Abstract
Tobacco smoking is one of the most important environmental risk factors involving bladder tumorigenesis. However, smoking-related genes in bladder carcinogenesis and corresponding genetic effects on bladder cancer risk remain unclear. Weighted correlation network analysis (WGCNA) underlying transcriptome of bladder cancer tissues was applied to identify smoking-related genes. The logistic regression model was utilized to estimate genetic effects of single nucleotide polymorphisms (SNPs) in smoking-related genes on bladder cancer risk in the Chinese and European populations with a total of 6510 cases and 6569 controls, as well as the interaction with smoking status. Transcriptome of cells and tissues was used to profile the expression pattern of candidate genes and their genetic variants. Our results demonstrated that a total of 24 SNPs in 14 smoking-related genes were associated with the risk of bladder cancer, of which rs9348451 in CDKAL1 exhibited an interaction with smoking status (ORinteraction = 1.38, Pinteraction = 1.08 × 10−2) and tobacco smoking might combine with CDKAL1 rs9348451 to increase the risk of bladder cancer (Ptrend = 4.27 × 10−4). Moreover, rs9348451 was associated with CDKAL1 expression in bladder cancer, especially in smokers (P < 0.001). Besides, CDKAL1 was upregulated in bladder cancer compared to normal adjacent tissues, as well as upregulated via treatment of cigarette smoke extracts. This study highlights the important role of nurture and nature, as well as their interaction on tumorigenesis, which provides a new way to decipher the etiology of bladder cancer with smoking status.
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Abbreviations
- WGCNA:
-
Weighted correlation network analysis
- SNP:
-
Single nucleotide polymorphism
- GWAS:
-
Genome-wide association study
- MIBC:
-
Muscle-invasive bladder cancer
- dbGaP:
-
Database of Genotypes and Phenotypes
- TCGA:
-
The Cancer Genome Atlas
- HWE:
-
Hardy–Weinberg equilibrium
- MAF:
-
Minor allele frequency
- LD:
-
Linkage disequilibrium
- BFDP:
-
Bayesian false discovery probability
- eQTL:
-
Expression quantitative trait locus
- GEO:
-
Gene Expression Omnibus
- GTEx:
-
Genotype-Tissue Expression
- CSEs:
-
Cigarette smoke extracts
- OR:
-
Odds ratio
- CI:
-
Confidence interval
- NATs:
-
Normal adjacent tissues
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Acknowledgements
We are grateful to all the people who helped us accomplish this project.
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This study was supported in part by the National Natural Science Foundation of China (82173603, 82103878 and 82130096) and the Gusu Health Talent Program (GSWS2021034).
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MLW, RZ and ZDZ designed the study and provided supervision. ZGM and YPX recruited study subjects. FG, HQL and MLD performed statistical analyses and summarized results. FG, HQL, MLD and SZW prepared the manuscript.
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Gao, F., Li, H., Mao, Z. et al. An integrative approach for identification of smoking-related genes involving bladder cancer. Arch Toxicol 97, 177–188 (2023). https://doi.org/10.1007/s00204-022-03380-5
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DOI: https://doi.org/10.1007/s00204-022-03380-5