Poster Presentation Advances in Neuroblastoma Research Congress 2016

Clinical significance of a seven-gene hypoxia signature in neuroblastoma (#254)

Davide Cangelosi 1 , Martina Morini 1 , Federica Raggi 1 , Angela Rita Sementa 2 , Marco Muselli 3 , Massimo Conte 4 , Maria Carla Bosco 1 , Alessandra Eva 1 , Annalisa Pezzolo 5 , Gudrun Schleiermacher 6 , Matthias Fischer 7 , Luigi Varesio 1
  1. Laboratory of Molecular Biology, Istituto Giannina Gaslini, Genoa, Italy
  2. Laboratory of Pathology, Istituto Giannina Gaslini, Genoa, Italy
  3. Institute of Electronics, Computer and Telecommunication Engineering, Italian National Research Council, Genoa, Italy
  4. Pediatric Oncology Unit, Istituto Giannina Gaslini, Genoa, Italy
  5. Laboratory of Oncology, Istituto Giannina Gaslini, Genoa, Italy
  6. Department of Pediatric Oncology, Institut Curie, Paris, France
  7. Department of Pediatric Oncology and Hematology, University of Cologne, Cologne, Germany

Background:

Survival of high-risk neuroblastoma (NB) patients remains poor. Advances in our understanding of neuroblastoma biology are critical for improving outcome. Hypoxia is a condition of low-oxygen tension occurring in poorly or abnormally vascularized tissues related to tumor aggressiveness. We report on the clinical significance of new 7 genes hypoxia signature.

 

Methods:

Gene expression of 498 samples from NB patients of all stages was measured by RNA-seq technology. Dataset was split into two groups of 49 and 449 patients to build a classifier and test its prognostic power. Classifier was built utilizing Logic Learning Machine algorithm (LLM).

 

Results:

We defined a new seven-gene signature (NB-hop) to assess hypoxia in primary NB tumors (PGK1, PDK1, EGLN1, ALDOC, FAM162a, AK4, and MTFP1 genes). A multi-gene classifier was built based on the expression of the aforementioned genes and patients’ outcome. In the test cohort, the clinical significance of NB-hop predictions was assessed in relevant subgroups of patients defined by combinations of established clinical risk factors. NB-hop stratified patients into groups with significantly divergent OS (P =.006) and EFS (P =.03) in the population of high-risk patients with metastatic neuroblastoma (INSS 4) diagnosed after 18 months of age. Furthermore, NB-hop classifier distinguished patients with different probability of relapse in the population of localized (INSS 1, 2) or metastatic (INSS 4s) MYCN not amplified tumors, which are notoriously at low-risk of relapse (P=.004). The NB-hop classifier emerged as an independent risk factor in multivariate cox regression models on both OS and EFS (OS HR 2.4; 95% CI 1.4-4.2 and EFS HR 2.5; 95% CI 1.7-3.8, both P<.001).

 

Conclusions:

NB-hop is a novel independent prognostic factor capable of improving stratification of clinically relevant neuroblastoma populations while measuring tumor hypoxia. NB-hop may guide the use of hypoxia-activated prodrugs.