A functional variant in the MTOR promoter modulates its expression and is associated with renal cell cancer risk

PLoS One. 2012;7(11):e50302. doi: 10.1371/journal.pone.0050302. Epub 2012 Nov 28.


Background: The mTOR signaling pathway plays a crucial role in the carcinogenesis of renal cell cancer (RCC). We sought to investigate the influence of genetic variations in the mTOR pathway-related genes on the risk of RCC.

Methods: We genotyped 8 potentially functional polymorphisms in AKT1, AKT2, PTEN and MTOR genes using the TaqMan method in a case-control study of 710 RCC patients and 760 cancer-free subjects. Unconditional logistic regression, adjusted for potential confounding factors, was used to assess the risk associations. We then examined the functionality of the important polymorphisms.

Results: Of the 8 polymorphisms, after adjusting for multiple comparisons, we found a significant association between one variant (rs2295080) in the promoter of MTOR and reduced RCC risk (P = 0.005, OR = 0.74, 95%CI = 0.59-0.91, TG/GG vs. TT). Another variant (rs701848) in the 3'UTR region of PTEN was associated with increased RCC risk (P = 0.014, OR = 1.45, 95%CI = 1.08-1.96, CC vs. TT); however, the association was not significant after adjusting for multiple comparisons. Furthermore, we observed lower MTOR mRNA levels in the presence of the rs2295080G allele in normal renal tissues. The luciferase reporter assay showed that the rs2295080G allele significantly decreased luciferase activity. No other significant association between the selected polymorphisms and RCC risk was observed.

Conclusions: Our results suggest that the functional MTOR promoter rs2295080 variant affects RCC susceptibility by modulating the endogenous MTOR expression level. The risk effects and the functional impact of the MTOR rs2295080 variant need further validation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Carcinoma, Renal Cell / diagnosis
  • Carcinoma, Renal Cell / genetics*
  • Case-Control Studies
  • Female
  • Genetic Variation
  • Genotype
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Kidney Neoplasms / diagnosis
  • Kidney Neoplasms / genetics*
  • Male
  • Middle Aged
  • PTEN Phosphohydrolase / genetics
  • Polymorphism, Genetic
  • Promoter Regions, Genetic*
  • Proto-Oncogene Proteins c-akt / genetics
  • Regression Analysis
  • Risk
  • Signal Transduction
  • TOR Serine-Threonine Kinases / genetics*


  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • AKT1 protein, human
  • AKT2 protein, human
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • PTEN protein, human

Grant support

This work was supported by the Program for Development of Innovative Research Team in the First Affiliated Hospital of Nanjing Medical University, Provincial Initiative Program for Excellency Disciplines of Jiangsu Province, by the National Natural Science Foundation of China [grant number 81171963 and 81102089] and the Natural Science Foundation of Jiangsu Province [grant number BK2008473 and BK2011773]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.