Comprehensive Co-expression Network Analysis Identifies HSP۹۰AA۱ as a Potential Biomarker for Lymphatic Invasion and Prognosis of Infiltrating Ductal Carcinoma

Introduction: Infiltrating Ductal Carcinoma (IDC) is the most prevalent form of breast cancer, accounting for ۷۰-۸۰% of all cases. Originating in the milk ducts, IDC has an invasive nature and the potential to metastasize to other parts of the body. Identifying molecular biomarkers with prognostic significance is critical for optimizing treatment and improving patient outcomes. One of the key factors in IDC prognosis is the pathologic N stage (pN), which assesses the extent of cancer spread to regional lymph nodes. As a central element of the TNM staging system, pN plays a pivotal role in determining cancer spread, predicting survival, and guiding clinical decisions. In this study, we aimed to identify differentially expressed genes associated with lymphatic invasion in IDC and assess their potential prognostic significance. Further, we focused to investigate biological pathways and ontologies significantly correlated with our hub genes. Methods: We utilized clinical traits and RNA-Seq data from ۷۸۰ patient samples in the UCSC Toil Recompute Compendium, integrating datasets from The Cancer Genome Atlas (TCGA), TARGET, and the Genotype-Tissue Expression project (GTEx), with a focus on breast tissue. Weighted gene co-expression network analysis (WGCNA) was applied to explore the correlation between gene networks and lymphatic invasion in IDC. One key gene module, comprising ۳۰۷ genes, was found to be significantly associated with pN, representing lymph node metastasis. Gene set enrichment analysis was performed using topGO, and survival analysis was conducted with RegParallel. The genes from this module were used to construct a protein-protein interaction (PPI) network using the STRING database in Cytoscape, with hub genes identified based on degree and betweenness centrality metrics. Finally, differential correlation analysis on our identified hub gene, HSP۹۰AA۱, was performed using the DGCA package, comparing its expression in normal tissue versus primary tumors. The above steps were performed based on the TOIL-TCGA-GTex protocol with some modifications. Results: we identified ۱۰ most significant hub genes, among differentially expressed ones. Based on network analyses, HSP۹۰AA۱, HSP۹۰AB۱, AURKA, TYMS, TOP۲A, CDCA۸, CCNB۱, CDK۱, RRM۱, PCNA, CHEK۱ were correlated with lymphatic invasion and prognosis of IDC. Mitocondrial and Golgi processes, Digestive system processes, cytoskeletal organization and aorta development were the most significantly enriched pathways for our DEG list. Our results suggests that HSP۹۰AA۱ may play a dual role in IDC, gaining importance in cell cycle regulation and chromosomal maintenance, while its involvement in fundamental metabolic processes like ribosomal activity decreases. This shift could be a hallmark of cancer progression, where the focus moves from maintaining normal cellular functions to supporting uncontrolled cell growth and division. Conclusion: The DGCA analysis of HSP۹۰AA۱, underscores its dual role in regulating the cell cycle and chromosomal maintenance, while its involvement in metabolic processes diminishes during cancer progression. These findings suggest that HSP۹۰AA۱ and other hub genes could serve as valuable prognostic biomarkers or therapeutic targets for IDC, offering insights into the molecular mechanisms driving lymphatic invasion and metastasis. Further investigation into these genes and the enriched pathways, such as mitochondrial and Golgi processes, may provide critical advancements in precision treatment strategies for IDC patients.

کلیدواژه ها:

HSP۹۰ Heat-Shock Proteins ، Ductal Carcinoma ، cancer biomarkers ، transcriptomics ، Lymphatic Metastasis