Genetic polymorphisms of mTOR and cancer risk: a systematic review and updated meta-analysis.

Jin Zining,Xu Lu,Yuan Yuan,He Caiyun

doi:10.18632/oncotarget.10805

Jin Zining, Xu Lu + Show 2 more

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https://doi.org/10.18632/oncotarget.10805

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Abstract

mTOR regulates several cellular processes that are critical for tumorigenesis. However, previous studies on the association of mTOR polymorphisms with predisposition to different cancer types are somewhat contradictory. Therefore, we performed a systematic review and updated meta-analysis of the available evidence regarding the relationship between mTOR single nucleotide polymorphisms (SNPs) and cancer risk. Up to November 2015, 23 original publications were identified covering 20 mTOR SNPs, of which seven SNPs (rs2536, rs2295080, rs1883965, rs1034528, rs17036508, rs3806317 and rs1064261) were included in the final meta-analysis. We estimated the summary odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for mTOR polymorphisms and cancer risk, and used the model-free approach to investigate the biological effect of each polymorphism. Our meta-analysis found that rs1883965, rs1034528, and rs17036508 were correlated with increased cancer risk in the complete over-dominant model (rs1883965 GA versus GG/AA: fixed-effects OR=1.15, 95% CI 1.02-1.29; rs1034528 GC versus GG/CC: fixed-effects OR=1.30, 95% CI 1.13-1.48; rs17036508 TC versus CC/TT: fixed-effects OR=1.23, 95% CI 1.06-1.43). Stratifying analyses by cancer type, we found that the rs2295080 G allele was associated with a significantly higher risk of acute leukemia in the recessive model (GG versus GT/TT: fixed-effects OR=2.08, 95% CI 1.34-3.22) and a lower risk of genitourinary cancers in the dominant model (TG/GG versus TT: fixed-effects OR=0.77, 95% CI 0.68-0.86). Interestingly, further expression analysis showed that homozygous variant genotype carriers of rs1883965, rs1034528 and rs17036508 had lower mTOR transcript levels, based on HapMap data.

Highlights

The mammalian target of rapamycin, a key downstream effector of the phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway, regulates several cellular processes that are critical for oncogenesis, such as cell proliferation, apoptosis, migration, metabolism, and angiogenesis [1,2,3,4]
A total of 23 case-control studies matched the inclusion criteria [10, 13-25, 2730, 49, 53, 54, 73, 74], including one that discussed the relationship between mTOR polymorphisms and meningioma [28], which is generally considered to be benign
Seven single nucleotide polymorphisms (SNPs) included in the final meta-analysis were analyzed in at least two series and were described in 14 studies

Summary

Introduction

The mammalian target of rapamycin (mTOR, known as FRAP1), a key downstream effector of the phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway, regulates several cellular processes that are critical for oncogenesis, such as cell proliferation, apoptosis, migration, metabolism, and angiogenesis [1,2,3,4]. Aberrant expression of mTOR, including both over-expression and over-activation, has been observed in lung adenocarcinoma, hepatocellular cancer, large intestine adenocarcinoma, renal cell carcinoma, and extrahepatic cholangiocarcinoma [6,7,8,9,10]. These changes may be caused by genetic alterations [11], and single nucleotide polymorphisms (SNPs) widespread in the human genome [12], have been extensively studied in mTOR to identify susceptibility loci for cancer.

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