Abstract
Single nucleotide polymorphisms (SNPs) in the PI3K/PTEN/AKT/mTOR signaling pathway may contribute to carcinogenesis. We genotyped five potentially functional PIK3R1 and mTOR SNPs in 1116 esophageal squamous cell cancer (ESCC) patients and 1117 cancer-free controls to assess their associations with ESCC risk. We observed no association with ESCC risk for any of the selected SNPs. However, the combined analysis of these SNPs revealed that subjects with one-to-three risk genotypes had an increased ESCC risk. Stratified analysis by body mass index (BMI) found that ESCC risk was significantly associated with each of three mTOR SNPs among subjects with BMI < 25.0. Specifically, we found that subjects carrying ≥ 1 risk genotypes had significantly increased ESCC risk, particularly for males, ever-smokers, ever-drinkers, and those with age > 60, or BMI < 25.0. Moreover, three mTOR haplotypes were associated with an increase in ESCC risk. Our meta-analysis of mTOR rs2295080 and cancer risk provided further evidence that mTOR SNPs might modulate cancer susceptibility. In this population, such risk effects might be modified by other risk factors, highlighting the importance of gene-environment interaction in esophageal carcinogenesis. Additional, larger studies are warranted to validate our findings.
Highlights
Single nucleotide polymorphisms (SNPs) in the PI3K/PTEN/AKT/mTOR signaling pathway may contribute to carcinogenesis
Slattery et al demonstrated that single nucleotide polymorphisms (SNPs) in PIK3CA and mTOR/FRAP1 genes were significantly associated with risk of colon and rectal cancers, respectively[22]
Since PIK3R1 and mTOR are located in different chromosomes, we only explored whether the haplotypes of three mTOR SNPs would influence esophageal squamous cell cancer (ESCC) risk
Summary
Single nucleotide polymorphisms (SNPs) in the PI3K/PTEN/AKT/mTOR signaling pathway may contribute to carcinogenesis. The dysregulation of the PI3K/PTEN/ AKT/mTOR pathway has been observed in a variety of human cancers, including cancers of the endometrium, stomach, lung, and esophagus[8,9,10,11,12,13,14,15] Today, this pathway is well known to regulate important cellular events, including proliferation, adhesion, survival, and motility, which drive malignant transformation of cells and tumor progression[16]. Accumulating evidence has shown that mutations in some genes (PIK3CA, RAS, PTEN, and AKT) of the pathway could result in neoplastic transformation in both cellular and animal models[15,16,18,19], suggesting a critical role of the pathway in carcinogenesis Aberrant activation of this pathway has been closely related to various cancers, including ESCC. Two independent studies indicated that the mTOR rs1883965 SNP was significantly associated with an increased risk of gastric cancer[24] and ESCC23
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