A transcriptome-wide association study (TWAS) was conducted on genome-wide association study (GWAS) summary statistics of malignant melanoma of skin (UK Biobank dataset) and The Cancer Genome Atlas-Skin Cutaneous Melanoma (TCGA-SKCM) gene expression weights to identify melanoma susceptibility genes. The GWAS included 2465 cases and 449,799 controls, while the gene expression testing was conducted on 103 cases. Afterward, a gene enrichment analysis was applied to identify significant TWAS associations. The melanoma’s gene–microRNA (miRNA) regulatory network was constructed from the TWAS genes and their corresponding miRNAs. At last, a disease enrichment analysis was conducted on the corresponding miRNAs. The TWAS detected 27 genes associated with melanoma withp-values less than 0.05 (the top three genes areLOC389458(RBAK),C16orf73(MEIOB), andEIF3CL). After the joint/conditional test, one gene (AMIGO1) was dropped, resulting in 26 significant genes. The Gene Ontology (GO) biological process associated the extended gene set (76 genes) with protein K11-linked ubiquitination and regulation of cell cycle phase transition. K11-linked ubiquitin chains regulate cell division. Interestingly, the extended gene set was related to different skin cancer subtypes. Moreover, the enriched pathways were nsp1 from SARS-CoV-2 that inhibit translation initiation in the host cell, cell cycle, translation factors, and DNA repair pathways full network. The gene-miRNA regulatory network identified 10 hotspot genes with the top three:TP53,BRCA1, andMDM2; and four hotspot miRNAs: mir-16, mir-15a, mir-125b, and mir-146a. Melanoma was among the top ten diseases associated with the corresponding (106) miRNAs. Our results shed light on melanoma pathogenesis and biologically significant molecular interactions.
本研究采用转录组范围关联分析(TWAS)方法，整合皮肤恶性黑色素瘤全基因组关联研究(GWAS)汇总数据（英国生物银行数据集）与癌症基因组图谱-皮肤黑色素瘤(TCGA-SKCM)基因表达权重，以识别黑色素瘤易感基因。GWAS分析包含2465例病例和449,799例对照，基因表达检测在103例病例中进行。随后通过基因富集分析鉴定显著TWAS关联，并基于TWAS基因及其对应微小RNA(miRNA)构建黑色素瘤基因-miRNA调控网络，最终对相关miRNA进行疾病富集分析。 TWAS共检测到27个与黑色素瘤相关的基因（p值<0.05），其中前三位基因为LOC389458(RBAK)、C16orf73(MEIOB)和EIF3CL。经联合/条件检验后排除AMIGO1基因，最终确定26个显著基因。基因本体(GO)生物过程分析显示，扩展基因集（76个基因）与蛋白质K11连接泛素化及细胞周期相变调控相关，其中K11连接泛素链可调控细胞分裂。值得注意的是，该扩展基因集与不同皮肤癌亚型均存在关联。富集通路分析发现SARS-CoV-2的nsp1蛋白可抑制宿主细胞翻译起始，主要富集通路涉及细胞周期、翻译因子及DNA修复完整网络。 基因-miRNA调控网络识别出10个热点基因（前三位：TP53、BRCA1、MDM2）和4个热点miRNA（mir-16、mir-15a、mir-125b、mir-146a）。在106个相关miRNA的疾病关联分析中，黑色素瘤位列前十。本研究结果揭示了黑色素瘤的发病机制及其具有生物学意义的分子相互作用。
肿瘤(癌症)患者之家