Zhou Linsa, Zhou Qiang, Guo Qian, Lai Peng, Rui Chen, Li Wanqing, Chen Xuemei, Zhuo Yue, Zhong Xiaoping, Lin Sen
Department of Burns and Plastic Surgery, The Second Affiliated Hospital of Shantou, University Medical College, Shantou, 515000, China.
Department of Otolaryngology, Ruian People's Hospital), The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325027, China.
BMC Cancer. 2025 Jan 20;25(1):104. doi: 10.1186/s12885-025-13481-w.
Cutaneous melanoma (CM) is strongly associated with ultraviolet (UV) radiation, which contributes to the transformation of melanocytes into melanoma by inducing specific DNA damage. Here, we investigated the causal relationship between CM and genes related to sun-damaged skin, exploring specific target genes through various bioinformatics analyses.
The Gene Expression Omnibus (GEO) database was used to obtain differential genes for CM and normal skin, and the Genome-Wide Association Studies (GWAS) analysis offered summary-level melanoma data for CM. Mendelian randomization (MR) analyses were used to examine the correlated linkage between CM and sun-exposed skin genes. The MR studies were conducted mainly using Inverse Variance Weighting (IVW), MR-Egger, Weighted Median, simple and weighted patterns to predict the correlation between sun-exposed skin and CM. Finally, the role of target genes in CM was revealed by pan-cancer analysis, expression and immune-infiltration evaluations, immuno-checking targeting analysis, immunotherapy response analysis, survival analysis, and protein-protein interactions (PPI) network and enrichment analyses.
Using matrix data from the GSE15605, GSE46517, and GSE111452 datasets, bioinformatics analysis revealed 232 differentially expressed genes (DEGs) between CM and typical tissues. MR analysis indicated that only CTSS has a deleterious effect linking skin exposure to sunlight and CM. Analysis of CTSS expression in tumors and tissues, along with the construction of a prognostic model, revealed that CTSS expression was higher in both primary CM and metastatic CM compared to normal skin tissue. However, patients with higher CTSS expression had a higher prognosis. In addition, high CTSS expression was significantly and positively correlated with tumor mutation rate, tumor microenvironment, immune cell infiltration, immune checkpoints and immunotherapy efficacy.
Using MR analysis, we found a positive causal relationship between the CTSS gene in sun-exposed skin and CM. Additionally, increased CTSS may provide a basis for biomarker prediction of CM prognosis, immune status and immunotherapy.
皮肤黑色素瘤（CM）与紫外线（UV）辐射密切相关，紫外线通过诱导特定的DNA损伤促使黑素细胞转变为黑色素瘤。在此，我们研究了CM与阳光损伤皮肤相关基因之间的因果关系，通过各种生物信息学分析探索特定的靶基因。
利用基因表达综合数据库（GEO）获取CM和正常皮肤的差异基因，全基因组关联研究（GWAS）分析提供CM的汇总水平黑色素瘤数据。采用孟德尔随机化（MR）分析来检验CM与阳光暴露皮肤基因之间的相关联系。MR研究主要使用逆方差加权法（IVW）、MR-Egger法、加权中位数法、简单和加权模式来预测阳光暴露皮肤与CM之间的相关性。最后，通过泛癌分析、表达和免疫浸润评估、免疫检查点靶向分析、免疫治疗反应分析、生存分析以及蛋白质-蛋白质相互作用（PPI）网络和富集分析揭示靶基因在CM中的作用。
使用来自GSE15605、GSE46517和GSE111452数据集的矩阵数据，生物信息学分析揭示了CM与典型组织之间232个差异表达基因（DEG）。MR分析表明，只有组织蛋白酶S（CTSS）具有将皮肤暴露于阳光与CM联系起来的有害作用。对肿瘤和组织中CTSS表达的分析以及预后模型的构建显示，与正常皮肤组织相比，原发性CM和转移性CM中CTSS的表达均较高。然而，CTSS表达较高的患者预后较好。此外，CTSS高表达与肿瘤突变率、肿瘤微环境、免疫细胞浸润、免疫检查点和免疫治疗疗效显著正相关。
通过MR分析，我们发现阳光暴露皮肤中的CTSS基因与CM之间存在正向因果关系。此外，CTSS的增加可能为CM预后、免疫状态和免疫治疗的生物标志物预测提供依据。
