Genetic variations in PI3K-AKT-mTOR pathway and ... - Oxford Journals

12 downloads 0 Views 90KB Size Report
Oct 29, 2009 - Meng Chen, Adrian Cassidy, Jian Gu, George L.Delclos1,. Fan Zhen2, Hushan Yang, Michelle A.T.Hildebrandt,. Jie Lin, Yuanqing Ye, Robert ...
Carcinogenesis vol.30 no.12 pp.2047–2052, 2009 doi:10.1093/carcin/bgp258 Advance Access publication October 29, 2009

Genetic variations in PI3K-AKT-mTOR pathway and bladder cancer risk Meng Chen, Adrian Cassidy, Jian Gu, George L.Delclos1, Fan Zhen2, Hushan Yang, Michelle A.T.Hildebrandt, Jie Lin, Yuanqing Ye, Robert M.Chamberlain, Colin P. Dinney3 and Xifeng Wu Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA, 1Division of Environmental and Occupational Health, The University of Texas Health Science Center at Houston School of Public Health, TX 77030, USA, 2Department of Experimental Therapeutics and 3Department of Urology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA  To whom correspondence should be addressed. Department of Epidemiology, Unit 1340, The University of Texas M. D. Anderson Cancer Center, 1155 Pressler Boulevard, Houston, TX 77030. Tel: þ1 713 745 2485; Fax: þ1 713 792 4657; Email: [email protected]

Genetic variations in phosphoinositide-3 kinase (PI3K)-AKTmammalian 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 5 0.002], rs7211818 (OR: 2.13, 95% CI: 1.35–3.36, P 5 0.001), rs7212142 (OR: 1.57, 95% CI: 1.19–2.07, P 5 0.002) and rs9674559 (OR: 2.05, 95% CI: 1.31–3.21, P 5 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