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. 2024 Aug;30(8):e13916.
doi: 10.1111/srt.13916.

Identification of potential therapeutic targets for skin cutaneous melanoma on the basic of transcriptomics

Fengling Shi  1   2 , Tao Li  1   2 , Huiling Shi  1   2 , Yushan Wei  1   2 , Juan Wang  1   2 , Canyu Liu  3 , Ruirong Liang  1   2   4
Affiliations

Identification of potential therapeutic targets for skin cutaneous melanoma on the basic of transcriptomics

Fengling Shi et al. Skin Res Technol. 2024 Aug.

Abstract

Background: Advanced skin cutaneous melanoma (SKCM) is responsible for the majority of skin cancer-related deaths. Apart from the rare BRAF V600F mutation, which can be targeted with specific drugs, there are currently no other novel effective therapeutic targets.

Methods: We used SMR analysis with cis-expressed quantitative trait locus (cis-eQTL) as the exposure variable and SKCM as the outcome variable to identify potential therapeutic targets for SKCM. Colocalization assays and HEIDI tests are used to test whether SKCM risk and gene expression are driven by common SNPs. Replication analysis further validated the findings, and we also constructed protein-protein interaction networks to explore the relationship between the identified genes and known SKCM targets. Drug prediction and molecular docking further validated the medicinal value of drug targets. Transcriptome differential analysis further validated that there were differences between normal tissues and SKCM for the selected targets.

Results: We identified 13 genes significantly associated with the risk of SKCM, including five protective genes and eight harmful genes. The HEIDI test and co-localization analysis further indicates a causal association between genes (SOX4, MAFF) and SKCM, categorized as Class 1 evidence targets. The remaining 11 genes, except for HELZ2 show a moderately causal association with SKCM, categorized as Class 2 evidence targets. Target druggability predictions from DGIdb suggest that SOX4, MAFF, ACSF3, CDK10, SPG7, and TCF25 are likely to be future drug targets.

Conclusion: The study provides genetic evidence for targeting available drug genes for the treatment of SKCM.

Keywords: Mendelian randomization; drug targets; genetics; skin cutaneous melanoma.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

FIGURE 1
FIGURE 1
Overview of this study.
FIGURE 2
FIGURE 2
SMR analysis of forest plots displaying the findings from the discovery phase for 13 significant genes.
FIGURE 3
FIGURE 3
Bayesian colocalization analysis for identified genes and SKCM. (A) MAFF; (B) SOX4.
FIGURE 4
FIGURE 4
(A) GO and KEGG enrichment results; (B) PPI network built with GeneMANIA; (C) Transcriptome differential analysis.
See this image and copyright information in PMC

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