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Open AccessArticle

Expression Patterns of Immune Genes Reveal Heterogeneous Subtypes of High-Risk Neuroblastoma

1
Department of Public Health Sciences, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA
2
Division of Pediatric Hematology and Oncology, Department of Pediatrics, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA
3
Division of Pediatric Surgery, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(7), 1739; https://doi.org/10.3390/cancers12071739
Received: 19 May 2020 / Revised: 13 June 2020 / Accepted: 24 June 2020 / Published: 30 June 2020
(This article belongs to the Section Cancer Informatics and Big Data)
High risk neuroblastoma (HR-NB) remains difficult to treat, and its overall survival (OS) is still below 50%. Although HR-NB is a heterogeneous disease, HR-NB patients are currently treated in a similar fashion. Through unsupervised biclustering, we further stratified HR-NB patients into two reproducible and clinically distinct subtypes, including an ultra-high risk neuroblastoma (UHR-NB) and high risk neuroblastoma (HR-NB). The UHR-NB subtype consistently had the worst OS in multiple independent cohorts ( P < 0 . 008 ). Out of 283 neuroblastoma-specific immune genes that were used for stratification, 39 of them were differentiated in UHR-NB, including four upregulated and 35 downregulated, as compared to HR-NB. The four UHR-NB upregulated genes (ADAM22, GAL, KLHL13 and TWIST1) were all upregulated in MYCN amplified neuroblastoma in 5 additional cohorts. TWIST1 and ADAM22 were also positively correlated with cancer stage, while GAL was an independent OS predictor in addition to MYCN and age. Furthermore, we identified 26 commonly upregulated and 311 downregulated genes in UHR-NB from all 4723 immune-related genes. While 43 KEGG pathways with molecular functions were enriched in the downregulated immune-related genes, only the P53 signaling pathway was enriched in the upregulated ones, which suggested that UHR-NB was a TP53 related subtype with reduced immune activities.
Keywords: ultra-high risk neuroblastoma; clinically distinct subtypes; immune-related gene signatures; prognostic markers; biclustering; TP53 signaling ultra-high risk neuroblastoma; clinically distinct subtypes; immune-related gene signatures; prognostic markers; biclustering; TP53 signaling
MDPI and ACS Style

Liu, Z.; Grant, C.N.; Sun, L.; Miller, B.A.; Spiegelman, V.S.; Wang, H.-G. Expression Patterns of Immune Genes Reveal Heterogeneous Subtypes of High-Risk Neuroblastoma. Cancers 2020, 12, 1739.

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