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Potential Therapeutic Targets for Neuroblastoma Screened through Mendelian Randomization Analysis
Zhenge Yang1,2, Yunlong Zhang1,2, Shan Wang1,2
1Department of Pediatric Surgical Oncology, Children's Hospital of Chongqing Medical University; National Clinical Research Center for Children and Adolescents' Health and Diseases; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China.
Background:
Neuroblastoma (NB) is the most prevalent extracranial solid tumor in children. Therefore, urgent exploration of novel therapeutic targets and more effective approaches is imperative to enhance the prognosis of these children.
Methods:
NB datasets were obtained from OpenGWAS-ieu-a-816 (1,627 cases; 3,254 controls; European ancestry) and prot-a-2003 (N=3,301; European ancestry)-and were combined by inverse-variance meta-analysis. Adrenal expression quantitative trait loci (eQTL) data were sourced from GTEx v8 (n=233). Bidirectional Mendelian randomization (MR) and summary-based MR analyses were conducted to infer the causal relationship between adrenal-related genes and NB, with validation by Steiger directionality testing and phenotype scanning. Blood cis-eQTL datasets were obtained from eQTLGen (n=31,684 across 37 cohorts), and immune-cell data were retrieved from OpenGWAS (731 traits; IDs ebi-a-GCST90001391-GCST90002121). Using immune-cell traits as intermediate variables, bidirectional MR assessed the causal relationship between blood-related genes and NB, and colocalization analysis was performed for blood-related genes and immune cells.
Results:
Using two-sample bidirectional MR, we identified eight adrenal genes associated with NB risk. Upregulated expression of CPNE1 (OR 0.94, 95% CI [0.93-0.95]; P=1.69×10-31), ZNF559 (OR 0.93, 95% CI [0.92-0.95]; P=5.96×10-11), TTC18 (OR 0.86, 95% CI [0.85-0.87]; P=1.04×10-110), DNAJC9 (OR 0.85, 95% CI [0.84-0.86]; P=1.62×10-109), and EP400NL (OR 0.84, 95% CI [0.83-0.84]; P<1×10-300) was associated with lower NB risk, whereas upregulation of BTNL2 (OR 1.07, 95% CI [1.07-1.07]; P<1×10-300), FAM182B (OR 1.07, 95% CI [1.06-1.08]; P=3.94×10-23), and NBPF3 (OR 1.13, 95% CI [1.12-1.13]; P=6.49×10-5) was associated with higher risk. In the blood, 43 genes influence NB by affecting the expression of 54 immune cell phenotypes. Among these genes and immune cells, eight exhibited colocalization effects with seven immune cells, indicating their potential as therapeutic targets.
Conclusion:
This study revealed that certain genes in the adrenal glands and blood affect the occurrence of NB, with immune cells playing a crucial role in the process influenced by blood genes. MR and colocalization prioritize candidate genes/putative therapeutic targets for NB.
