Genetic variations in PI3K-AKT-mTOR pathway and bladder cancer risk.
Genetic variations in phosphoinositide-3 kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway may affect critical cellular functions and increase an individual's cancer risk. We systematically evaluate 231 single-nucleotide polymorphisms (SNPs) in 19 genes in the PI3K-AKT-mTOR signaling pathway as predictors of bladder cancer risk. In individual SNP analysis, four SNPs in regulatory associated protein of mTOR (RAPTOR) remained significant after correcting for multiple testing: rs11653499 [odds ratio (OR): 1.79, 95% confidence interval (CI): 1.24-2.60, P = 0.002], rs7211818 (OR: 2.13, 95% CI: 1.35-3.36, P = 0.001), rs7212142 (OR: 1.57, 95% CI: 1.19-2.07, P = 0.002) and rs9674559 (OR: 2.05, 95% CI: 1.31-3.21, P = 0.002), among which rs7211818 and rs9674559 are within the same haplotype block. In haplotype analysis, compared with the most common haplotypes, haplotype containing the rs7212142 wild-type allele showed a protective effect of bladder cancer (OR: 0.83, 95% CI: 0.70-0.97). In contrast, the haplotype containing the rs7211818 variant allele showed a 1.32-fold elevated bladder cancer risk (95% CI: 1.09-1.60). In combined analysis of three independent significant RAPTOR SNPs (rs11653499, rs7211818 and rs7212142), a significant trend was observed for increased risk with an increase in the number of unfavorable genotypes (P for trend <0.001). Compared with the subjects without any of the unfavorable genotypes, those carrying all three unfavorable genotypes showed a 2.22-fold (95% CI: 1.33-3.71) increased bladder cancer risk. This is the first study to evaluate the role of germ line genetic variations in PI3K-AKT-mTOR pathway as cancer susceptibility factors that will help us identify high-risk individuals for bladder cancer.
Chen
Meng
M
Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Cassidy
Adrian
A
Gu
Jian
J
Delclos
George L
GL
Zhen
Fan
F
Yang
Hushan
H
Hildebrandt
Michelle A T
MA
Lin
Jie
J
Ye
Yuanqing
Y
Chamberlain
Robert M
RM
Dinney
Colin P
CP
Wu
Xifeng
X
D000368:Aged; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011494:Protein Kinases / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D012306:Risk; D058570:TOR Serine-Threonine Kinases; D001749:Urinary Bladder Neoplasms / Q000235:genetics*
D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human