哺乳动物雷帕霉素靶蛋白基因多态性(rs2295080)与结直肠癌患者预后的关联性研究
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摘要
[目的]对哺乳动物雷帕霉素靶蛋白(mTOR)基因多态性(rs2295080)与结直肠癌患者预后的相关性进行分析。[方法]随访行结直肠癌根治术的488例患者,提取患者静脉血标本的DNA并进行基因分型,分析mTOR rs2295080多态性与结直肠癌患者生存预后的关联。[结果]在结肠癌患者中,rs22995080 GG基因型携带者的预后生存较TG/TT基因型明显下降(HR=3.07,95%CI:1.15~8.22)。同时发现该作用在中分化(HR=3.74,P=0.008),无淋巴结转移(HR=11.87,P<0.001)和Ⅱ期(HR=14.74,P<0.001)的结肠癌患者中更加明显。而在直肠癌患者中,rs2295080 TG/GG基因型较TT基因型可明显提升患者的预后生存(HR=0.48,95%CI:0.23~0.99)。该保护作用在无远处转移(HR=0.28,P=0.011)和Ⅲ期(HR=0.21,P=0.019)的直肠癌患者中更加明显。[结论]mTOR rs2295080可能与结直肠癌患者的生存相关并可作为结直肠癌预测预后的生物标志物。
[Purpose ] To investigate the association of polymorphisms in mTOR(rs2295080) and prognosis of colorectal cancer patients. [Methods] 488 surgically resected colorectal cancer patients were divided into several groups according to their genotypes,in order to explore the links between SNP rs2295080 and the survival of colorectal cancer patients in a Chinese population. [Results]Patients carrying rs2295080 GG genotype survived less than those with the TG/TT genotypes(HR=3.07,95% CI:1.15 ~8.22) in the colon cancer subgroup. This risk effect was more remarkable among patients with moderately differentiated cancers,no lymph node metastasis,and TNM stageⅡ. For rectal cancer patients,rs2295080 TG/GG genotypes had better prognosis compared with the TT genotype(HR=0.48,95%CI:0.23~0.99). This risk effect was more remarkable among patients with no distant metastasis and TNM stage Ⅲ. [Conclusions] SNP rs2295080 may be related to the survival of colorectal cancer patients and can be a potential prognostic biomarker of colorec-tal cancer.
[Purpose ] To investigate the association of polymorphisms in mTOR(rs2295080) and prognosis of colorectal cancer patients. [Methods] 488 surgically resected colorectal cancer patients were divided into several groups according to their genotypes,in order to explore the links between SNP rs2295080 and the survival of colorectal cancer patients in a Chinese population. [Results]Patients carrying rs2295080 GG genotype survived less than those with the TG/TT genotypes(HR=3.07,95% CI:1.15 ~8.22) in the colon cancer subgroup. This risk effect was more remarkable among patients with moderately differentiated cancers,no lymph node metastasis,and TNM stageⅡ. For rectal cancer patients,rs2295080 TG/GG genotypes had better prognosis compared with the TT genotype(HR=0.48,95%CI:0.23~0.99). This risk effect was more remarkable among patients with no distant metastasis and TNM stage Ⅲ. [Conclusions] SNP rs2295080 may be related to the survival of colorectal cancer patients and can be a potential prognostic biomarker of colorec-tal cancer.
引文
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[37]Wang JP,Yang ZL,Wang L.Multi-variate regression analysis of clinicopathological characteristics and prognosis of colorectal cancer[J].Chinese Journal of Oncology,2003,25(1):59-61.[汪建平,杨祖立,王磊.结直肠癌临床病理特征与预后的多因素回归分析[J].中华肿瘤杂志,2003,25(1):59-61.]
[38]Alici S,Aykan NF,Sakar B,et al.Colorectal cancer in young patients:characteristics and outcome[J].Tohoku J Exp Med,2003,199(2):85-93.
[39]Paraf F,Jothy S.Colorectal cancer before the age of 40:a case-control study[J].Dis Colon Rectum,2000,43(9):1222-1226.
[2]Gill S,Blackstock AW,Goldberg RM.Colorectal cancer[J].Mayo Clin Proc,2007,82(1):114-129.
[3]Stintzing S.Management of colorectal cancer[J].F1000Prime Rep,2014,6:108.
[4]Stadtlander CT,Waterbor JW.Molecular epidemiology pathogenesis and prevention of gastric cancer[J].Carcinogenesis,1999,20(19):2195-2208.
[5]Sato K,Close TJ,Bhat P,et al.Single nucleotide polymorphism mapping and alignment of recombinant chromosome substitution lines in barley[J].Plant Cell Physiol,2011,52(5):728-737.
[6]Hayes BJ.Efficient parentage assignment and pedigree reconstruction with dense single nucleotide polymorphism data[J].J Dairy Sci,2011,94(4):2114-2117.
[7]Dancey JE.Therapeutic targets:m TOR and related pathways[J].Cancer Biol Ther,2006,5(9):1065-1073.
[8]Hudes GR.Targeting m TOR in renal cell carcinoma[J].Cancer,2009,115(10 Suppl):2313-2320.
[9]Sanghera KP,Mathalone N,Baigi R,et al.The PI3K/Akt/m TOR pathway mediates retinal progenitor cell survival under hypoxic and superoxide stress[J].Mol Cell Neurosci,2011,47(2):145-153.
[10]Edinger AL,Thompson CB.Akt maintains cell size and survival by increasing m TOR-dependent nutrient uptake[J].Mol Biol Cell,2002,13(7):2276-2288.
[11]Daniel CC,Matthew BC,David JP,et al.The efficacy of the novel dual PI3-Kinase/m TOR inhibitor NVP-BEZ235compared to rapamycin in renal cell carcinoma[J].Clin Cancer Res,2010,16(14):3628-3638.
[12]Wysocki PJ.m TOR in renal cell cancer:modulator of tumor biology and therapeutic target[J].Expert Rev Mol Diagn,2009,9(3):231-241.
[13]Smrz D,Kim MS,Zhang S,et al.m TORC1 and m TORC2differentially regulate homeostasis of neoplastic and nonneoplastic human mast cells[J].Blood,2011,118(26):6803-6813.
[14]Downward J.Targeting RAS signalling pathways in cancertherapy[J].Nat Rev Cancer,2003,3(1):11-22.
[15]Li Q,Gu C,Zhu Y,et al.Polymorphisms in the m TOR gene and risk of sporadic prostate cancer in an Eastern Chinese population[J].PLo S One,2013,8(8):e71968.
[16]Cao Q,Ju X,Li P,et al.A functional variant in the MTOR promoter modulates its expression and is associated with renal cell cancer risk[J].PLo S One,2012,7(11):e50302.
[17]Chen J,Shao P,Cao Q,et al.Genetic variations in a PTEN/AKT/m TOR axis and prostate cancer risk in a Chinese population[J].PLo S One,2012,7(7):e40817.
[18]Huang L,Huang J,Wu P,et al.Association of genetic variations in m TOR with risk of childhood acute lymphoblastic leukemia in a Chinese population[J].Leuk Lymphoma,2012,53(5):947-951.
[19]Ming X,Guoquan T,Meiyun K,et al.A polymorphism(rs2295080)in m TOR promoter region and its association with gastric cancer in a Chinese population[J].PLo S One,2013,8(3):e60080.
[20]He J,Wang MY,Qiu LX,et al.Genetic variations of m TORC1 genes and risk of gastric cancer in an eastern chinese population[J].Mol Carcinog,2013,52(Suppl):E70-E79.
[21]Zhu ML,Yu H,Shi TY,et al.Polymorphisms in m TORC1genes modulate risk of esophageal squamous cell carcinoma in eastern Chinese populations[J].J Thorac Oncol,2013,8(6):788-795.
[22]Shao J,Li Y,Zhao P,et al.Association of m TOR polymorphisms with cancer risk and clinical outcomes:a metaanalysis[J].PLo S One,2014,9(5):e97085.
[23]Yu J,Yaba A,Kasiman C,et al.m TOR controls ovarian follicle growth by regulating granulosa cell proliferation[J].PLo S One,2011,6(7):e21415.
[24]Hildebrandt MA,Yang H,Hung MC,et al.Genetic variations in the PI3K/PTEN/AKT/m TOR pathway are associated with clinical outcomes in esophageal cancer patients treated with chemoradiotherapy[J].J Clin Oncol,2009,27(6):857-871.
[25]Chen M,Cassidy A,Gu J,et al.Genetic variations in PI3K-AKT-m TOR pathway and bladder cancer risk[J].Carcinogenesis,2009,30(12):2047-2052.
[26]Gheeyoung C,Steve H,Timothy F,et al.Analysis of the phosphatidylinositol 3-kinase signaling pathyway in glioblastoma patients in vivo[J].Cancer Res,2003,63(11):2742-2746.
[27]Neve RM,Holbor T,Hynes NE.Distinct roles for phosphoinostide 3-kinase,mitogen activated protein kinase and P38 MAPK in mediating cell cycle progression of breast cancer cells[J].Oncogene,2002,21(29):4567-4576.
[28]Philp AJ,Campbell IG,Leet C,et al.The phosphatidylinositol 3-kinase p85 alpha gene is an oncogene in human ovarian and colon tumors[J].Cancer Res,2001,61(20):7426-7429.
[29]Kozma SC,Thomas G.Regulation of cell size in growth,development and human disease:P13K,PKB and S6K[J].Bioessays,2002,24(1):65-71.
[30]Liu LZ,Zhou XD,Qian G,et al.AKT1 amplification regulates cisplatin resistance in human lung cancer cells through the mammalian target of rapamycin/p70S6K1 pathway[J].Cancer Res,2007,67(13):6325-6332.
[31]Faried LS,Faried A,Kanuma T,et al.Expression of an activated mammalian target of rapamycin in adenocarcinoma of the cervix:a potential biomarker and molecular target therapy[J].Mol Carcinog,2008,47(6):446-457.
[32]Faried LS,Faried A,Kanuma T,et al.Predictive and prognostic role of activated mammalian target of rapamycin in cervical cancer treated with cisplatin-based neoadjuvant chemotherapy[J].Oncol Rep,2006,16(1):57-63.
[33]Hou G,Xue L,Lu Z,et al.An activated m TOR/p70S6K signaling pathway in esophageal squamous cell carcinoma cell lines and inhibition of the pathway by rapamycin and si RNA against m TOR[J].Cancer Lett,2007,253(2):236-248.
[34]Lee S,Choi EJ,Jin C,et al.Activation of PI3K/Akt pathway by PTEN reduction and PIK3CA m RNA amplification contributes to cisplatin resistance in an ovarian cancer cell line[J].Gynecol Oncol,2005,97(1):26-34.
[35]Jessica BO,Melinda AM,Clifford YK.Colon cancer survival rates with the new American joint committee on cancer sixth edition staging[J].J Natl Cancer Inst,2004,96(19):1420-1425.
[36]Kang JW.High risk factors of death after resection of advanced colorectal cancer[J].Journal of Abdominal Surgery,2003,16(3):157-158.[康建物.影响进展期大肠癌切除术后长期生存的高危因素分析[J].腹部外科,2003,16(3):157-158.]
[37]Wang JP,Yang ZL,Wang L.Multi-variate regression analysis of clinicopathological characteristics and prognosis of colorectal cancer[J].Chinese Journal of Oncology,2003,25(1):59-61.[汪建平,杨祖立,王磊.结直肠癌临床病理特征与预后的多因素回归分析[J].中华肿瘤杂志,2003,25(1):59-61.]
[38]Alici S,Aykan NF,Sakar B,et al.Colorectal cancer in young patients:characteristics and outcome[J].Tohoku J Exp Med,2003,199(2):85-93.
[39]Paraf F,Jothy S.Colorectal cancer before the age of 40:a case-control study[J].Dis Colon Rectum,2000,43(9):1222-1226.