Growth Hormone and Cancer Risk: A Two-Sample Bidirectional Mendelian Randomization Study with Mediation Testing

Area of Science:

• Endocrinology
• Oncology
• Genetics

Background:

• Growth Hormone (GH) therapy is associated with potential cancer risks, but the causal link remains unclear.
• Investigating the relationship between genetically predicted GH levels and cancer risk is crucial for understanding these potential adverse effects.

Purpose of the Study:

• To examine the causal relationship between genetically predicted Growth Hormone (GH) levels and the risk of 16 different cancer types using Mendelian randomization.
• To explore potential mediating roles of specific metabolites in the association between GH and cancer risk.

Main Methods:

• Utilized Mendelian randomization (MR) with genetic variants associated with serum GH levels from GWAS as instrumental variables.
• Employed inverse-variance weighted MR, MR-Egger regression, and sensitivity analyses (MR-PRESSO, pleiotropy tests) for robust estimation.
• Conducted mediation analysis to identify metabolites contributing to GH's effect on cancer risk.

Main Results:

• Genetically predicted GH levels were associated with an increased risk of breast cancer, prostate cancer, and malignant lymphoma.
• A potentially protective association was observed for oral/oropharyngeal cancer and skin cancer.
• Metabolites such as isovalerylglycine and the proline/trans-4-hydroxyproline ratio partially mediated GH's effect on breast cancer, while the histidine/glutamine ratio mediated its effect on prostate cancer.

Conclusions:

• GH exhibits tissue-specific effects on carcinogenesis, with identified mediating roles for specific metabolic pathways.
• Findings suggest a need for careful risk-benefit assessment in GH therapy and highlight the potential for metabolite monitoring to mitigate cancer risk.