Bridging the gap: exploring the causal relationship between metformin and tumors

Area of Science:

• Oncology
• Pharmacology
• Genetics

Background:

• Metformin is widely studied for its potential to reduce tumor development.
• Conflicting results exist, necessitating robust evaluation of metformin's anti-cancer effects.

Purpose of the Study:

• To explore the causal relationship between metformin and various tumors using a Mendelian randomization phenome-wide association study (MR-PheWAS).
• To identify specific tumor types potentially influenced by metformin.

Main Methods:

• Utilized two-sample Mendelian randomization (MR) analysis with inverse-variance weighted (IVW) method.
• Integrated data from UK Biobank and FinnGen_R10 cohorts for meta-analysis.
• Employed mediational MR analysis to investigate underlying mechanisms.

Main Results:

• MR analysis identified a causal relationship between metformin and 13 tumor-associated phenotypes in the training cohort.
• Metformin showed a protective effect against brain meningiomas, HER-positive breast cancer, oral cavity, tonsils, and base of tongue cancers.
• Meta-analysis of two cohorts revealed 12 statistically significant results, with mediational analysis suggesting Oxalobacteraceae may influence metformin's effect on brain meningiomas.

Conclusions:

• Metformin demonstrates potential preventive and therapeutic effects on brain meningioma, HER-positive breast cancer, oral cavity/tonsils, and base of tongue tumors.
• These findings highlight specific cancer types where metformin may be beneficial.
• Large-scale randomized controlled trials are recommended for definitive confirmation.