title: A functional variant in the MTOR promoter modulates its expression and is associated with renal cell cancer risk.
abstract: 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.
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Urology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Cao
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Ju
authors.forename: Pu
authors.initials: P
authors.lastname: Li
authors.forename: Xiaoxin
authors.initials: X
authors.lastname: Meng
authors.forename: Pengfei
authors.initials: P
authors.lastname: Shao
authors.forename: Hongzhou
authors.initials: H
authors.lastname: Cai
authors.forename: Meilin
authors.initials: M
authors.lastname: Wang
authors.forename: Zhengdong
authors.initials: Z
authors.lastname: Zhang
authors.forename: Chao
authors.initials: C
authors.lastname: Qin
authors.forename: Changjun
authors.initials: C
authors.lastname: Yin
mesh_terms: D000328:Adult; D000368:Aged; D002292:Carcinoma, Renal Cell / Q000175:diagnosis / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007680:Kidney Neoplasms / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000235:genetics; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D012044:Regression Analysis; D012306:Risk; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*
chemical_list: C546842:MTOR protein, human; C494918:AKT1 protein, human; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human