A key genomic signature associated with lymphovascular invasion in head and neck squamous cell carcinoma [post]

2020 unpublished
Lymphovascular invasion (LOI), a key pathological feature of head and neck squamous cell carcinoma (HNSCC), is predictive of poor survival; however, the associated clinical characteristics and underlying molecular mechanisms remain largely unknown. Methods: We performed weighted gene co-expression network analysis to construct gene co-expression networks and investigate the relationship between key modules and the LOI clinical phenotype. Functional enrichment and KEGG pathway analyses were
more » ... analyses were performed with differentially expressed genes. A protein-protein interaction network was constructed using Cytoscape, and module analysis was performed using MCODE. Prognostic value, expression analysis, and survival analysis were conducted using hub genes; GEPIA and the Human Protein Atlas database were used to determine the mRNA and protein expression levels of hub genes, respectively. Multivariable Cox regression analysis was used to establish a prognostic risk formula and the areas under the receiver operating characteristic curve (AUCs) were used to evaluate prediction efficiency. Finally, potential small molecular agents that could target LOI were identified with DrugBank. Results: Ten co-expression modules in two key modules (turquoise and pink) associated with LOI were identified. Functional enrichment and KEGG pathway analysis revealed that turquoise and pink modules played significant roles in HNSCC progression. Seven hub genes (CNFN, KIF18B, KIF23, PRC1, CCNA2, DEPDC1, and TTK) in the two modules were identified and validated by survival and expression analyses, and the following prognostic risk formula was established: risk score = EXP DEPDC1 0.32636 + EXP CNFN (−0.07544). The low-risk group showed better overall survival than the high-risk group ( P < 0.0001), and the AUCs for 1-, 3-, and 5-year overall survival were 0.582, 0.634, and 0.636, respectively. Eight small molecular agents, namely XL844, AT7519, AT9283, alvocidib, nelarabine, benzamidine, L-glutamine, and zinc, were identified as novel candidates for controlling LOI in HNSCC ( P < 0.05). Conclusions: The two-mRNA signature (CNFN and DEPDC1) could serve as an independent biomarker to predict LOI risk and provide new insights into the mechanisms underlying LOI in HNSCC. In addition, the small molecular agents appear promising for LOI treatment. Background 4 Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers with high morbidity and mortality rates worldwide; >90% of head and neck cancers are squamous cell carcinomas that arise in the oral cavity, oropharynx, and larynx [1] . Metastasis is the main cause of treatment failure and an important factor affecting prognosis [2] . Thus, elucidating the underlying genomic changes seems valuable for controlling lymph node metastases. In case of HNSCC, advanced TNM stage, histological grade, and lymph node status, which are wellknown major risk factors of metastatic disease and poor overall survival (OS) and disease-free survival, are poor prognostic indicators [3] [4] [5]. Lymphovascular invasion (LOI) has been associated with lymph node metastasis in HNSCC [6][7][8]. Thus, identification of effective molecular prognosticators of LOI should be a useful way to decrease the risk of metastasis in patients with HNSCC. According to recent studies, the clinical characteristics of and parameters contributing to LOI remain uncertain. In fact, the incidence of LOI in patients with HNSCC is highly inconsistent, varying from 14% to 47% [9, 10]. This considerable variation can be attributed to small sample sizes, distribution differences, and heterogeneity of HNSCC. Therefore, it is imperative to conduct clinical studies with large sample sizes to analyze the genomic and clinical characteristics of LOI. This should, consequently, facilitate the development of novel therapeutic targets, enhancing the survival of HNSCC patients with LOI. The Cancer Genome Atlas (TCGA) has generated comprehensive, multidimensional maps of key genomic changes in several types of cancers, including HNSCC, and provided histopathological annotations and clinical survival data relevant to patients with HNSCC over a follow-up duration of 10 years. This has enabled the systematic evaluation of the relationship between LOI and gene signatures, providing clarity on key gene modules involved in LOI in patients with HNSCC. This has in turn provided us with comprehensive, systemic understanding of LOI not only at the genomic but also at the prognostic level. Methods Patient selection and data pre-processing Data pertaining to patients with HNSCC were downloaded from TCGA database. RNA expression nelarabine are novel candidate drugs for controlling LOI in HNSCC. Abbreviations LOI: Lymphovascular invasion, HNSCC: head and neck squamous cell carcinoma, DEGs: differentially expressed genes, MEs: module eigengenes, WGCNA: Weighted gene co-expression network analysis, MCODE: Molecular Complex Detection Declarations Ethics approval and consent to participate
doi:10.21203/rs.2.18349/v3 fatcat:yjl5fj6ie5cnbhhiyumazsqnsi