A key genomic signature associated with lymphovascular invasion in head and neck squamous cell carcinoma.
- 作者列表："Zhang J","Lin H","Jiang H","Jiang H","Xie T","Wang B","Huang X","Lin J","Xu A","Li R","Zhang J","Yuan Y
BACKGROUND: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 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 = EXPDEPDC1 * 0.32636 + EXPCNFN * (- 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.
背景: 淋巴血管侵犯 (LOI) 是头颈部鳞状细胞癌 (HNSCC) 的一个关键病理特征，可预测生存率低; 然而,相关的临床特征和潜在的分子机制在很大程度上仍然未知。 方法: 我们进行加权基因共表达网络分析，构建基因共表达网络，并研究关键模块与 LOI 临床表型之间的关系。用差异表达基因进行功能富集和 KEGG 通路分析。使用 Cytoscape 构建蛋白质-蛋白质相互作用网络，使用 MCODE 进行模块分析。使用 hub 基因进行预后价值、表达分析和生存分析; 使用 GEPIA 和人类蛋白图谱数据库分别确定 hub 基因的 mRNA 和蛋白表达水平。采用多变量 Cox 回归分析建立预后风险公式，采用受试者工作特征曲线 (AUCs) 下面积评价预测效率。最后，用 DrugBank 鉴定了可能靶向 LOI 的潜在小分子药物。 结果: 确定了与 LOI 相关的两个关键模块 (绿松石和粉红色) 中的 10 个共表达模块。功能富集和 KEGG 通路分析发现，绿松石和粉红色模块在 HNSCC 进展中发挥显著作用。两个模块中的 7 个中心基因 (CNFN 、 KIF18B 、 KIF23 、 PRC1 、 CCNA2 、 DEPDC1 和 TTK) 通过生存和表达分析进行了鉴定和验证。并建立了以下预后风险公式: [风险评分 = EXPDEPDC1 * 0.32636 + expcnfn * (-0.07544)]。低危组总体生存率优于高危组 (p <0.0001)，1-、 3-、 5 年总生存率分别为 0.582 、 0.634 和 0.636。8 种小分子制剂，分别为 XL844 、 AT7519 、 AT9283 、 alvocidib 、 nelarabine 、苄脒、 L-谷氨酰胺和锌,被确定为控制 HNSCC 中 LOI 的新候选者 (p <0.05)。 结论: 双 mRNA 标记 (CNFN 和 DEPDC1) 可以作为预测 LOI 风险的独立生物标志物，并为 HNSCC 中 LOI 的潜在机制提供新的见解。此外，小分子药物似乎有希望用于 LOI 治疗。
METHODS:INTRODUCTION:Human papillomavirus (HPV) is the most common sexually transmitted infection and is associated with several types of cancer. The number of cases of HPV-associated head and neck squamous cell carcinomas (HNSCCs), especially oropharyngeal carcinomas, has increased significantly in recent years despite decreased tobacco smoking rates. Currently, no data concerning the risk factors and prevalence of HPV in HNSCC patients in all regions of Brazil are available, making it difficult to promote advances in this field of public health. Therefore, our goal is to determine the impact of infection by HPV, including HPVs with different genotypes, on head and neck cancer and the risk factors associated with the development of head and neck cancer in all regions of Brazil. METHODS AND ANALYSIS:This is a case-control study that will include 622 patients and 622 controls from all regions of Brazil. A questionnaire will be applied to gather information on sociodemographic, behavioural and health factors. Oral, cervical or penile/scrotal, and anal specimens and serum samples will be collected from all participants. Formalin-fixed paraffin-embedded tissue from tumour biopsies will be analysed only in the case group. Molecular and serological analyses will be performed to evaluate the presence and role of HPV in the development of head and neck cancer. ETHICS AND DISSEMINATION:This project was approved by the research ethical committee of the proposing institution (Hospital Moinhos de Vento, number 2.852.060). Ethical approval from the collaborators is currently under evaluation and is not yet complete. The results of this study will be presented at meetings with the Brazilian Ministry of Health through technical reports and to the scientific community at national and international events, with subsequent publication of scientific articles.
METHODS:BACKGROUND:Factors related to head and neck cancer and the treatment of the disease can affect quality of life. The aim of this study was to determine factors associated with the severity of impact on oral health-related quality of life (OHRQoL) in survivors of head and neck cancer using a multivariate analysis. METHODS:This cross-sectional study evaluated 90 volunteers who had completed radiotherapy at least 3 months earlier. OHRQoL was assessed using oral health impact profile (OHIP-14) and the data were analyzed using robust variance poisson regression models. RESULTS:The mean total OHIP-14 score was 23.98 ± 12.55. Patients with hyposalivation had 56% higher (worse) mean OHIP-14 total scores (CI:1.11-2.18) and patients with advanced stage tumors had 31% higher mean OHIP-14 total scores (CI:1.03-1.66) in multivariate analyses. CONCLUSION:OHRQoL of survivors of head and neck cancer experienced a negative impact following radiotherapy. The impact was associated with hyposalivation and advanced stage tumors.
METHODS:BACKGROUND:To immunohistochemically evaluate the association between the presence of cancer-associated fibroblasts (CAFs) and the tumour expression of podoplanin (PDPN) in head and neck squamous cell carcinoma (HNSCC) and their association with clinicopathological variables. MATERIAL AND METHODS:A tissue microarray (TMA) with biopsy sections from patients diagnosed with HNSCC was stained with antibodies against the CAFs marker, α-smooth muscle actin (α-SMA), and PDPN. We subsequently evaluated their expression to determine the association between them and with clinicopathological variables including age, primary tumour site, TNM stage, and tumour differentiation grade. RESULTS:Positive reaction to α-SMA was observed in the tumour stroma, revealing spindle-shaped cells compatible with CAFs, which showed a high expression in 62% of cases and a significant association with laryngeal carcinomas, advanced clinical stages, and lower tumour differentiation (P ≤ 0.05). PDPN staining on tumour cells showed low expression in 72% of cases, and it was not associated with any clinicopathological variable or with the presence of CAFs. CONCLUSIONS:The presence of CAFs in the tumour stroma is related to an aggressive phenotype and could increase as the disease progresses, although based on our findings, it would have no relationship, at least directly, with the expression of PDPN.