Systematic proteome-wide Mendelian randomization to prioritize causal plasma proteins for skin cancers

Area of Science:

• Genetics
• Oncology
• Proteomics

Background:

• Skin cancer is a prevalent global malignancy.
• Known risk factors include sun exposure and MC1R variants.
• Identifying additional genetic factors is crucial for new therapies.

Purpose of the Study:

• To perform a proteome-wide Mendelian randomization (MR) analysis.
• To identify novel genetic factors associated with skin cancer risk.
• To explore potential therapeutic and biomarker targets for skin cancers.

Main Methods:

• Utilized plasma protein quantitative trait loci (pQTLs) and UK Biobank genome-wide association study (GWAS) data.
• Conducted Mendelian randomization (MR) analysis.
• Performed replication analyses (DeCODE pQTLs, FinnGen GWAS) and sensitivity analyses (Steiger filtering, reverse MR, Bayesian colocalization).

Main Results:

• Replicated the association of ASIP with increased risk of basal cell carcinoma (BCC) and malignant melanoma.
• Newly identified CTSS significantly associated with a decreased risk of BCC.
• Sensitivity and replication analyses supported the findings.

Conclusions:

• The study highlights potential protein targets for novel therapeutic or preventive strategies for skin cancers.
• Identified CTSS as a potential biomarker for BCC.
• Emphasizes the utility of proteome-wide MR in discovering genetic associations for complex diseases.