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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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Risk factors and survival of 72 MYCN not amplified patients. Patients are divided in poor and good prognosis groups according to the NB-hypo. Columns represent individual patients. The first line represents the patients according to the International Neuroblastoma Staging System (INSS). The second line represents the patients according to the age at diagnosis (> 1 year vs. < 1 year). In the last line, the patients are divided in deceased, black squares, and alive, gray squares.
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Figure 5: Risk factors and survival of 72 MYCN not amplified patients. Patients are divided in poor and good prognosis groups according to the NB-hypo. Columns represent individual patients. The first line represents the patients according to the International Neuroblastoma Staging System (INSS). The second line represents the patients according to the age at diagnosis (> 1 year vs. < 1 year). In the last line, the patients are divided in deceased, black squares, and alive, gray squares.

Mentions: We created a multivariate Cox proportional hazard regression model of age, INSS stage and NB-hypo (Table 6). The NB-hypo (p = 0.001; HR = 5.04; 95% CI, 2.00 to 12.69) is a significant independent predictor of outcome and it is equivalent to the INSS stage (p = 0.002; HR = 7.35; 95% CI, 2.13 to 25.40). Although the limited number of patients did not allow further sub grouping with statistical significance, it is interesting to analyze the association of the patients' risk factors profile with poor and good prognosis groups (Figure 5). All stage 1 and stage 4S patients and every stage 2 and stage 3 patients who survived were correctly classified by NB-hypo as good prognosis. Interestingly, NB-hypo correctly classified in the poor prognosis group the only stage 3, age>1 year intermediate risk and stage 2, age>1 year low risk patients who died.


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)

Risk factors and survival of 72 MYCN not amplified patients. Patients are divided in poor and good prognosis groups according to the NB-hypo. Columns represent individual patients. The first line represents the patients according to the International Neuroblastoma Staging System (INSS). The second line represents the patients according to the age at diagnosis (> 1 year vs. < 1 year). In the last line, the patients are divided in deceased, black squares, and alive, gray squares.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Risk factors and survival of 72 MYCN not amplified patients. Patients are divided in poor and good prognosis groups according to the NB-hypo. Columns represent individual patients. The first line represents the patients according to the International Neuroblastoma Staging System (INSS). The second line represents the patients according to the age at diagnosis (> 1 year vs. < 1 year). In the last line, the patients are divided in deceased, black squares, and alive, gray squares.
Mentions: We created a multivariate Cox proportional hazard regression model of age, INSS stage and NB-hypo (Table 6). The NB-hypo (p = 0.001; HR = 5.04; 95% CI, 2.00 to 12.69) is a significant independent predictor of outcome and it is equivalent to the INSS stage (p = 0.002; HR = 7.35; 95% CI, 2.13 to 25.40). Although the limited number of patients did not allow further sub grouping with statistical significance, it is interesting to analyze the association of the patients' risk factors profile with poor and good prognosis groups (Figure 5). All stage 1 and stage 4S patients and every stage 2 and stage 3 patients who survived were correctly classified by NB-hypo as good prognosis. Interestingly, NB-hypo correctly classified in the poor prognosis group the only stage 3, age>1 year intermediate risk and stage 2, age>1 year low risk patients who died.

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