Transcriptome-Wide Association Study Reveals New Molecular Interactions Associated with Melanoma

Abstract

The journey of discovering melanoma biomarkers is never ending. Under that assumption, this study is attempted to partially fill in a gap in that journey by identifying biomarkers related to melanoma. 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. Afterwards, a gene enrichment analysis was applied on the TWAS significant 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 having P-value less than 0.05, namely, AMIGO1, GSTM3, MDM4, COPA, DENND4B, RAB13, IL1A, ANAPC13, CRIPAK, LOC389458, LOC441204, MTERFD1, CBWD1, B3GAT1, HOXC10, DDX11, PROZ, DHRS1, SPATA5L1, C16orf73, EIF3CL, FANCA, SCRN2, ALDH16A1, UPK1A, EDEM2, and TEF. After Joint/Conditional test, one gene (AMIGO1) was dropped out, resulting in 26 significant genes. The gene ontology (GO) biological process ended with the association of the extended gene set (76 genes) with protein K11-linked ubiquitination, and regulation of cell cycle phase transition. K11-linked ubiquitin chains regulates cell division. Interestingly, the extended gene set was related to different skin cancer subtypes. Moreover, the enriched pathways were nsp1 from SARS-CoV-2 inhibits 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: TP53, BRCA1, FANCA, BLM, USP7, MDM2, MDM4, IL1A, EIF3F, and ANAPC16; and 4 hotspot miRNAs: mir-16, mir-15a, mir-125b, and mir-146a. Melanoma was one of the top ten diseases associated with the corresponding (106) miRNAs. Our results shed light on melanoma pathogenesis and biologically significant molecular interactions. Besides, our study gives a comprehensive pipeline for the TWASs generally.