Background: Neuroblastoma (NB) is a common solid tumor in children, with a dismal prognosis in high-risk cases. Despite advancements in NB treatment, the clinical need for precise prognostic models remains critical, particularly to address the heterogeneity of cancer stemness which plays a pivotal role in tumor aggressiveness and patient outcomes. By utilizing machine learning (ML) techniques, we aimed to explore the cancer stemness features in NB and identify stemness-related hub genes for future investigation and potential targeted therapy.
Methods: The public dataset GSE49710 was employed as the training set for acquire gene expression data and NB sample information, including age, stage, and MYCN amplification status and survival. The messenger RNA (mRNA) expression-based stemness index (mRNAsi) was calculated and patients were grouped according to their mRNAsi value. Stemness-related hub genes were identified from the differentially expressed genes (DEGs) to construct a gene signature. This was followed by evaluating the relationship between cancer stemness and the NB immune microenvironment, and the development of a predictive nomogram. We assessed the prognostic outcomes including overall survival (OS) and event-free survival, employing machine learning methods to measure predictive accuracy through concordance indices and validation in an independent cohort E-MTAB-8248.
Results: Based on mRNAsi, we categorized NB patients into two groups to explore the association between varying levels of stemness and their clinical outcomes. High mRNAsi was linked to the advanced International Neuroblastoma Staging System (INSS) stage, amplified MYCN, and elder age. High mRNAsi patients had a significantly poorer prognosis than low mRNAsi cases. According to the multivariate Cox analysis, the mRNAsi was an independent risk factor of prognosis in NB patients. After least absolute shrinkage and selection operator (LASSO) regression analysis, four key genes (ERCC6L, DUXAP10, NCAN, DIRAS3) most related to mRNAsi scores were discovered and a risk model was built. Our model demonstrated a significant prognostic capacity with hazard ratios (HR) ranging from 18.96 to 41.20, P values below 0.0001, and area under the receiver operating characteristic curve (AUC) values of 0.918 in the training set, suggesting high predictive accuracy which was further confirmed by external verification. Individuals with a low four-gene signature score had a favorable outcome and better immune responses. Finally, a nomogram for clinical practice was constructed by integrating the four-gene signature and INSS stage.
Conclusions: Our findings confirm the influence of CSC features in NB prognosis. The newly developed NB stemness-related four-gene signature prognostic signature could facilitate the prognostic prediction, and the identified hub genes may serve as promising targets for individualized treatments.
Keywords: Neuroblastoma (NB); cancer stemness; messenger RNA expression-based stemness index (mRNAsi); prognosis.
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