García-Cortés Diana, Hernández-Lemus Enrique, Espinal-Enríquez Jesús
Computational Genomics Division, National Institute of Genomic Medicine, Mexico City, Mexico.
Programa de Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico.
Front Genet. 2021 Apr 20;12:629475. doi: 10.3389/fgene.2021.629475. eCollection 2021.
Luminal A is the most common breast cancer molecular subtype in women worldwide. These tumors have characteristic yet heterogeneous alterations at the genomic and transcriptomic level. Gene co-expression networks (GCNs) have contributed to better characterize the cancerous phenotype. We have previously shown an imbalance in the proportion of intra-chromosomal () over inter-chromosomal () interactions when comparing cancer and healthy tissue GCNs. In particular, for breast cancer molecular subtypes (Luminal A included), the majority of high co-expression interactions connect gene-pairs in the same chromosome, a phenomenon that we have called loss of co-expression. Despite this phenomenon has been described, the functional implication of this specific network topology has not been studied yet. To understand the biological role that communities of co-expressed genes may have, we constructed GCNs for healthy and Luminal A phenotypes. Network modules were obtained based on their connectivity patterns and they were classified according to their chromosomal homophily (proportion of interactions). A functional overrepresentation analysis was performed on communities in both networks to observe the significantly enriched processes for each community. We also investigated possible mechanisms for which the loss of co-expression emerges in cancer GCN. To this end we evaluated transcription factor binding sites, CTCF binding sites, differential gene expression and copy number alterations (CNAs) in the cancer GCN. We found that communities in Luminal A present more significantly enriched categories than ones. Processes, such as angiogenesis, cell proliferation, or cell adhesion were found in modules. The differential expression analysis showed that FOXM1, CENPA, and CIITA transcription factors, exert a major regulatory role on their communities by regulating expression of their target genes in other chromosomes. Finally, identification of CNAs, displayed a high enrichment of deletion peaks in communities. With this approach, we demonstrate that network topology determine, to at certain extent, the function in Luminal A breast cancer network. Furthermore, several mechanisms seem to be acting together to avoid co-expression. Since this phenomenon has been observed in other cancer tissues, a remaining question is whether the loss of long distance co-expression is a novel hallmark of cancer.
管腔A型是全球女性中最常见的乳腺癌分子亚型。这些肿瘤在基因组和转录组水平上具有特征性但异质性的改变。基因共表达网络（GCNs）有助于更好地表征癌性表型。我们之前已经表明，在比较癌症和健康组织的GCNs时，染色体内（）与染色体间（）相互作用的比例存在失衡。特别是对于乳腺癌分子亚型（包括管腔A型），大多数高共表达相互作用连接的是同一染色体上的基因对，我们将这种现象称为共表达缺失。尽管已经描述了这种现象，但这种特定网络拓扑结构的功能含义尚未得到研究。为了理解共表达基因群落可能具有的生物学作用，我们构建了健康和管腔A型表型的GCNs。基于其连接模式获得网络模块，并根据其染色体同嗜性（相互作用的比例）对其进行分类。对两个网络中的群落进行功能过度表达分析，以观察每个群落中显著富集的过程。我们还研究了癌症GCN中出现共表达缺失的可能机制。为此，我们评估了癌症GCN中的转录因子结合位点、CTCF结合位点、差异基因表达和拷贝数改变（CNAs）。我们发现管腔A型中的群落比中的群落呈现出更显著富集的类别。在模块中发现了诸如血管生成、细胞增殖或细胞粘附等过程。差异表达分析表明，FOXM1、CENPA和CIITA转录因子通过调节其他染色体上靶基因的表达，对其群落发挥主要调节作用。最后，CNAs的鉴定显示群落中缺失峰高度富集。通过这种方法，我们证明网络拓扑结构在一定程度上决定了管腔A型乳腺癌网络的功能。此外，似乎有几种机制共同作用以避免共表达。由于在其他癌症组织中也观察到了这种现象，一个遗留的问题是长距离共表达的缺失是否是癌症的一个新标志。
