Potential drug targets for tumors identified through Mendelian randomization analysis

Area of Science:

• Genetics
• Oncology
• Pharmacology

Background:

• Cancer incidence and mortality remain high, with existing treatments showing unsatisfactory efficacy.
• There is a critical need to identify novel drug targets and biomarkers for effective cancer prevention and therapy.
• Human proteins are evaluated for their causal relationship to cancer risk and potential as therapeutic targets.

Purpose of the Study:

• To investigate the causal relationship between human proteins and the risk of nine major cancer types using genetic data.
• To identify potential protein biomarkers and drug targets for breast, colorectal, lung, liver, bladder, prostate, kidney, head and neck, and pancreatic cancers.
• To validate findings using Mendelian randomization, external cohorts, and drug databases.

Main Methods:

• Mendelian randomization (MR) analysis utilizing summary statistics from FinnGen and cis-protein quantitative trait loci (cis-pQTL) data.
• Exploration of associations between potential drug targets and nine cancer types.
• Validation through bidirectional MR, Steiger filtering, colocalization analysis, and the DrugBank database.

Main Results:

• S100A16 identified as protective and S100A14 as a risk protein for HER-positive breast cancer (FDR < 0.05).
• Phosphodiesterase 5A (PDE5A) identified as a risk protein for colorectal cancer (CRC).
• Melanoma inhibitory activity (MIA) identified as a protective protein for non-small cell lung carcinoma (NSCLC).
• Colocalization analysis confirmed shared causal variation for S100A14, S100A16 with HER-positive breast cancer, and PDE5A with CRC.

Conclusions:

• Circulating S100A14 and S100A16 are associated with increased and decreased risk of HER-positive breast cancer, respectively.
• Circulating PDE5A is linked to increased CRC risk, while MIA is linked to decreased NSCLC risk.
• These four proteins (S100A14, S100A16, PDE5A, MIA) represent promising biomarkers for cancer prevention and potential drug targets for therapeutic development.