Integrated network toxicology, transcriptomic, and Mendelian randomization analyses explore potential molecular links between acrylamide exposure and clear cell renal cell carcinoma.

Abstract

Acrylamide is a potential carcinogen widely encountered in occupational settings and heat-processed foods. However, the potential molecular relationships between acrylamide-associated targets and clear cell renal cell carcinoma remain poorly characterized. The toxicological characteristics of acrylamide were predicted using ProTox-3.0 and ADMETlab 3.0. Potential acrylamide-associated targets were identified using SwissTargetPrediction, the Similarity Ensemble Approach, and TargetNet and were intersected with clear cell renal cell carcinoma (ccRCC)-related genes obtained from GeneCards. Protein-protein interaction networks and functional enrichment analyses were performed using Search Tool for the Retrieval of Interacting Genes/Proteins, Cytoscape, and bioinformatics approaches to characterize the biological functions of the shared targets. Using The Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma transcriptomic data, least absolute shrinkage and selection operator-Cox regression was applied to identify prognostic genes and construct a risk-prediction model. Two-sample Mendelian randomization analysis was subsequently conducted to evaluate associations between genetically predicted candidate-gene expression and kidney cancer risk. Representative immunohistochemical images from the Human Protein Atlas were examined as qualitative supporting evidence. Acrylamide was predicted to have potential carcinogenic properties. Among 161 putative acrylamide-associated targets and 1235 ccRCC-related genes, 50 overlapping targets were identified and were mainly enriched in chemical stress, oxidative stress, hypoxia-related processes, phosphoinositide 3-kinase-protein kinase B, hypoxia-inducible factor 1 (HIF-1), FoxO, and central carbon metabolism pathways. Least absolute shrinkage and selection operator identified 8 prognostic genes: TP53, EGFR, PTEN, IL6, MTOR, SLC2A1, SCARB1, and IKBKB. The internally assessed 1-, 3-, and 5-year area under the curves were 0.688, 0.647, and 0.698, indicating moderate apparent discrimination. SLC2A1 was significantly upregulated in ccRCC, and genetically predicted higher SLC2A1 expression was associated with increased kidney cancer risk (odds ratio = 1.762, 95% confidence interval: 1.247-2.491, raw P = .001, false discovery rate-adjusted P = .006). TP53 showed a less robust inverse association (odds ratio = 0.506, 95% confidence interval: 0.291-0.881, raw P = .016, false discovery rate-adjusted P = .048), with evidence of directional horizontal pleiotropy. Representative Human Protein Atlas images provided qualitative support for the transcriptomic findings. This integrative analysis identified SLC2A1 as a prioritized candidate at the intersection of predicted acrylamide-associated targets and ccRCC-related biological processes. The convergent network, transcriptomic, and genetic findings provide a hypothesis for further investigation but do not establish that SLC2A1 or TP53 mediates an effect of acrylamide on renal carcinogenesis.