Functional variants of RPS6KB1 and PIK3R1 in the autophagy pathway genes and risk of bladder cancer

• Published in: Archives of toxicology Vol. 96; no. 1; pp. 367 - 375
• Main Authors: Ma, Lan, Zhang, Dongjian, Huang, Zhengkai, Zheng, Rui, Du, Mulong, Lv, Qiang, Qin, Chao, Chu, Haiyan, Yuan, Lin, Zhang, Zhengdong
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 2022; Springer Nature B.V
• Subjects: Annotations; Autophagy; Autophagy - genetics; Biomedical and Life Sciences; Biomedicine; Bladder; Bladder cancer; Cancer; Case-Control Studies; Cell proliferation; Cell survival; Class Ia Phosphatidylinositol 3-Kinase - genetics; Environmental Health; Gene expression; Gene mapping; Genes; Genetic diversity; Genetic Predisposition to Disease; Genetic variance; Genome-Wide Association Study; Genomic analysis; Genotoxicity and Carcinogenicity; Genotype; Genotypes; Health risks; Humans; Magma; Occupational Medicine/Industrial Medicine; Pharmacology/Toxicology; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Regression models; Risk; Single-nucleotide polymorphism; Tumorigenesis; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - pathology; Genetic variants; Susceptibility; Autophagy; Bladder cancer
• ISSN: 0340-5761; 1432-0738
• DOI: 10.1007/s00204-021-03173-2

Autophagy plays a critical role in cancer, since it can either suppress tumorigenesis by inhibiting cancer cell survival, or facilitate tumorigenesis by promoting cancer cell proliferation and tumor growth. However, the role of genetic variants of autophagy-regulated key genes for bladder cancer risk remained unclear. Here, we aimed to explore the association of bladder cancer with genetic variants on genes involved in autophagy pathway. Gene-based analysis was performed with multi-marker analysis of genomic annotation (MAGMA) in 580 bladder cancer cases and 1101 controls. The logistic regression model was used to calculate the SNP effects on bladder cancer susceptibility. Expression quantitative trait loci (eQTL) analysis was conducted by the genotype-tissue expression (GTEx) project. Gene expression was evaluated based on the Cancer Genome Atlas (TCGA) database. Three potentially functional SNPs RPS6KB1 rs1292038, PIK3R1 rs34303, and rs56352616 were demonstrated to be associated with risk of bladder cancer (OR = 0.71, 95% CI = 0.61–0.82, P  = 7.88 × 10 −6 for rs1292038; OR = 1.25, 95% CI = 1.09–1.45, P  = 2.11 × 10 −3 for rs34303; OR = 0.74, 95% CI = 0.62–0.90, P  = 2.47 × 10 −3 for rs56352616). An increasing number of risk genotypes of these three SNPs were associated with a higher risk of developing bladder cancer. Besides, rs1292038 exhibited an eQTL effect for RPS6KB1 in whole blood ( P  = 3.90 × 10 −7 ). Furthermore, the higher expression of RPS6KB1 and lower expression of PIK3R1 were both significantly associated with bladder cancer risk. Our findings indicated that genetic variants in autophagy pathway genes RPS6KB1 and PIK3R1 confer bladder cancer susceptibility.