Andonegui-Elguera Sergio Daniel, Zamora-Fuentes José María, Espinal-Enríquez Jesús, Hernández-Lemus Enrique
Computational Genomics Division, National Institute of Genomic Medicine, Mexico City, Mexico.
Centro de Ciencias de la Complejidad, Universidad Nacional Autónoma de México, Mexico City, Mexico.
Front Genet. 2021 Mar 10;12:625741. doi: 10.3389/fgene.2021.625741. eCollection 2021.
Lung cancer is one of the deadliest, most aggressive cancers. Abrupt changes in gene expression represent an important challenge to understand and fight the disease. Gene co-expression networks (GCNs) have been widely used to study the genomic regulatory landscape of human cancer. Here, based on 1,143 RNA-Seq experiments from the TCGA collaboration, we constructed GCN for the most common types of lung tumors: adenocarcinoma (TAD) and squamous cells (TSCs) as well as their respective control networks (NAD and NSC). We compared the number of intra-chromosome () and inter-chromosome () co-expression interactions in normal and cancer GCNs. We compared the number of shared interactions between TAD and TSC, as well as in NAD and NSC, to observe which phenotypes were more alike. By means of an over-representation analysis, we associated network topology features with biological functions. We found that TAD and TSC present mostly small disconnected components, whereas in control GCNs, both types have a giant component. In both cancer networks, we observed components in which genes not only belong to the same chromosome but to the same cytoband or to neighboring cytobands. This supports the hypothesis that in lung cancer, gene co-expression is constrained to small neighboring regions. Despite this loss of distant co-expression observed in TAD and TSC, there are some remaining clusters. These clusters seem to play relevant roles in the carcinogenic processes. For instance, some clusters in TAD and TSC are associated with the immune system, response to virus, or control of gene expression. Additionally, other non-enriched clusters are composed of one gene and several associated pseudo-genes, as in the case of the FTH1 gene. The appearance of those common clusters reflects that the gene co-expression program in lung cancer conserves some aspects for cell maintenance. Unexpectedly, 0.48% of the edges are shared between control networks; conversely, 35% is shared between lung cancer GCNs, a 73-fold larger intersection. This suggests that in lung cancer a process of de-differentiation may be occurring. To further investigate the implications of the loss of distant co-expression, it will become necessary to broaden the investigation with other omic-based approaches. However, the present approach provides a basis for future work toward an integrative perspective of abnormal transcriptional regulatory programs in lung cancer.
肺癌是最致命、最具侵袭性的癌症之一。基因表达的突然变化是理解和对抗这种疾病的一个重要挑战。基因共表达网络（GCNs）已被广泛用于研究人类癌症的基因组调控格局。在此，基于来自TCGA合作项目的1143个RNA测序实验，我们构建了最常见类型的肺肿瘤——腺癌（TAD）和鳞状细胞癌（TSC）以及它们各自的对照网络（NAD和NSC）的GCN。我们比较了正常和癌症GCN中染色体内部（）和染色体之间（）共表达相互作用的数量。我们比较了TAD和TSC之间以及NAD和NSC之间共享相互作用的数量，以观察哪些表型更相似。通过超几何富集分析，我们将网络拓扑特征与生物学功能联系起来。我们发现TAD和TSC大多呈现小的不相连组件，而在对照GCN中，两种类型都有一个巨大组件。在两个癌症网络中，我们都观察到一些组件，其中的基因不仅属于同一条染色体，而且属于同一个细胞带或相邻的细胞带。这支持了肺癌中基因共表达被限制在小的相邻区域的假说。尽管在TAD和TSC中观察到远距离共表达的丧失，但仍有一些剩余的簇。这些簇似乎在致癌过程中发挥着相关作用。例如，TAD和TSC中的一些簇与免疫系统、对病毒的反应或基因表达的控制有关。此外，其他未富集的簇由一个基因和几个相关的假基因组成，如FTH1基因的情况。这些共同簇的出现反映出肺癌中的基因共表达程序在细胞维持方面保留了一些方面。出乎意料的是，对照网络之间有0.48%的边是共享的；相反，肺癌GCN之间有35%是共享的，交集大73倍。这表明在肺癌中可能正在发生去分化过程。为了进一步研究远距离共表达丧失的影响，有必要用其他基于组学的方法拓宽研究范围。然而，目前的方法为未来从综合角度研究肺癌异常转录调控程序的工作提供了基础。
