Crotonylation and the Risk of Head and Neck Cancer: Insights from a Two-Sample Mendelian Randomization Study

Area of Science:

• Genetics
• Oncology
• Metabolomics

Background:

• Head and neck cancer (HNC) presents a significant global health challenge with stagnant survival rates.
• The role of crotonylation in tumor biology is recognized, but its direct impact on HNC risk remains unestablished.

Purpose of the Study:

• To investigate the causal relationship between crotonylation-related gene expression and HNC risk.
• To explore potential mediating roles of metabolites and immune cells in this association.

Main Methods:

• Two-sample Mendelian randomization (MR) study utilizing eQTL-instrumented gene expression.
• Differential gene expression analysis using The Cancer Genome Atlas (TCGA) data.
• Mediation MR, single-cell RNA sequencing (scRNA-seq), and quantitative PCR (qPCR) for comprehensive analysis.

Main Results:

• Genetically predicted GCDH and ACSS2 expression causally increased HNC risk; DPF2 and HDAC7 showed protective effects.
• GCDH expression was consistently associated with HNC risk in TCGA data.
• Immune cell traits, specifically CX3CR1 on monocytes and CD8 on T cells, partially mediated GCDH's effect on HNC. GCDH was upregulated in tumor tissues.

Conclusions:

• GCDH expression shows a potential causal link to increased HNC risk, partly mediated by immune responses.
• GCDH emerges as a promising target for further research and potential therapeutic strategies in HNC.
• Findings suggest precision medicine approaches targeting GCDH could improve HNC patient outcomes.