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

Abstract

BackgroundHypoxia 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.ResultsWe 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.ConclusionsOur 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.

Integrative Analysis of DCE-MRI and Gene Expression Profiles in Construction of a Gene Classifier for Assessment of Hypoxia-Related Risk of Chemoradiotherapy Failure in Cervical Cancer

“…Out of our classifier genes, only KCTD11 and P4HA2 were present in three (10)(11)(12) or one (11) of the six signatures, respectively. These results support the view that there are molecular differences in the aggressive hypoxic phenotype across cancers (19) and that cancer-type specific hypoxia gene classifiers are more effective (18). Furthermore, although some of the other signatures were statistically significantly correlated with A Brix (Supplementary Document S3), the signature of our classifier genes showed a stronger A Brix -association and was thus the best one for describing the aggressive phenotype reflected in the DCE-MR images of cervical cancer.…”

“…Several hypoxia signatures have been constructed in different tissues (10)(11)(12)(13)(14)(15)(16)(17)(18), but a common cancer signature seems difficult to derive (19). The only hypoxia signature presented for cervical cancer was discovered in our previous work by combining global gene expression profiles and dynamic contrast enhanced (DCE)-MRI of the same patients (20).…”

In Vitro Modeling of Tissue-Specific 3D Microenvironments and Possibile Application to Pediatric Cancer Research

“…The angiogenic switch, intimately correlated with the hypoxic condition [281], is also involved in NBL progression. Indeed, it has been demonstrated that several angiogenic factors, such as VEGF, are expressed in NBL tissues in vivo; moreover, a positive correlation was observed between VEGF expression and poor outcome [282].…”

Neuroblastoma and Whole Genome Searches

“…In one study published in the 2010, (Fardin et al, 2010) and co-workers investigated the prognostic potential of hypoxia induced genes in neuroblastoma tumors. Hypoxia, a condition of low oxygen tension occurring in poorly vascularized areas, has profound effects on tumor cell growth, susceptibility to apoptosis, and resistance to radio-and chemotherapy.…”