Genetic polymorphisms in mTOR gene may be associated with cancer risk and clinical outcomes of cancer patients by affecting mTOR gene expression or its activation. However, inconsistent results have been reported. The aim of this study is to systematically evaluate the association between mTOR polymorphisms (rs2295080, rs2536 and rs11121704) and cancer risk as well as clinical outcome by a meta-analysis. We identified 10 eligible studies and extracted data by two investigators. Based on dominant and recessive models, odds ratio (ORs) and 95% confidence intervals (CIs) were calculated by using Stata, version 11 to evaluate the association strength. Our meta-analysis results showed that the wild genotype TT of rs2295080 polymorphism was associated with increased cancer risk under dominant model (OR = 1.24, 95%CI: 1.12–1.36, p<0.0005) in Chinese but not with clinical outcome parameters, while the TT genotype of rs11121704 was associated with poor clinical outcome parameters (OR = 1.53, 95%CI: 1.01–2.32, p = 0.044), such as death, metastasis and resistance to chemotherapy. However, rs2536 may not influence cancer susceptibility. In conclusion, this meta-analysis indicated the common polymorphisms in mTOR gene might be genetic risk factors for the carcinogenesis and clinical outcomes of cancer patients. However, further investigation on large population and different ethnicities are warranted.
References
[1]
Heitman J, Movva NR, Hall MN (1991) Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 253: 905–909. doi: 10.1126/science.1715094
[2]
Strimpakos AS, Karapanagiotou EM, Saif MW, Syrigos KN (2009) The role of mTOR in the management of solid tumors: an overview. Cancer Treat Rev 35: 148–159. doi: 10.1016/j.ctrv.2008.09.006
[3]
Rosner M, Hanneder M, Siegel N, Valli A, Fuchs C, et al. (2008) The mTOR pathway and its role in human genetic diseases. Mutat Res 659: 284–292. doi: 10.1016/j.mrrev.2008.06.001
[4]
Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat. Rev. Cancer 2: 489–501. doi: 10.1038/nrc839
[5]
Faivre S, Kroemer G, Raymond E (2006) Current development of mTOR inhibitors as anticancer agents. Nat. Rev. Drug Discov 5: 671–688. doi: 10.1038/nrd2062
[6]
Liu LZ, Zhou XD, Qian G, Shi X, Fang J, et al. (2007) AKT1 amplification regulates cisplatin resistance in human lung cancer cells through the mammalian target of rapamycin/p70S6K1 pathway. Cancer Res 67: 6325–6332. doi: 10.1158/0008-5472.can-06-4261
[7]
Faried LS, Faried A, Kanuma T, Aoki H, Sano T, et al. (2008) Expression of an activated mammalian target of rapamycin in adenocarcinoma of the cervix: a potential biomarker and molecular target therapy. Mol. Carcinog 47: 446–457. doi: 10.1002/mc.20402
[8]
Faried LS, Faried A, Kanuma T, Sano T, Nakazato T, et al. (2006) Predictive and prognostic role of activated mammalian target of rapamycin in cervical cancer treated with cisplatin-based neoadjuvant chemotherapy. Oncol Rep16: 57–63. doi: 10.3892/or.16.1.57
[9]
Hou G, Xue L, Lu Z, Fan T, Tian F, et al. (2007) An activated mTOR/p70S6K signaling pathway in esophageal squamous cell carcinoma cell lines and inhibition of the pathway by rapamycin and siRNA against mTOR. Cancer Lett 253: 236–248. doi: 10.1016/j.canlet.2007.01.026
[10]
Lee S, Choi EJ, Jin C, Kim DH (2005) Activation of PI3K/Akt pathway by PTEN reduction and PIK3CA mRNA amplification contributes to cisplatin resistance in an ovarian cancer cell line. Gynecol Onco 97: 26–34. doi: 10.1016/j.ygyno.2004.11.051
[11]
Sato T, Nakashima A, Guo L, Coffman K, Tamanoi F (2010) Single amino-acid changes that confer constitutive activation of mTOR are discovered in human cancer. Oncogene 29: 2746–2752. doi: 10.1038/onc.2010.28
[12]
Li Q, Gu C, Zhu Y, Wang M, Yang Y, et al. (2013) Polymorphisms in the mTOR gene and risk of sporadic prostate cancer in an Eastern Chinese population. PLoS On 8(8): e71968. doi: 10.1371/journal.pone.0071968
[13]
Cao Q, Ju X, Li P, Meng X, Shao P, et al. (2012) A functional variant in the MTOR promoter modulates its expression and is associated with renal cell cancer risk. PLoS One 7(11): e50302. doi: 10.1371/journal.pone.0050302
[14]
Chen J, Shao P, Cao Q, Li P, Li J, et al. (2012) Genetic variations in a PTEN/AKT/mTOR axis and prostate cancer risk in a Chinese population. PLoS One 7(7): e40817. doi: 10.1371/journal.pone.0040817
[15]
Huang L, Huang J, Wu P, Li Q, Rong L, et al. (2012) Association of genetic variations in mTOR with risk of childhood acute lymphoblastic leukemia in a Chinese population. Leuk Lymphoma 53: 947–951. doi: 10.3109/10428194.2011.628062
[16]
Xu M, Tao G, Kang M, Gao Y, Zhu H, et al. (2013) A polymorphism (rs2295080) in mTOR promoter region and its association with gastric cancer in a Chinese population. PLoS One 8(3): e60080. doi: 10.1371/journal.pone.0060080
[17]
He J, Wang MY, Qiu LX, Zhu ML, Shi TY, et al. (2013) Genetic variations of mTORC1 genes and risk of gastric cancer in an eastern chinese population. Mol Carcinog 52 Suppl 170–179. doi: 10.1002/mc.22013
[18]
Zhu ML, Yu H, Shi TY, He J, Wang MY, et al. (2013) Polymorphisms in mTORC1 genes modulate risk of esophageal squamous cell carcinoma in eastern Chinese populations. J Thorac Oncol 8: 788–795. doi: 10.1097/jto.0b013e31828916c6
[19]
Hildebrandt MA, Yang H, Hung MC, Izzo JG, Huang M, et al. (2009) Genetic variations in the PI3K/PTEN/AKT/mTOR pathway are associated with clinical outcomes in esophageal cancer patients treated with chemoradiotherapy. J Clin Oncol 27: 857–871. doi: 10.1200/jco.2008.17.6297
[20]
Pu X, Hildebrandt MA, Lu C, Lin J, Stewart DJ, et al. (2011) PI3K/PTEN/AKT/mTOR pathway genetic variation predicts toxicity and distant progression in lung cancer patients receiving platinum-based chemotherapy. Lung Cancer 71: 82–88. doi: 10.1016/j.lungcan.2010.04.008
[21]
DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7: 177–188. doi: 10.1016/0197-2456(86)90046-2
[22]
Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22: 719–748.
Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in metaanalysis detected by a simple, graphical test. BMJ 315: 629–634. doi: 10.1136/bmj.315.7109.629
[25]
Duval S, Tweedie R (2000) Trim and fill: A simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics 56: 455–463. doi: 10.1111/j.0006-341x.2000.00455.x
[26]
Kim JG, Chae YS, Sohn SK, Kang BW, Moon JH, et al. (2010) Clinical significance of genetic variations in the PI3K/PTEN/AKT/mTOR pathway in Korean patients with colorectal cancer. Oncology 79: 278–282. doi: 10.1159/000320761
[27]
Wang LE, Ma H, Hale KS, Yin M, Meyer LA, et al. (2012) Roles of genetic variants in the PI3K and RAS/RAF pathways in susceptibility to endometrial cancer and clinical outcomes. J Cancer Res Clin Oncol138: 377–385. doi: 10.1007/s00432-011-1103-0
[28]
Hildebrandt MA, Lippman SM, Etzel CJ, Kim E, Lee JJ, et al. (2012) Genetic variants in the PI3K/PTEN/AKT/mTOR pathway predict head and neck cancer patient second primary tumor/recurrence risk and response to retinoid chemoprevention. Clin Cancer Res 18: 3705–3713. doi: 10.1158/1078-0432.ccr-11-3271
[29]
Slattery ML, Herrick JS, Lundgreen A, Fitzpatrick FA, Curtin K, et al. (2010) Genetic variation in a metabolic signaling pathway and colon and rectal cancer risk: mTOR, PTEN, STK11, RPKAA1, PRKAG2, TSC1, TSC2, PI3K and Akt1. Carcinogenesis 31: 1604–1611. doi: 10.1093/carcin/bgq142
[30]
Slattery ML, Lundgreen A, Herrick JS, Caan BJ, Potter JD, et al. (2011) Diet and colorectal cancer: analysis of a candidate pathway using SNPS, haplotypes, and multi-gene assessment. Nutr Cancer 63: 1226–1234. doi: 10.1080/01635581.2011.607545
[31]
Lin J, Wang J, Greisinger AJ, Grossman HB, Forman MR, et al. (2010) Energy balance, the PI3K-AKT-mTOR pathway genes, and the risk of bladder cancer. Cancer Prev Res (Phila) 3: 505–517. doi: 10.1158/1940-6207.capr-09-0263
[32]
Chen M, Cassidy A, Gu J, Delclos GL, Zhen F, et al. (2009) Genetic variations in PI3K-AKT-mTOR pathway and bladder cancer risk. Carcinogenesis 30: 2047–2052. doi: 10.1093/carcin/bgp258
[33]
Xu J, Wang Z, Hu L, Yin Z, Huang M, et al. (2012) Genetic variants in the PI3K/PTEN/AKT/mTOR pathway predict platinum-based chemotherapy response of advanced non-small cell lung cancers in a Chinese population. Asian Pac J Cancer Prev 13(5): 2157–2162. doi: 10.7314/apjcp.2012.13.5.2157
[34]
Kremer CL, Klein RR, Mendelson J, Browne W, Samadzedeh LK, et al. (2006) Expression of mTOR signaling pathway markers in prostate cancer progression. Prostate 66: 1203–1212. doi: 10.1002/pros.20410
[35]
Li Q, Yang J, Yu Q, Wu H, Liu B, et al. (2013) Associations between Single-Nucleotide Polymorphisms in the PI3K-PTEN-AKT-mTOR Pathway and Increased Risk of Brain Metastasis in Patients with Non-Small Cell Lung Cancer. Clin Cancer Res 19: 6252–6260. doi: 10.1158/1078-0432.ccr-13-1093