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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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Kaplan-Meier and log-rank analysis for 72 neuroblastoma patients without MYCN amplification. OS (A) and EFS (B) of patients classified according to the NB-hypo. Solid and dashed curves represent good and poor prognosis patients, respectively. The p-value of the log-rank test is shown.
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Figure 4: Kaplan-Meier and log-rank analysis for 72 neuroblastoma patients without MYCN amplification. OS (A) and EFS (B) of patients classified according to the NB-hypo. Solid and dashed curves represent good and poor prognosis patients, respectively. The p-value of the log-rank test is shown.

Mentions: MYCN amplification is a very important risk factor in neuroblastoma and correlates with unfavorable prognosis. However, within patients lacking MYCN amplification, the commonly used prognostic factors give little information regarding outcome [34]. Thus, it was important to determine the predictive power of the NB-hypo in MYCN not amplified tumors found in 72 out of 88 patients. We classified the neuroblastoma patients into two classes by applying k-means clustering to the gene expression values of the 62 probesets. The Kaplan-Meier curves and log-rank test for overall survival (OS) (Figure 4A) and event-free survival (EFS) (Figure 4B) are shown. The results demonstrate a significant separation of the two curves in both OS (p < 0.001) and EFS (p < 0.001) thereby identifying good and poor prognosis MYCN not amplified patients. The good prognosis cluster consists of 61 patients, whereas 11 patients belong to the poor prognostic cluster. OS curves are characterized by a survival rate of 81.4% for the patients with good prognosis, compared with a survival rate of 24.2% for the patients with poor prognosis (HR = 6.71, 95% CI 8.74-182.30). EFS curves are characterized by a survival rate of 74.8% for the patients with good prognosis, compared with a survival rate of 27.3% for the patients with poor prognosis (HR = 4.53, 95% CI 3.49-50.25).


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)

Kaplan-Meier and log-rank analysis for 72 neuroblastoma patients without MYCN amplification. OS (A) and EFS (B) of patients classified according to the NB-hypo. Solid and dashed curves represent good and poor prognosis patients, respectively. The p-value of the log-rank test is shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Kaplan-Meier and log-rank analysis for 72 neuroblastoma patients without MYCN amplification. OS (A) and EFS (B) of patients classified according to the NB-hypo. Solid and dashed curves represent good and poor prognosis patients, respectively. The p-value of the log-rank test is shown.
Mentions: MYCN amplification is a very important risk factor in neuroblastoma and correlates with unfavorable prognosis. However, within patients lacking MYCN amplification, the commonly used prognostic factors give little information regarding outcome [34]. Thus, it was important to determine the predictive power of the NB-hypo in MYCN not amplified tumors found in 72 out of 88 patients. We classified the neuroblastoma patients into two classes by applying k-means clustering to the gene expression values of the 62 probesets. The Kaplan-Meier curves and log-rank test for overall survival (OS) (Figure 4A) and event-free survival (EFS) (Figure 4B) are shown. The results demonstrate a significant separation of the two curves in both OS (p < 0.001) and EFS (p < 0.001) thereby identifying good and poor prognosis MYCN not amplified patients. The good prognosis cluster consists of 61 patients, whereas 11 patients belong to the poor prognostic cluster. OS curves are characterized by a survival rate of 81.4% for the patients with good prognosis, compared with a survival rate of 24.2% for the patients with poor prognosis (HR = 6.71, 95% CI 8.74-182.30). EFS curves are characterized by a survival rate of 74.8% for the patients with good prognosis, compared with a survival rate of 27.3% for the patients with poor prognosis (HR = 4.53, 95% CI 3.49-50.25).

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