p16、DAPK和APC基因甲基化在肺癌早期诊断中的价值
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摘要
目的检测肺癌患者外周血中p16、死亡相关蛋白激酶(DAPK)和结肠腺瘤样息肉蛋白(APC)基因启动子异常甲基化情况并分析其在肺癌早期诊断中的意义。方法收集79例原发性肺癌患者(肺癌组)、40例肺良性病变患者(对照组)的外周血标本,应用甲基化特异性PCR(MSP)法检测两组p16、DAPK和APC基因启动子的甲基化情况,并分析3个基因与肺癌患者的各项临床特征的关联情况。结果肺癌组血清中p16、DAPK和APC的甲基化率分别为51.9%(41/79)、50.6%(40/79)、35.4%(28/79),对照组中分别为2.5%(1/40)、5.0%(2/40)、2.5%(1/40),两组比较差异均有统计学意义(P均<0.05)。p16、DAPK和APC基因甲基化单项鉴别肺癌的灵敏度分别为51.9%(41/79)、50.6%(40/79)、35.4%(28/79)。3种基因甲基化联合鉴别肺癌的灵敏度为73.4%(58/79),高于单项指标。3个基因的甲基化与肺癌患者性别、年龄、吸烟史、组织学类型、肿瘤分期和淋巴结转移等多项临床资料均无相关性(P>0.05)。结论外周血p16、DAPK和APC基因启动子甲基化与肺癌有关,联合检测p16、DAPK和APC基因甲基化可提高肺癌诊断的准确性。
Objective To investigate the abnormal methylation of multiple tumor suppressor 1( p16),death-associated protein kinase( DAPK) and adenomatosis polyposis coli( APC) genes promoters in peripheral blood of the patients with lung cancer and its significance in the early diagnosis of lung cancer.Methods The peripheral blood of 79 patients with primary lung cancer( lung cancer group) and 40 patients with lung benign lesions( control group) were collected. Then the methylation of p16,DAPK and APC genes promoters were detected by methylation specific PCR. The correlation of the three genes with the clinical characteristics was analyzed in the lung cancer patients. Results The methylation rates of serum p16,DAPK and APC in the lung cancer group [51. 9%( 41/79),50. 6%( 40/79) and 35. 4%( 28/79) respectively]were higher than those in the control group [2. 5%( 1/40),5. 0%( 2/40) and 2. 5%( 1/40) respectively]( P < 0. 05). The sensitivity of p16,DAPK and APC gene methylation for identifying lung cancer were51. 9%( 41/79),50. 6%( 40/79) and 35. 4%( 28/79) respectively. The sensitivity of the combination of the three genes methylation for identifying lung cancer was 73. 4%( 58/79) and was higher than that of the single gene methylation. There was no correlation between methylation of each gene and sex,age,smoking history,histological type,tumor stage or lymph node metastasis( P > 0. 05). Conclusion The methylation of p16,DAPK and APC genes promoters in the peripheral blood is related to lung cancer. The combined detection of p16,DAPK and APC genes methylation can improve the diagnostic accuracy of lung cancer.
Objective To investigate the abnormal methylation of multiple tumor suppressor 1( p16),death-associated protein kinase( DAPK) and adenomatosis polyposis coli( APC) genes promoters in peripheral blood of the patients with lung cancer and its significance in the early diagnosis of lung cancer.Methods The peripheral blood of 79 patients with primary lung cancer( lung cancer group) and 40 patients with lung benign lesions( control group) were collected. Then the methylation of p16,DAPK and APC genes promoters were detected by methylation specific PCR. The correlation of the three genes with the clinical characteristics was analyzed in the lung cancer patients. Results The methylation rates of serum p16,DAPK and APC in the lung cancer group [51. 9%( 41/79),50. 6%( 40/79) and 35. 4%( 28/79) respectively]were higher than those in the control group [2. 5%( 1/40),5. 0%( 2/40) and 2. 5%( 1/40) respectively]( P < 0. 05). The sensitivity of p16,DAPK and APC gene methylation for identifying lung cancer were51. 9%( 41/79),50. 6%( 40/79) and 35. 4%( 28/79) respectively. The sensitivity of the combination of the three genes methylation for identifying lung cancer was 73. 4%( 58/79) and was higher than that of the single gene methylation. There was no correlation between methylation of each gene and sex,age,smoking history,histological type,tumor stage or lymph node metastasis( P > 0. 05). Conclusion The methylation of p16,DAPK and APC genes promoters in the peripheral blood is related to lung cancer. The combined detection of p16,DAPK and APC genes methylation can improve the diagnostic accuracy of lung cancer.
引文
[1]Chen W,Zheng R,Zhang S,et al.Annual report on status of cancer in China,2010[J].Chin J Cancer Res,2014,26(1):48-58.
[2]Yee DS,Tang Y,Li X,et al.The Wnt inhibitory factor 1restoration in prostate cancer cells was associated with reduced tumor growth,decreased capacity of cell migration and invasion and a reversal of epithelial to mesenchymal transition[J].Mol Cancer,2010,9(1):162.
[3]Travis WD,Brambilla E,Burke AP,et al.WHO Classification of Tumours of the Lung,Pleura,Thymus and Heart[M].4th edition·Lyon:International Agency for Research on Cancer,2015:9-96.
[4]Goldstraw P,Crowley J,Chansky K,et al.The IASLC Lung Cancer Staging Project:proposalsfor the revision of the TNM stage groupings in the forthcoming(seventh)edition of the TNM Classification of malignant tumours[J].J Thorac Oncol,2007,2(8):706-714.
[5]Ali A,Kumar S,Kakaria VK,et al.Detection of Promoter DNA Methylation of APC,DAPK,and GSTP1 Genes in tissue Biopsy and Matched Serum of Advanced-Stage Lung Cancer Patients[J].Cancer Investigation,2017,35(6):423-430.
[6]Shin K,Lee K,Lee C,et al.MAGE A1-A6 RT-PCR and MAGE A3 and p16 methylation analysis in induced sputum from patients with lung cancer and non-malignant lung diseases[J].Oncol Rep,2012,27(4):911-916.
[7]骆江龙,李鲲,冯旭,等.血浆WIF-1基因启动子甲基化检测在肺癌早期诊断中的临床意义[J].微创医学,2017,12(2):175-178.
[8]Erdem B,Küükyildιrim S,Saˇglar E,et al.Promoter hypermethylation of p16 and APC in gastrointestinal cancer patients[J].Turk J Gastroenterol,2014,25(5):512-517.
[9]Yan R,Chi L,Zheng X,et al.A meta-analysis of serum p16 gene promoter methylation for diagnosis of nonsmall cell lung cancer[J].Indian J Cancer,2015,52(Suppl 2):e116-e118.
[10]彭再梅,山长婷,王惠芳.诱导痰RASSFIA,p16和DAPK基因启动子区甲基化在肺癌诊断中的价值[J].中南大学学报(医学版),2010,35(3):247-253.
[11]Anjum R,Roux PP,Ballif BA,et al.The tumor suppressor DAP kinase is a target of RSK-mediated survival signaling[J].Curr Biol,2005,15(19):1762-1767.
[12]Tang X,Khuri FR,Lee JJ,et al.Hypermethylation of the death-associated protein(DAP)kinase promoter and aggressiveness in stage I non-small-cell lung cancer[J].J Natl Cancer Inst,92(18):1511-1516.
[13]Ogawa T,Liggett TE,Melnikov AA,et al.Methylation of death-associated protein kinase is associated with cetuximab and erlotinib resistance[J].Cell Cycle,2012,11(8):1656-1663.
[14]Tang J,Salama R,Gadgeel SM,et al.Erlotinib resistance in lung cancer:current progress and future perspectives[J].Front Pharmacol,2013,4:15.
[15]Schneikert J,Behrens J.The canonical Wnt signaling pathway and its APC partner in colon cancer development[J].Gut,2007,56(3):417-425.
[16]Feng H,Zhang Z,Qing X,et al.Promoter methylation of APC and RAR-βgenes as prognostic markers in non-small cell lung cancer(NSCLC)[J].Exp Mol Pathol,2016,100(1):109-113.
[17]Huang T,Li J,Zhang C,et al.Distinguishing Lung Adenocarcinoma from Lung Squamous Cell Carcinoma by Two Hypomethylated and Three Hypermethylated Genes:A MetaAnalysis[J].PLo S One,2016,11(2):e0149088.
[2]Yee DS,Tang Y,Li X,et al.The Wnt inhibitory factor 1restoration in prostate cancer cells was associated with reduced tumor growth,decreased capacity of cell migration and invasion and a reversal of epithelial to mesenchymal transition[J].Mol Cancer,2010,9(1):162.
[3]Travis WD,Brambilla E,Burke AP,et al.WHO Classification of Tumours of the Lung,Pleura,Thymus and Heart[M].4th edition·Lyon:International Agency for Research on Cancer,2015:9-96.
[4]Goldstraw P,Crowley J,Chansky K,et al.The IASLC Lung Cancer Staging Project:proposalsfor the revision of the TNM stage groupings in the forthcoming(seventh)edition of the TNM Classification of malignant tumours[J].J Thorac Oncol,2007,2(8):706-714.
[5]Ali A,Kumar S,Kakaria VK,et al.Detection of Promoter DNA Methylation of APC,DAPK,and GSTP1 Genes in tissue Biopsy and Matched Serum of Advanced-Stage Lung Cancer Patients[J].Cancer Investigation,2017,35(6):423-430.
[6]Shin K,Lee K,Lee C,et al.MAGE A1-A6 RT-PCR and MAGE A3 and p16 methylation analysis in induced sputum from patients with lung cancer and non-malignant lung diseases[J].Oncol Rep,2012,27(4):911-916.
[7]骆江龙,李鲲,冯旭,等.血浆WIF-1基因启动子甲基化检测在肺癌早期诊断中的临床意义[J].微创医学,2017,12(2):175-178.
[8]Erdem B,Küükyildιrim S,Saˇglar E,et al.Promoter hypermethylation of p16 and APC in gastrointestinal cancer patients[J].Turk J Gastroenterol,2014,25(5):512-517.
[9]Yan R,Chi L,Zheng X,et al.A meta-analysis of serum p16 gene promoter methylation for diagnosis of nonsmall cell lung cancer[J].Indian J Cancer,2015,52(Suppl 2):e116-e118.
[10]彭再梅,山长婷,王惠芳.诱导痰RASSFIA,p16和DAPK基因启动子区甲基化在肺癌诊断中的价值[J].中南大学学报(医学版),2010,35(3):247-253.
[11]Anjum R,Roux PP,Ballif BA,et al.The tumor suppressor DAP kinase is a target of RSK-mediated survival signaling[J].Curr Biol,2005,15(19):1762-1767.
[12]Tang X,Khuri FR,Lee JJ,et al.Hypermethylation of the death-associated protein(DAP)kinase promoter and aggressiveness in stage I non-small-cell lung cancer[J].J Natl Cancer Inst,92(18):1511-1516.
[13]Ogawa T,Liggett TE,Melnikov AA,et al.Methylation of death-associated protein kinase is associated with cetuximab and erlotinib resistance[J].Cell Cycle,2012,11(8):1656-1663.
[14]Tang J,Salama R,Gadgeel SM,et al.Erlotinib resistance in lung cancer:current progress and future perspectives[J].Front Pharmacol,2013,4:15.
[15]Schneikert J,Behrens J.The canonical Wnt signaling pathway and its APC partner in colon cancer development[J].Gut,2007,56(3):417-425.
[16]Feng H,Zhang Z,Qing X,et al.Promoter methylation of APC and RAR-βgenes as prognostic markers in non-small cell lung cancer(NSCLC)[J].Exp Mol Pathol,2016,100(1):109-113.
[17]Huang T,Li J,Zhang C,et al.Distinguishing Lung Adenocarcinoma from Lung Squamous Cell Carcinoma by Two Hypomethylated and Three Hypermethylated Genes:A MetaAnalysis[J].PLo S One,2016,11(2):e0149088.