poor prognosis groups.Multivariate Cox analysis revealed that the NB-hypo is a significant independent predictor after controlling for commonly used risk factors including the amplification of MYCN oncogene.NB-hypo increases the resolution of the MYCN stratification by dividing patients with MYCN not amplified tumors in good and poor outcome suggesting that hypoxia is associated with the aggressiveness of neuroblastoma tumor independently from MYCN amplification.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Molecular Biology, Gaslini Institute, Genoa, Italy. paolofardin@ospedale-gaslini.ge.it

ABSTRACT

Background: Hypoxia is a condition of low oxygen tension occurring in the tumor microenvironment and it is related to poor prognosis in human cancer. To examine the relationship between hypoxia and neuroblastoma, we generated and tested an in vitro derived hypoxia gene signature for its ability to predict patients' outcome.

Results: We obtained the gene expression profile of 11 hypoxic neuroblastoma cell lines and we derived a robust 62 probesets signature (NB-hypo) taking advantage of the strong discriminating power of the l1-l2 feature selection technique combined with the analysis of differential gene expression. We profiled gene expression of the tumors of 88 neuroblastoma patients and divided them according to the NB-hypo expression values by K-means clustering. The NB-hypo successfully stratifies the neuroblastoma patients into good and poor prognosis groups. Multivariate Cox analysis revealed that the NB-hypo is a significant independent predictor after controlling for commonly used risk factors including the amplification of MYCN oncogene. NB-hypo increases the resolution of the MYCN stratification by dividing patients with MYCN not amplified tumors in good and poor outcome suggesting that hypoxia is associated with the aggressiveness of neuroblastoma tumor independently from MYCN amplification.

Conclusions: Our results demonstrate that the NB-hypo is a novel and independent prognostic factor for neuroblastoma and support the view that hypoxia is negatively correlated with tumors' outcome. We show the power of the biology-driven approach in defining hypoxia as a critical molecular program in neuroblastoma and the potential for improvement in the current criteria for risk stratification.

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Related in: MedlinePlus

Heatmap of the 62 probesets in the 88 neuroblastoma tumors. The expression data for each individual probeset have been scaled and are represented by pseudo-colors in the heatmap. Red color corresponds to high level of expression and green color corresponds to low level of expression. The 88 patients (columns) were divided into two groups by k-means clustering. Cluster 1 consists of 21 patients and cluster 2 consists of 67 patients. The expression values of the 62 probesets were grouped by hierarchical clustering (rows). Hierarchical clustering dendrogram is on the left and the corresponding probesets on the right.
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Figure 2: Heatmap of the 62 probesets in the 88 neuroblastoma tumors. The expression data for each individual probeset have been scaled and are represented by pseudo-colors in the heatmap. Red color corresponds to high level of expression and green color corresponds to low level of expression. The 88 patients (columns) were divided into two groups by k-means clustering. Cluster 1 consists of 21 patients and cluster 2 consists of 67 patients. The expression values of the 62 probesets were grouped by hierarchical clustering (rows). Hierarchical clustering dendrogram is on the left and the corresponding probesets on the right.

Mentions: To study the prognostic value of the NB-hypo, we classified 88 neuroblastoma patients into two groups by applying a k-means clustering to the gene expression values of the 62 probesets (Figure 2). The significance of the clustering performance was assessed by permutation tests of 62 random probesets. The misclassification distance was calculated each time and the t-test (p < 0.001, data not shown) indicated that the NB-hypo significantly stratified patients into two clusters of 21 (cluster 1) and 67 (cluster 2) patients respectively. The expression levels of the probesets were grouped by hierarchical clustering and are represented in the heatmap in Figure 2. Cluster 1 consists of tumors in which the hypoxia probesets are highly expressed and stable whereas cluster 2 consists of tumors in which the expression levels are lower and less stable.


A biology-driven approach identifies the hypoxia gene signature as a predictor of the outcome of neuroblastoma patients.

Fardin P, Barla A, Mosci S, Rosasco L, Verri A, Versteeg R, Caron HN, Molenaar JJ, Ora I, Eva A, Puppo M, Varesio L - Mol. Cancer (2010)

Heatmap of the 62 probesets in the 88 neuroblastoma tumors. The expression data for each individual probeset have been scaled and are represented by pseudo-colors in the heatmap. Red color corresponds to high level of expression and green color corresponds to low level of expression. The 88 patients (columns) were divided into two groups by k-means clustering. Cluster 1 consists of 21 patients and cluster 2 consists of 67 patients. The expression values of the 62 probesets were grouped by hierarchical clustering (rows). Hierarchical clustering dendrogram is on the left and the corresponding probesets on the right.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2908582&req=5

Figure 2: Heatmap of the 62 probesets in the 88 neuroblastoma tumors. The expression data for each individual probeset have been scaled and are represented by pseudo-colors in the heatmap. Red color corresponds to high level of expression and green color corresponds to low level of expression. The 88 patients (columns) were divided into two groups by k-means clustering. Cluster 1 consists of 21 patients and cluster 2 consists of 67 patients. The expression values of the 62 probesets were grouped by hierarchical clustering (rows). Hierarchical clustering dendrogram is on the left and the corresponding probesets on the right.
Mentions: To study the prognostic value of the NB-hypo, we classified 88 neuroblastoma patients into two groups by applying a k-means clustering to the gene expression values of the 62 probesets (Figure 2). The significance of the clustering performance was assessed by permutation tests of 62 random probesets. The misclassification distance was calculated each time and the t-test (p < 0.001, data not shown) indicated that the NB-hypo significantly stratified patients into two clusters of 21 (cluster 1) and 67 (cluster 2) patients respectively. The expression levels of the probesets were grouped by hierarchical clustering and are represented in the heatmap in Figure 2. Cluster 1 consists of tumors in which the hypoxia probesets are highly expressed and stable whereas cluster 2 consists of tumors in which the expression levels are lower and less stable.

Bottom Line: The NB-hypo successfully stratifies the neuroblastoma patients into good and poor prognosis groups.Multivariate Cox analysis revealed that the NB-hypo is a significant independent predictor after controlling for commonly used risk factors including the amplification of MYCN oncogene.NB-hypo increases the resolution of the MYCN stratification by dividing patients with MYCN not amplified tumors in good and poor outcome suggesting that hypoxia is associated with the aggressiveness of neuroblastoma tumor independently from MYCN amplification.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Molecular Biology, Gaslini Institute, Genoa, Italy. paolofardin@ospedale-gaslini.ge.it

ABSTRACT

Background: Hypoxia is a condition of low oxygen tension occurring in the tumor microenvironment and it is related to poor prognosis in human cancer. To examine the relationship between hypoxia and neuroblastoma, we generated and tested an in vitro derived hypoxia gene signature for its ability to predict patients' outcome.

Results: We obtained the gene expression profile of 11 hypoxic neuroblastoma cell lines and we derived a robust 62 probesets signature (NB-hypo) taking advantage of the strong discriminating power of the l1-l2 feature selection technique combined with the analysis of differential gene expression. We profiled gene expression of the tumors of 88 neuroblastoma patients and divided them according to the NB-hypo expression values by K-means clustering. The NB-hypo successfully stratifies the neuroblastoma patients into good and poor prognosis groups. Multivariate Cox analysis revealed that the NB-hypo is a significant independent predictor after controlling for commonly used risk factors including the amplification of MYCN oncogene. NB-hypo increases the resolution of the MYCN stratification by dividing patients with MYCN not amplified tumors in good and poor outcome suggesting that hypoxia is associated with the aggressiveness of neuroblastoma tumor independently from MYCN amplification.

Conclusions: Our results demonstrate that the NB-hypo is a novel and independent prognostic factor for neuroblastoma and support the view that hypoxia is negatively correlated with tumors' outcome. We show the power of the biology-driven approach in defining hypoxia as a critical molecular program in neuroblastoma and the potential for improvement in the current criteria for risk stratification.

Show MeSH
Related in: MedlinePlus