Wnt信号通路与mCRC含伊立替康化疗疗效及预后的易感性研究
|
摘要
目的:探讨Wnt信号通路关键基因单核苷酸多态性(single nucleotide polymorphisms,SNPs)与转移性结直肠癌(metastatic colorectal cancer,m CRC)含伊立替康化疗疗效及预后的相关性。方法:筛选Wnt信号通路上的关键基因,对110例含伊立替康化疗的m CRC患者进行SNPs分型。运用Logistic和Cox回归法分别分析SNPs不同基因型对疗效及预后的影响。结果:LRP6 rs10772542 C等位基因患者的疾病控制率(disease control rate,DCR)相对于T等位基因更低(OR=2.49,95%CI=1.28~4.83,P=0.007)。LEF1 rs749414 G等位基因的无进展生存期(progression-free survival,PFS)相对于T等位基因更长(HR=0.55,95%CI=0.40~0.78,P=0.001);WNT7B rs10448605 T等位基因的PFS相对于C等位基因更短(HR=1.65,95%CI=1.13~2.41,P=0.009);而WNT2 rs2239957 C等位基因的总生存期(overall survival,OS)相对于G等位基因更长(HR=0.54,95%CI=0.35~0.85,P=0.007)。结论:Wnt信号通路上的LRP6、LEF1、WNT7B和WNT2基因多态性与mCRC含伊立替康化疗疗效及预后之间存在明显的相关性。
Objective:To explore the association between single nucleotide polymorphisms(SNPs)in the Wnt signaling pathway genes and the curative effect and prognostic of metastatic colorectal cancer(m CRC)patients who received irinotecan-based chemotherapy. Methods:We selected seven key genes in the Wnt signaling pathway and genotyped the SNPs within seven genes among 110 mCRC patients treated with irinotecan-based chemotherapy. Logistic regression and cox regression analysis were performed to evaluate the association between SNPs and the curative effect and prognostic of m CRC patients. Results:Patients with the LRP6 rs10772542 C alleles had a lower disease control rate(DCR)compared with those with T alleles(OR=2.49,95%CI=1.28~4.83,P=0.007). LEF1 rs749414 G alleles had a longer progression-free survival(PFS)compared with the T alleles(HR=0.55,95%CI=0.40~0.78,P=0.001)and WNT7 B rs10448605 T alleles had a shorter PFS compared with the C alleles(HR=1.65,95%CI=1.13~2.41,P=0.009). Furthermore,WNT2 rs2239957 C alleles had a longer overall survival(OS)compared with the G alleles(HR=0.54,95%CI=0.35~0.85,P=0.007). Conclusion:Genetic variants in the Wnt signaling pathway genes contribute to the curative effect and prognostic of mCRC patients who received irinotecan-based chemotherapy.
Objective:To explore the association between single nucleotide polymorphisms(SNPs)in the Wnt signaling pathway genes and the curative effect and prognostic of metastatic colorectal cancer(m CRC)patients who received irinotecan-based chemotherapy. Methods:We selected seven key genes in the Wnt signaling pathway and genotyped the SNPs within seven genes among 110 mCRC patients treated with irinotecan-based chemotherapy. Logistic regression and cox regression analysis were performed to evaluate the association between SNPs and the curative effect and prognostic of m CRC patients. Results:Patients with the LRP6 rs10772542 C alleles had a lower disease control rate(DCR)compared with those with T alleles(OR=2.49,95%CI=1.28~4.83,P=0.007). LEF1 rs749414 G alleles had a longer progression-free survival(PFS)compared with the T alleles(HR=0.55,95%CI=0.40~0.78,P=0.001)and WNT7 B rs10448605 T alleles had a shorter PFS compared with the C alleles(HR=1.65,95%CI=1.13~2.41,P=0.009). Furthermore,WNT2 rs2239957 C alleles had a longer overall survival(OS)compared with the G alleles(HR=0.54,95%CI=0.35~0.85,P=0.007). Conclusion:Genetic variants in the Wnt signaling pathway genes contribute to the curative effect and prognostic of mCRC patients who received irinotecan-based chemotherapy.
引文
[1]Torre LA,Bray F,Siegel RL,et al.Global cancer statistics,2012[J].CA Cancer J Clin,2015,65(2):87-108
[2]Ulukan H,Swaan PW.Camptothecins:a review of their chemotherapeutic potential[J].Drugs,2002,62(14):2039-2057
[3]Coate L,Cuffe S,Horgan A,et al.Germline genetic variation,cancer outcome,and pharmacogenetics[J].J Clin Oncol,2010,28(26):4029-4037
[4]Scripture CD,Sparreboom A,Figg WD.Modulation of cytochrome P450 activity:implications for cancer therapy[J].Lancet Oncol,2005,6(10):780-789
[5]Toffoli G,Cecchin E,Corona G,et al.Pharmacogenetics of irinotecan[J].Curr Med Chem Anticancer Agents,2003,3(3):225-237
[6]Shtutman M,Zhurinsky J,Simcha I,et al.The cyclin D1gene is a target of the beta-catenin/LEF-1 pathway[J].Proc Natl Acad Sci USA,1999,96(10):5522-5527
[7]Koesters R,von Knebel Doeberitz M.The Wnt signalingpathway in solid childhood tumors[J].Cancer Lett,2003,198(2):123-138
[8]Pennisi E.How a growth control path takes a wrong turn tocancer[J].Science,1998,281(5382):1438-1439,1441
[9]Gao Y,Xiao X,Zhang C,et al.Melatonin synergizes thechemotherapeutic effect of 5-fluorouracil in colon cancerby suppressing PI3K/AKT and NF-kappa B/i NOS signal-ing pathways[J].J Pineal Res,2017,62(2).doi:10.1111/jpi.e12380
[10]Nam HJ,Im SA,Oh DY,et al.Antitumor activity of sara-catinib(AZD0530),a c-Src/Abl kinase inhibitor,alone orin combination with chemotherapeutic agents in gastriccancer[J].Mol Cancer Ther,2013,12(1):16-26
[11]Fu L,Zhang C,Zhang LY,et al.Wnt2 secreted by tumour fibroblasts promotes tumour progression in oesophageal cancer by activation of the Wnt/beta-catenin signalling pathway[J].Gut,2011,60(12):1635-1643
[12]Moon RT,Kohn AD,De Ferrari GV,et al.WNT and betacatenin signalling:diseases and therapies[J].Nat Rev Genet,2004,5(9):691-701
[13]Arensman MD,Kovochich AN,Kulikauskas RM,et al.WNT7B mediates autocrine Wnt/beta-catenin signaling and anchorage-independent growth in pancreatic adenocarcinoma[J].Oncogene,2014,33(7):899-908
[14]Al-Hajeili M,Marshall JL,Smaglo BG.Neoadjuvant treatment for surgically resectable metastatic colorectal cancer[J].Oncology(Williston Park),2016,30(1):10-16
[15]Glimelius B,Hoffman K,Graf W,et al.Quality of life during chemotherapy in patients with symptomatic advanced colorectal cancer.The Nordic Gastrointestinal Tumor Adjuvant Therapy Group[J].Cancer,1994,73(3):556-562
[16]Kim SS,Cho HJ,Lee HY,et al.Genetic polymorphisms in the Wnt/beta-catenin pathway genes as predictors of tumor development and survival in patients with hepatitis B virus-associated hepatocellular carcinoma[J].Clin Biochem,2016,49(10-11):792-801
[17]Lin PI,Chien YL,Wu YY,et al.The WNT2 gene polymorphism associated with speech delay inherent to autism[J].Res Dev Disabil,2012,33(5):1533-1540
[18]Deng D,Zhang Y,Bao W,et al.Low-density lipoprotein receptor-related protein 6(LRP6)rs10845498 polymorphism is associated with a decreased risk of non-small cell lung cancer[J].Int J Med Sci,2014,11(7):685-690
[19]Wang H,Liu QJ,Chen MZ,et al.Association of common polymorphisms in the LRP6 gene with sporadic coronary artery disease in a Chinese population[J].Chin Med J(Engl),2012,125(3):444-449
[20]Xu S,Cheng J,Chen YN,et al.The LRP6 rs2302685polymorphism is associated with increased risk of myocardial infarction[J].Lipids Health Dis,2014,13:94
[21]Miyake M,Yamashiro K,Tabara Y,et al.Identification of myopia-associated WNT7B polymorphisms provides insights into the mechanism underlying the development of myopia[J].Nat Commun,2015,6:6689
[22]Wang M,Gu D,Du M,et al.Common genetic variation in ETV6 is associated with colorectal cancer susceptibility[J].Nat Commun,2016,7:11478
[2]Ulukan H,Swaan PW.Camptothecins:a review of their chemotherapeutic potential[J].Drugs,2002,62(14):2039-2057
[3]Coate L,Cuffe S,Horgan A,et al.Germline genetic variation,cancer outcome,and pharmacogenetics[J].J Clin Oncol,2010,28(26):4029-4037
[4]Scripture CD,Sparreboom A,Figg WD.Modulation of cytochrome P450 activity:implications for cancer therapy[J].Lancet Oncol,2005,6(10):780-789
[5]Toffoli G,Cecchin E,Corona G,et al.Pharmacogenetics of irinotecan[J].Curr Med Chem Anticancer Agents,2003,3(3):225-237
[6]Shtutman M,Zhurinsky J,Simcha I,et al.The cyclin D1gene is a target of the beta-catenin/LEF-1 pathway[J].Proc Natl Acad Sci USA,1999,96(10):5522-5527
[7]Koesters R,von Knebel Doeberitz M.The Wnt signalingpathway in solid childhood tumors[J].Cancer Lett,2003,198(2):123-138
[8]Pennisi E.How a growth control path takes a wrong turn tocancer[J].Science,1998,281(5382):1438-1439,1441
[9]Gao Y,Xiao X,Zhang C,et al.Melatonin synergizes thechemotherapeutic effect of 5-fluorouracil in colon cancerby suppressing PI3K/AKT and NF-kappa B/i NOS signal-ing pathways[J].J Pineal Res,2017,62(2).doi:10.1111/jpi.e12380
[10]Nam HJ,Im SA,Oh DY,et al.Antitumor activity of sara-catinib(AZD0530),a c-Src/Abl kinase inhibitor,alone orin combination with chemotherapeutic agents in gastriccancer[J].Mol Cancer Ther,2013,12(1):16-26
[11]Fu L,Zhang C,Zhang LY,et al.Wnt2 secreted by tumour fibroblasts promotes tumour progression in oesophageal cancer by activation of the Wnt/beta-catenin signalling pathway[J].Gut,2011,60(12):1635-1643
[12]Moon RT,Kohn AD,De Ferrari GV,et al.WNT and betacatenin signalling:diseases and therapies[J].Nat Rev Genet,2004,5(9):691-701
[13]Arensman MD,Kovochich AN,Kulikauskas RM,et al.WNT7B mediates autocrine Wnt/beta-catenin signaling and anchorage-independent growth in pancreatic adenocarcinoma[J].Oncogene,2014,33(7):899-908
[14]Al-Hajeili M,Marshall JL,Smaglo BG.Neoadjuvant treatment for surgically resectable metastatic colorectal cancer[J].Oncology(Williston Park),2016,30(1):10-16
[15]Glimelius B,Hoffman K,Graf W,et al.Quality of life during chemotherapy in patients with symptomatic advanced colorectal cancer.The Nordic Gastrointestinal Tumor Adjuvant Therapy Group[J].Cancer,1994,73(3):556-562
[16]Kim SS,Cho HJ,Lee HY,et al.Genetic polymorphisms in the Wnt/beta-catenin pathway genes as predictors of tumor development and survival in patients with hepatitis B virus-associated hepatocellular carcinoma[J].Clin Biochem,2016,49(10-11):792-801
[17]Lin PI,Chien YL,Wu YY,et al.The WNT2 gene polymorphism associated with speech delay inherent to autism[J].Res Dev Disabil,2012,33(5):1533-1540
[18]Deng D,Zhang Y,Bao W,et al.Low-density lipoprotein receptor-related protein 6(LRP6)rs10845498 polymorphism is associated with a decreased risk of non-small cell lung cancer[J].Int J Med Sci,2014,11(7):685-690
[19]Wang H,Liu QJ,Chen MZ,et al.Association of common polymorphisms in the LRP6 gene with sporadic coronary artery disease in a Chinese population[J].Chin Med J(Engl),2012,125(3):444-449
[20]Xu S,Cheng J,Chen YN,et al.The LRP6 rs2302685polymorphism is associated with increased risk of myocardial infarction[J].Lipids Health Dis,2014,13:94
[21]Miyake M,Yamashiro K,Tabara Y,et al.Identification of myopia-associated WNT7B polymorphisms provides insights into the mechanism underlying the development of myopia[J].Nat Commun,2015,6:6689
[22]Wang M,Gu D,Du M,et al.Common genetic variation in ETV6 is associated with colorectal cancer susceptibility[J].Nat Commun,2016,7:11478