{"title":"Integrative genomic analyses identify neuroblastoma risk genes involved in neuronal differentiation.","authors":"Matilde Tirelli, Ferdinando Bonfiglio, Sueva Cantalupo, Annalaura Montella, Marianna Avitabile, Teresa Maiorino, Sharon J Diskin, Achille Iolascon, Mario Capasso","doi":"10.1007/s00439-024-02700-2","DOIUrl":null,"url":null,"abstract":"<p><p>Genome-Wide Association Studies (GWAS) have been decisive in elucidating the genetic predisposition of neuroblastoma (NB). The majority of genetic variants identified in GWAS are found in non-coding regions, suggesting that they can be causative of pathogenic dysregulations of gene expression. Nonetheless, pinpointing the potential causal genes within implicated genetic loci remains a major challenge. In this study, we integrated NB GWAS and expression Quantitative Trait Loci (eQTL) data from adrenal gland to identify candidate genes impacting NB susceptibility. We found that ZMYM1, CBL, GSKIP and WDR81 expression was dysregulated by NB predisposing variants. We further investigated the functional role of the identified genes through computational analysis of RNA sequencing (RNA-seq) data from single-cell and whole-tissue samples of NB, neural crest, and adrenal gland tissues, as well as through in vitro differentiation assays in NB cell cultures. Our results indicate that dysregulation of ZMYM1, CBL, GSKIP, WDR81 may lead to malignant transformation by affecting early and late stages of normal program of neuronal differentiation. Our findings enhance the understanding of how specific genes contribute to NB pathogenesis by highlighting their influence on neuronal differentiation and emphasizing the impact of genetic risk variants on the regulation of genes involved in critical biological processes.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":null,"pages":null},"PeriodicalIF":3.8000,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Human Genetics","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1007/s00439-024-02700-2","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
引用次数: 0
Abstract
Genome-Wide Association Studies (GWAS) have been decisive in elucidating the genetic predisposition of neuroblastoma (NB). The majority of genetic variants identified in GWAS are found in non-coding regions, suggesting that they can be causative of pathogenic dysregulations of gene expression. Nonetheless, pinpointing the potential causal genes within implicated genetic loci remains a major challenge. In this study, we integrated NB GWAS and expression Quantitative Trait Loci (eQTL) data from adrenal gland to identify candidate genes impacting NB susceptibility. We found that ZMYM1, CBL, GSKIP and WDR81 expression was dysregulated by NB predisposing variants. We further investigated the functional role of the identified genes through computational analysis of RNA sequencing (RNA-seq) data from single-cell and whole-tissue samples of NB, neural crest, and adrenal gland tissues, as well as through in vitro differentiation assays in NB cell cultures. Our results indicate that dysregulation of ZMYM1, CBL, GSKIP, WDR81 may lead to malignant transformation by affecting early and late stages of normal program of neuronal differentiation. Our findings enhance the understanding of how specific genes contribute to NB pathogenesis by highlighting their influence on neuronal differentiation and emphasizing the impact of genetic risk variants on the regulation of genes involved in critical biological processes.
全基因组关联研究（GWAS）在阐明神经母细胞瘤（NB）的遗传易感性方面发挥了决定性作用。在全基因组关联研究中发现的大多数基因变异都存在于非编码区，这表明它们可能会导致基因表达的致病性失调。然而，在受影响的基因位点中准确定位潜在的致病基因仍然是一项重大挑战。在本研究中，我们整合了肾上腺的NB GWAS和表达定量性状位点（eQTL）数据，以确定影响NB易感性的候选基因。我们发现，ZMYM1、CBL、GSKIP 和 WDR81 的表达受 NB 易感变异的调控。我们通过对来自 NB、神经嵴和肾上腺组织的单细胞和全组织样本的 RNA 测序（RNA-seq）数据进行计算分析，并通过 NB 细胞培养物的体外分化试验，进一步研究了所发现基因的功能作用。我们的研究结果表明，ZMYM1、CBL、GSKIP和WDR81的失调可能会影响神经元分化正常程序的早期和晚期阶段，从而导致恶性转化。我们的研究结果突出了特定基因对神经元分化的影响，强调了遗传风险变异对参与关键生物过程的基因调控的影响，从而加深了人们对特定基因如何导致 NB 发病的理解。
期刊介绍：
Human Genetics is a monthly journal publishing original and timely articles on all aspects of human genetics. The Journal particularly welcomes articles in the areas of Behavioral genetics, Bioinformatics, Cancer genetics and genomics, Cytogenetics, Developmental genetics, Disease association studies, Dysmorphology, ELSI (ethical, legal and social issues), Evolutionary genetics, Gene expression, Gene structure and organization, Genetics of complex diseases and epistatic interactions, Genetic epidemiology, Genome biology, Genome structure and organization, Genotype-phenotype relationships, Human Genomics, Immunogenetics and genomics, Linkage analysis and genetic mapping, Methods in Statistical Genetics, Molecular diagnostics, Mutation detection and analysis, Neurogenetics, Physical mapping and Population Genetics. Articles reporting animal models relevant to human biology or disease are also welcome. Preference will be given to those articles which address clinically relevant questions or which provide new insights into human biology.
Unless reporting entirely novel and unusual aspects of a topic, clinical case reports, cytogenetic case reports, papers on descriptive population genetics, articles dealing with the frequency of polymorphisms or additional mutations within genes in which numerous lesions have already been described, and papers that report meta-analyses of previously published datasets will normally not be accepted.
The Journal typically will not consider for publication manuscripts that report merely the isolation, map position, structure, and tissue expression profile of a gene of unknown function unless the gene is of particular interest or is a candidate gene involved in a human trait or disorder.
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