Gene utility recapitulates chromosomal aberrancies in advanced stage neuroblastoma.
Gene utility recapitulates chromosomal aberrancies in advanced stage neuroblastoma.
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DOI：
10.1016/j.csbj.2022.06.024
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发表时间：
2022
影响因子：
6
通讯作者：
中科院分区：
文献类型：
--
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神经母细胞瘤（NB）是儿童颅外最常见的实体瘤。虽然只有少数复发的体细胞突变已被确定，染色体异常，包括杂合性丢失（洛）在染色体1 p和增益的染色体17 q，经常被视为在高危情况下。驱动这种遗传异常的生物学基础和进化力量仍然是个谜。在这里，我们概念化的基因效用模型（GUM），旨在确定基因驱动的生物信号通过其集体基因效用和应用它来了解这些差异利用基因的影响，约束NB核型的演变。通过采用计算过程引导的流算法对基于转录组数据构建的蛋白质-蛋白质网络中的基因效用进行建模，我们进行了几次成对比较分析，以揭示具有不同分类的阶段4 NB中具有差异效用的基因。然后，我们通过将这些差异利用的基因映射到它们各自的染色体位点来构建实用核型。有趣的是，实用核型的热点，在一定程度上，可以始终概括的主要染色体异常的NB，也提供了线索，尚未确定的易感位点。因此，我们的研究不仅从基因效用的角度提供了一个新的视角，通过整合基因组测序工作检测到已知的染色体异常，而且还提供了对NB病因学的新见解，并提供了一个框架，以促进这种毁灭性儿童癌症的新治疗靶点的鉴定。
Neuroblastoma (NB) is the most common extracranial solid tumor in children. Although only a few recurrent somatic mutations have been identified, chromosomal abnormalities, including the loss of heterozygosity (LOH) at the chromosome 1p and gains of chromosome 17q, are often seen in the high-risk cases. The biological basis and evolutionary forces that drive such genetic abnormalities remain enigmatic. Here, we conceptualize the Gene Utility Model (GUM) that seeks to identify genes driving biological signaling via their collective gene utilities and apply it to understand the impact of those differentially utilized genes on constraining the evolution of NB karyotypes. By employing a computational process-guided flow algorithm to model gene utility in protein–protein networks that built based on transcriptomic data, we conducted several pairwise comparative analyses to uncover genes with differential utilities in stage 4 NBs with distinct classification. We then constructed a utility karyotype by mapping these differentially utilized genes to their respective chromosomal loci. Intriguingly, hotspots of the utility karyotype, to certain extent, can consistently recapitulate the major chromosomal abnormalities of NBs and also provides clues to yet identified predisposition sites. Hence, our study not only provides a new look, from a gene utility perspective, into the known chromosomal abnormalities detected by integrative genomic sequencing efforts, but also offers new insights into the etiology of NB and provides a framework to facilitate the identification of novel therapeutic targets for this devastating childhood cancer.
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影响因子：
8
作者：
Islam, A;Kageyama, H;Nakagawara, A
通讯作者：
Nakagawara, A
影响因子：
8
作者：
Carpentier, A;Balitrand, N;Chomienne, C
通讯作者：
Chomienne, C
影响因子：
158.5
作者：
Bown, N;Cotterill, S;Speleman, F
通讯作者：
Speleman, F
泛神经母细胞瘤分析揭示了年龄和签名相关的驱动因素改变。
影响因子：
16.6
作者：
Brady SW;Liu Y;Ma X;Gout AM;Hagiwara K;Zhou X;Wang J;Macias M;Chen X;Easton J;Mulder HL;Rusch M;Wang L;Nakitandwe J;Lei S;Davis EM;Naranjo A;Cheng C;Maris JM;Downing JR;Cheung NV;Hogarty MD;Dyer MA;Zhang J
通讯作者：
Zhang J
影响因子：
8.8
作者：
Garcia-Lopez, Jesus;Wallace, Kirby;Otero, Joel H.;Olsen, Rachelle;Wang, Yong-dong;Finkelstein, David;Gudenas, Brian L.;Rehg, Jerold E.;Northcott, Paul;Davidoff, Andrew M.;Freeman, Kevin W.
通讯作者：
Freeman, Kevin W.