联合检测p53基因和端粒酶对肺癌的诊断意义
|
摘要
p53基因是与人类恶性肿瘤相关性最高的肿瘤抑制基因,是当前癌基因研究热点之一,有资料认为,p53突变普遍存在于肺癌的整个过程中,早期突变阳性的表达高于中晚期肺癌,p53是一种早期筛选的分子指标,且对高危人群的筛选具有一定的前景。端粒酶是一种能以自身RNA为模板,逆转录合成端粒DNA加于染色体末端的核糖核蛋白酶。近年研究表明,肺癌中的高端粒酶活性与肿瘤细胞的高增殖率、病理分期和恶性程度有一定的相关性。国内外研究表明端粒酶在肺癌的早期诊断、治疗和预后预测中有重要意义。
本研究为了从肿瘤分子生物学角度探讨多种标本、多基因、多因素联合检测对肺癌早期诊断、病情预后及肿瘤防治方面的意义,我们选择天津医科大学总医院肺癌研究所和青岛大学医学院附属医院肿瘤中心的80例肺癌伴胸腔积液患者和50例肺部良性病变伴胸腔积液患者作为研究对象,采用聚合酶链反应-单链构象多肽性分析(PCR-SSCP)方法和聚合酶链反应-酶联免疫吸附测定法(PCR-TRAP-ELISA)分别检测其外周血、痰、胸腔积液和纤维支气管镜活检组织中p53基因突变率和端粒酶活性。
本研究对p53基因突变检测的结果显示：(1)肺癌伴胸腔积液患者外周血、痰、胸腔积液和纤维支气管镜活组织中p53基因突变率均明显高于肺部良性病变伴胸腔积液患者(P<0.01)；(2)不同病理类型、不同分化程度的肺癌伴胸腔积液患者间四种标本的p53基因突变率差异无统计学意义(P>0.05),而吸烟与非吸烟p53基因突变率差异有统计学意义(P<0.05)。(3)p53基因突变率在四种标本间无统计学意义(P>0.05)。(4)四种标本的p53基因突变率联合细胞学诊断肺癌的敏感性高于相应标本的细胞学诊断敏感性,差异有统计学意义(P<0.05)。(5)四种标本联合的p53基因突变检出率高于单一标本p53基因突变检出率,差异有统计学意义(P<0.05)
本研究对端粒酶活性检测的结果显示：(1)肺癌伴胸腔积液患者外周血、痰、胸腔积液和纤维支气管镜活组织中端粒酶活性均明显高于肺部良性病变伴胸腔积液患者(P<0.01)；(2)不同病理类型、不同分化程度的肺癌伴胸腔积液患者间四种标本的端粒酶活性差异无统计学意义(P>0.05),而吸烟与非吸烟端粒酶活性差异有统计学意义(P<0.05)。(3)在端粒酶活性四种标本间差异无统计学意义(P>0.05)。(4)四种标本的端粒酶活性联合细胞学诊断肺癌的敏感性高于相应标本的细胞学诊断敏感性,差异有统计学意义(P<0.05)。(5)四种标本联合的端粒酶活性阳性率高于单一标本端粒酶活性阳性率,差异有统计学意义(P<0.05)。
本研究对p53基因突变和端粒酶活性联合检测的结果显示：(1)四种标本联合检测p53基因突变率和端粒酶活性高于一种标本的检出率,差异有统计学意义(P<0.05)。(2)联合检测p53基因突变率和端粒酶活性对肺癌伴胸腔积液患者的诊断敏感性高于单项检测敏感性,差异有统计学意义(P<0.05)
结论：联合检测外周血、痰、胸腔积液和纤维支气管镜活检组织p53基因突变和端粒酶活性可提高肺癌早期诊断的敏感性和检出率,对判断疾病的性质及病情预后有一定的指导意义。而且临床标本简便易得,患者依从性好。
p53 gene is one of the most relevant to human tumor suppressor gene and also is one of the current hot spot in cancer gene research.It is thought that p53 gene mutation is general in the entire process of lung cancer.Also, the mutation of p53 gene is higher in early lung cancers than in advanced ones.
Telomerase is a ribonucleoprotein that synthesizes telomeric DNA onto chromosomal ends using an component as a template. Research has shown that the detection of telomerase activity is important to early diagnosis, treatment and prognosis prediction of lung cancer patients.
This study is to investigate the significance of multisample, polygene and multifactor combining detection in early diagnosis, prognosis and prevention of lung cancer from the point of view of the tumor molecular biology. We selected 80 lung cancer patients with pleural effusion and 50 benign lung disease patients with pleural effusion from lung cancer institute of tianjin medical university general hospital and cancer center of the affiliated hospital of medical college qingdao university. We employed the technique of PCR-SSCP and TRAP (telomeric repeat amplification protocal)-PCR-ELISA to detect the mutative rates of p53 gene, and the activity of telomerase in peripheral blood, the sputum, pleural effusion and fiberobronchoscopic biopsy of 80 lung cancer patients with pleural effusion and 50 benign lung disease patients with pleural effusion.
This study of mutative rates of p53 gene showed as follows:(1) Mutative rates of p53 gene in peripheral blood, the sputum, pleural effusion and fiberobronchoscopic biopsy of 80 lung cancer patients with pleural effusion were higher than 50 benign lung disease patients with pleural effusion significantly. (P<0.01) (2) There was no significant difference in mutative rates of p53 among the different pathologic types and subtype (P>0.05), while there was significant difference among patients of smoking (P<0.05). (3) There was no significant difference in mutative rates of p53 among the different clinical samples (P>0.05) (4) The sensitivity of combined of the detection of p53 point mutative and cytological examination for the four samples was higher than the sensitivity of pole cytological examination significantly (P<0.05). (5) The mutative rates of p53 was significant high in combined four samples than one sample (P<0.05)
The study of telomemse activity showed as follows:(1) Telomemse activity in peripheral blood, the sputum, pleural effusion and fiberobronchoscopic biopsy of 80 lung cancer patients with pleural effusion were higher than 50 benign lung disease patients with pleural effusion significantly. (P<0.01) (2) There was no significant difference in telomemse activity among the different pathologic types and subtype (P>0.05), while there was significant difference among patients of smoking (P<0.05). (3) There was no significant difference in telomemse activity among the different clinical samples (P>0.05). (4) The sensitivity of combined of the detection of telomemse activity and cytological examination for the four samples was higher than the sensitivity of pole cytological examination significantly (P<0.05). (5) The telomemse activity was significant high in combined four samples than one sample (P<0.05)
The combined detection of p53 point mutative and telomerase activity also gived us the follow results. (1) There was significant higher positive rate of p53 point mutative and telomerase activity in combined four samples than one sample. (2) The sensitivity of combined detection of p53 point mutative and telomemse activity for the four samples was higher than the sensitivity of single examination significantly.
Conclusion:The polygene and multifactor combining detection in peripheral blood, the sputum, pleural effusion and fiberobronchoscopic biopsy of 80 lung cancer patients with pleural effusion can improve sensitivity and detectable rate of early lung cancer diagnosis, and has instructive significance for the judgement of the property and prognosis of the disease. The detection of blood, sputum, pleural effusion and fiberobronchoscopic biopsy are safe and convenient. The compliance of patients is good.
本研究为了从肿瘤分子生物学角度探讨多种标本、多基因、多因素联合检测对肺癌早期诊断、病情预后及肿瘤防治方面的意义,我们选择天津医科大学总医院肺癌研究所和青岛大学医学院附属医院肿瘤中心的80例肺癌伴胸腔积液患者和50例肺部良性病变伴胸腔积液患者作为研究对象,采用聚合酶链反应-单链构象多肽性分析(PCR-SSCP)方法和聚合酶链反应-酶联免疫吸附测定法(PCR-TRAP-ELISA)分别检测其外周血、痰、胸腔积液和纤维支气管镜活检组织中p53基因突变率和端粒酶活性。
本研究对p53基因突变检测的结果显示：(1)肺癌伴胸腔积液患者外周血、痰、胸腔积液和纤维支气管镜活组织中p53基因突变率均明显高于肺部良性病变伴胸腔积液患者(P<0.01)；(2)不同病理类型、不同分化程度的肺癌伴胸腔积液患者间四种标本的p53基因突变率差异无统计学意义(P>0.05),而吸烟与非吸烟p53基因突变率差异有统计学意义(P<0.05)。(3)p53基因突变率在四种标本间无统计学意义(P>0.05)。(4)四种标本的p53基因突变率联合细胞学诊断肺癌的敏感性高于相应标本的细胞学诊断敏感性,差异有统计学意义(P<0.05)。(5)四种标本联合的p53基因突变检出率高于单一标本p53基因突变检出率,差异有统计学意义(P<0.05)
本研究对端粒酶活性检测的结果显示：(1)肺癌伴胸腔积液患者外周血、痰、胸腔积液和纤维支气管镜活组织中端粒酶活性均明显高于肺部良性病变伴胸腔积液患者(P<0.01)；(2)不同病理类型、不同分化程度的肺癌伴胸腔积液患者间四种标本的端粒酶活性差异无统计学意义(P>0.05),而吸烟与非吸烟端粒酶活性差异有统计学意义(P<0.05)。(3)在端粒酶活性四种标本间差异无统计学意义(P>0.05)。(4)四种标本的端粒酶活性联合细胞学诊断肺癌的敏感性高于相应标本的细胞学诊断敏感性,差异有统计学意义(P<0.05)。(5)四种标本联合的端粒酶活性阳性率高于单一标本端粒酶活性阳性率,差异有统计学意义(P<0.05)。
本研究对p53基因突变和端粒酶活性联合检测的结果显示：(1)四种标本联合检测p53基因突变率和端粒酶活性高于一种标本的检出率,差异有统计学意义(P<0.05)。(2)联合检测p53基因突变率和端粒酶活性对肺癌伴胸腔积液患者的诊断敏感性高于单项检测敏感性,差异有统计学意义(P<0.05)
结论：联合检测外周血、痰、胸腔积液和纤维支气管镜活检组织p53基因突变和端粒酶活性可提高肺癌早期诊断的敏感性和检出率,对判断疾病的性质及病情预后有一定的指导意义。而且临床标本简便易得,患者依从性好。
p53 gene is one of the most relevant to human tumor suppressor gene and also is one of the current hot spot in cancer gene research.It is thought that p53 gene mutation is general in the entire process of lung cancer.Also, the mutation of p53 gene is higher in early lung cancers than in advanced ones.
Telomerase is a ribonucleoprotein that synthesizes telomeric DNA onto chromosomal ends using an component as a template. Research has shown that the detection of telomerase activity is important to early diagnosis, treatment and prognosis prediction of lung cancer patients.
This study is to investigate the significance of multisample, polygene and multifactor combining detection in early diagnosis, prognosis and prevention of lung cancer from the point of view of the tumor molecular biology. We selected 80 lung cancer patients with pleural effusion and 50 benign lung disease patients with pleural effusion from lung cancer institute of tianjin medical university general hospital and cancer center of the affiliated hospital of medical college qingdao university. We employed the technique of PCR-SSCP and TRAP (telomeric repeat amplification protocal)-PCR-ELISA to detect the mutative rates of p53 gene, and the activity of telomerase in peripheral blood, the sputum, pleural effusion and fiberobronchoscopic biopsy of 80 lung cancer patients with pleural effusion and 50 benign lung disease patients with pleural effusion.
This study of mutative rates of p53 gene showed as follows:(1) Mutative rates of p53 gene in peripheral blood, the sputum, pleural effusion and fiberobronchoscopic biopsy of 80 lung cancer patients with pleural effusion were higher than 50 benign lung disease patients with pleural effusion significantly. (P<0.01) (2) There was no significant difference in mutative rates of p53 among the different pathologic types and subtype (P>0.05), while there was significant difference among patients of smoking (P<0.05). (3) There was no significant difference in mutative rates of p53 among the different clinical samples (P>0.05) (4) The sensitivity of combined of the detection of p53 point mutative and cytological examination for the four samples was higher than the sensitivity of pole cytological examination significantly (P<0.05). (5) The mutative rates of p53 was significant high in combined four samples than one sample (P<0.05)
The study of telomemse activity showed as follows:(1) Telomemse activity in peripheral blood, the sputum, pleural effusion and fiberobronchoscopic biopsy of 80 lung cancer patients with pleural effusion were higher than 50 benign lung disease patients with pleural effusion significantly. (P<0.01) (2) There was no significant difference in telomemse activity among the different pathologic types and subtype (P>0.05), while there was significant difference among patients of smoking (P<0.05). (3) There was no significant difference in telomemse activity among the different clinical samples (P>0.05). (4) The sensitivity of combined of the detection of telomemse activity and cytological examination for the four samples was higher than the sensitivity of pole cytological examination significantly (P<0.05). (5) The telomemse activity was significant high in combined four samples than one sample (P<0.05)
The combined detection of p53 point mutative and telomerase activity also gived us the follow results. (1) There was significant higher positive rate of p53 point mutative and telomerase activity in combined four samples than one sample. (2) The sensitivity of combined detection of p53 point mutative and telomemse activity for the four samples was higher than the sensitivity of single examination significantly.
Conclusion:The polygene and multifactor combining detection in peripheral blood, the sputum, pleural effusion and fiberobronchoscopic biopsy of 80 lung cancer patients with pleural effusion can improve sensitivity and detectable rate of early lung cancer diagnosis, and has instructive significance for the judgement of the property and prognosis of the disease. The detection of blood, sputum, pleural effusion and fiberobronchoscopic biopsy are safe and convenient. The compliance of patients is good.
引文
1 Jemal A, Tiwaei RC, Murray T, et al. Cancer Statistics[J]. CA Cancer J Clin,2004,54(2):92-119.
2 Sun Z, Fu X, Zhang L, et al. A protein chip system for parallel analysis of multi-tumor markers and its application in cancerdetection[J].Anticancer Res,2004,24(2C):1159-1165.
3 Ahrendt SA, Hu Y, Buta M, et al. p53 mutations and survival in stage I non-small-cell lung cancer:results of a prospective study[J]. J Natl Cancer Inst, 2003,95(13):961-970.
4 Coulet F, Blons H, Cabelguenne A, et al. Detection of plasma tumour DNA in head and neck squamous cell carcinoma by microsatellite typing and p53 mutation analysis[J]. Cancer Res,2000,60(3):707-711.
5 Mack U, Ukena D, Montenarh M, et al. Serum anti-p53 antibodies in patiens with lung cancer[J]. Oncol Rep,2000,7(3):669-674.
6 Phatak P, Burger AM. Telomerase and its potential for therapeutic intervention[J]. Br J Pharmacol,2007,152(7):1003-1011.
7 Li X, Niddzuka H, Tsutsumi K, et al. Slructure, interactions and effects on activity ofthe 5'terminal region of human telomerase RNA[J]. J Bio chem, 2007,141(5):755-765.
8 Soder, AI, Hoare S, Muir S, et al. Amplification,increased dosage and in situ expression of the telomerase RNA gene in human cancer[J]. Oncogene,1997,14(19):1013-1021.
9 Hsu CP, Miawa J, Shai SE, et al. Correlation between telomerase expression and terminal restriction fragment length ratio in non-small cel lung cancer-an adjusted measurement and its clinical significance[J]. Eur J Cardiothoracic Surgery,2004,26(2):425-431.
10 Gauthier LR, Granotier C, Soria J, et al. Detection of circulation carcinoma cell by telomerase activity[J]. Br J Cancer,2001,84(7):631-635.
11 Scott E, Dessain H, Roger R, et al. Methylation of human telomerase gene CPG island in blood[J]. Cancer Res,2000,60(6):537-541.
12 Garcia M,Jemal A,Ward EM,et al.Global Cancer Facts&Figures 2007 (M).Atlanta,GA:American Cancer Society,2007.
13 Farber E. The multistep nature of cancer development[J]. Cancer Res, 1984,44(27):4214-4223.
14 Leea JH, Hongb YS, Jeong SR, et al. p53 and FHIT mutations and micro satellite alterations in malignancy-associated pleural effusion[J]. Lung Cancer,2004,44(1):33-42.
15 Sozzi G, Conte D, Mariani L, et al. Analysis of circulating tumor DNA in plasmat diagnosis and during follow-up of lung cancer patients[J]. Cancer Res, 2001,61(12):4675-4678.
16 Takehisa H, Yoshio T, Moriaki H, et al. p53 null mutations undetected by imm-unohistochemical staining predict a poor outcome with early-stage non-small cell lung carcinomas[J]. Cancer Res,1999,59(21):5572-5577.
17 Silva JM, Dominguez G, Garcia JM. Presence of tumor DNA in plasma of breast cancer patients[J]. Cancer Res,1999,59(13):3251-3256.
18白莉,孙燕,李申德.肺癌组织抑癌基固p53异常分析借变.畸变、突变[J].1996,8(6)：321-326.
19 Sapio A, Morra I, Pradotto L, et al. Molecular genetic changes in a series of neuroepithelial tumors of childhood[J]. J Neuro oncol,2002,59(2):117-122.
20 Navada S, Lai P, Schwartz AG, et al. Temporal trends in small-cell lung cancer: analysis of the national surveillance epidemiology and end results (SEER)database[J]. J Clin Oncol,2006,24(18Suppl):S384.
21 Visser O, Belderbos J, Kwa H, et al. Improved stage specific survival of NSCLC in northern Holland Flevoland, the netherland effect of intensified treatment or stage migration[J]. Lung Cancer,2005,49(Suppl 2):S198.
22 Samgimura T, Vahijima T. Genetic and epigenetie alterations in carciogenesis[J]. Mutation Res,2000,462(2-3):235.
23李小华,陈德基,江曼,等.实验性肺癌癌变过程中p53、mdm2、k-ras及PCNA蛋白的表达[J].癌症杂志,2001,20(9)：921.
24 Soussi T. p53 antibodies in the sera of patiens with various type of cancer:a review[J]. Cancer Res,2000,60(19):1777-1788.
25郭雪君,邓伟吾,黄绍光.肺癌基因和抑制基因的研究进展[J].中华结核和呼吸杂志,1995,18(3)：267.
26 Takahashi T, Carbone D, etal. Wild-type but mutant p53 soppresses the growth of human lung cancer cells bearing multiple genetic lesions[J]. Cancer Res,1992,52(5):2340.
27 Mitsudomi T, Takahashi T, Genetic abnormalities in lung call and their prognostic implications[J]. Gan To Kagaku Ryoho,1996,23(8):990.
28张振峰.p53与人类肺癌研究进展[J].国外医学内科学分册,1999,26(6)：255.
29 Chen PL, Chen YM, Bookstein R, et al. Genetic mechanisms of tumor suppression by the human p53 gene[J]. Science,1990,250(4987):1576.
30 Soussi T, Loano G. p53 mutation heterogenety in cancer[J]. Biochem Biophysier Commun,2005,331(3):834.
31 Laudanski J, Burzykowski T, Niklinska W, et al. Prognostic value of serum p53 an tibodies in patiens with resected non-small cell lung cancer[J]. Lung Cancer, 1998,22(3):191-200.
32 Andriani F, Conte D, Mastrangelo T, et al. Detecting lung cancer in plasma with the use of multiple genetic markers[J]. Int J Cancer,2004,108(1):91-96.
33 Gonzaiez R, Silva JM, Sanchez A, et al. Microsatellite alterations and p53 mutations in plasma DNA of small-cell lung cancer patients:follow-up study and prognostie significance[J]. Ann Oncol,2000,11(9):1097-1104.
34 Mao L, Hruban RH, Boyle JO, et al. Detection of one-gene mutationsin sputum precedes diagnosis of lung cancer[J]. Cancer Res,1994,54(12):1634-1637.
35 Li Mao, Hruben RH,Boyle JO, et al. Detection of oncogene mutations in sputum procedes diagnosis of lung cancer[J]. Cancer Res,1994, No(3):1663.
36 Mitsudomi T, Oyama T, Kusano T, et al.Mutation of the p53 gene as a predictor of poor prognosis in patients with non-small cell lung cancer[J]. J Natl Cancer Int,1993,No(4):2018.
37 Dai Y, Morishita Y, Mase K, et al. Application of the p53 and K-ras gene mutation patterns for cytologle diagnosis of recurrent lung carcinomas[J]. Cancer,2000,90(4):258-263.
38 Tocknan MS, Gupta PK, Myers JD, et al. Sensitive and specific monoclonal antibody recognition of human lung cancer antigen on observed sputum cell:a new approach to early lung cancer detection[J]. J Clin Oneol,1988,No(11):1685.
39 Jacobson DR, Fishman CL, Mills NE. Molecular genetic tumor markers in the early diagnosis and screening of non-small cell lung cancer[J]. Ann Oncol,1995,6(Suppl 3):S3-8.
40 Hu Y, McDermott MP, Ahrendt SA. The p53 codon 72 proline allele is associated with p53 gene mutation in non-small cell lung cancer[J]. Clin Cancer Res.2005,11(7):2502.
41 Fouquet C, Antoine M, Tisserand P, el al. Rapid and sensitive p53 alteration analysis in biopsies from lung canoer patients using a functional assay and a universal oligonucleotide array prospective study[J]. Clin Cancer Res. 2004,10(10):3479.
42 Mitsudomi T, lam S, Shirakusa T, et al. Detection and sequencing of the p53 gene mutations in bronchial biopsy samples in patients with lung cancer[J]. Chest,1993,104(5):362.
43郭雪君,倪培华,李莉,等.可疑肺癌病人纤支镜检查标本的p53基因突变检测[J].癌症杂志,2000,19(3)：216.
44.赖百塘.端粒酶在肺癌诊断和治疗中的价值[J].中国肺癌杂志,2000,3(2)：81-83.
45.陈鲁琦,陈鲁豫,王宁,等.肺癌支气管肺泡灌洗液细胞端粒酶测定的临床意义[J].中华结核和呼吸杂志,1998,21(12)：730-732.
46.王勇,胡杰贵,江丰收,等.端粒酶活性在肺癌患者外周血中的表达研究[J].现代肿瘤医学,2008,16(7)：1142-1144.
47. Yang C T, Lee M H, Lan R S,et al. Telomerase activity inpleural effusions. Diagnostic significance[J]. Clin Oneol,1998,16(2):567-573.
48.王金亮,王嘉祺,安真光,等.端粒酶活性在肺癌患者痰脱落细胞中表达的临床价值[J].中国肺癌杂志,2002,5(1)：38-40.
49. Yahata N,ohyashiki K,Ohyashiki JH,et al.Telomerase activity in lung cancer cells obtained From bronchial washings[J]. J Nalt Cancer Inst,1998,90(9):84-90.
50. Tockman MS. Advances in sputum analysis for screening and early detection of lung cancer[J]. Cancer Control,2000,7(11):19-24.
51.成柏君,陆舜,冯久贤,等.端粒酶与p53、p16基因在非小细胞肺癌中的表达及其意义[J].中国癌症杂志,2001,11(5)：437-440.
52.刘华,温志震,王嘉祺,等.肺癌痰液p53和Kras基因及端粒酶联合检测的临床研究[J].临床研究,2006,13(17)：1304-1307.
53.姚珂 余祖滨 闭家新,等.肺癌组织中端粒酶活性检测及临床意义[J].中国肺癌杂志2003,6(5)：364-366.
54. Gauthier LR, Granotier C,Soria J,et al.Detection of circulation carcinoma cell by telomerase activity[J]. Br J Cancer,2001,84(7):631-635.
55.韦尉东,黄植蕃,戎铁华,等.端粒酶活性表达及p53异常在非小细胞肺癌中表 达及临床意义[J].癌症,2001,20(3)：301-304.
56. Kim NW, Piatyszek MA, Prowse K, et al. Specific association of human telomerase activity with immortal cells and cancer[J]. Science,1994, 266(27):2011-2015.
57 Dejmek A. Yahata N, Ohyashiki K. et al.[J]. Cancer,2000,90 (2):117-125.
58刘瑾,杨青,亚佳.等[J].中国肺癌杂志,2001,4(4)：299-302.
59 Arai T, Yasuda Y, Takaya T. et al [J]. Oncol Rep.1998,5(4):405-408.
60 Sen S, Reddy VG, Khanna N, et al. A comparative study of telomerase activity in sputum, bronchial washing and biopsy specimens of lung cancer[J]. Lung Cancer,2001,33(1):41-49.
61 Petty TL. The early identification of lung carcinoma by sputum cytology[J]. Cancer,2000,89(15):2461-2466.
62 Metso T, Haahtela T, Seveus L. Identification of intracellular markers in induced sputum and bronchoalveolar lavage samples in patients with respiratory disorders and healthy persons[J]. Respir Med,2002,96(11):918-926.
63申社林,李兵.血液基因组DNA的快速提取方法[J].生物技术通报2007,12(4)：146-147.
64于世寰,霍建民,石玉枝,等.纤维支气管镜活组织端粒酶活性检测对肺癌的诊断价值[J].中国内镜杂志,2004,10(8)：15-17.
65张月,康健,等.端粒酶及端粒酶逆转录酶在良、恶性胸腔积液中的表达及意义[J].山东医药,2008,48(40)：40-41.
66王强修,刘杜先,仲伟霞,等.端粒酶的检测与肿瘤诊治进展[J].肿瘤防治杂志,2000,7(5)：515-517.
67 Yahata N, Ohyashiki K, Ohyashiki JH, et al. Telomerase activity in lung cancer cells obtained from bronchial washings[J]. J Natl Cancer Inst, 1998,90(9):684-690.
68 Hiyama K, Hiyama E, Ishioka S, et al. Telomerase activity in small cell and non-small cell lung cancer[J]. J Natl Cancer Inst,1995,87(10):895-902.
69王安潮,黄礼年,陈余清,等.支气管活检标本的端粒酶活性检测对肺癌的诊断价值[J].中华结核和呼吸杂志,2000,23(8)：475-477.
70 Xinarianoa G, Scott FM, Litoglou T, et al. Evaluation of tetomerase activity in bronchial lavage as a potential diagnostic marker for malignant lung disease[J]. Lung Cancer,2000,28(1):37.
71 Shayjw, Gazdar AF. Telomerase in the early detection of cancer[J]. Clin Pathol,1997,50(2):106.
72 Gauthier LR. Detection of circulating carcinoma cells by telomerase activity[J]. Br J Cancer,2001,84(5):631-635.
73何平,闫灵,吴宝刚,等.肺癌患者外周血单个核细胞TERT基因表达在诊断中的价值[J].中国实用内科杂志,2005,25(8)：708-709.
74 Sen S, Reddy VG, Khanna N. et al. A comparative study of telomera activity in putama,bronchial washing and biopsy specimens of lung Cancer[J]. Lung Cancer,2001,33(1):41-49.
75刘东海,王丰民,冯伟云等.孤立性肺部结节肺泡灌洗液端粒酶活性测定对肺癌早期诊断的研究[J].江西医学检验,2005,23(10)：443.
76 Oremek GM, Sauer-eppel H, Bruzdziak TH. Value of tumour and inflammatory markers in lungcancer[J]. Anticancer Res,2007,27(4A):1911-1915.
77 Liu YQ, Liu JM, Lan X, et al. Tumor markers in differential diagnosis of the hydrothorax[J]. Clinical Medicine of China,2006,22(3):235-237.
78 Shi GL, Hu XL, Yue SD, et al. The value of serum tumor marker in the diagnosis of lung cancer[J]. Chin J Oncol,2005,27(5):299-301.
79 Gauthier LR, Granotier C, Soria J, et al. Detection of circulation carcinoma cell by telomerase activity[J]. Br J Cancer,2001,84(7):631-635.
80 Scott E, Dessain H, Roger R, et al. Methylation of human telomerase gene CPG island in blood[J]. Cancer Res,2000,60(7):537-541.
81姚连昌.痰标本中肺癌相关基因检测用于肺癌早期诊断的研究进展[J].中国肺癌杂志,2000,3(3)：239-243.
82郑永咏,王茹,尹帆.端粒、端粒酶及p16、p53基因在肺癌早期诊断中的研究进展[J].医学综述,2002,8(1)：4-5.
83 Nishio Y, Nakanishi K, Ozeki Y, et al. Telomere length, telomerase activity, and expressions of human telomerase mRNA component(hTERC)and hunmn telomerase reverse transcriptase(hTERT)mRNA in pulmonary neuroendocrine tumors[J]. Jpn J Clin Oncol,2007,37(1):16-22.
84 Dikmen G, Dikmen E, Kara M, et al. Diagnostic implications of telomerase activity in pleural effusions[J]. Eur Respir J,2003,22(3):422-426.
1 Jemal A,Tiwaei RC,Murray T, et al. Cancer Statistics[J]. CA Cancer J Clin, 2004,54(2):92-119.
2顾宗元,胡宏,王磊,等.影响肺癌相关肿瘤标志物因素分析临床[J].肺科杂志,2003,8(1)：11-12.
3陆舜,蔡映云.肺癌与端粒酶[J].国外医学呼吸系统分册,2002,22：4-5.
4中华医学会检验医学分会肿瘤标志物专家委员会.肿瘤标志物临床检测的基本原则[J].中华检验医学杂志,2004,27(6)：393.
5李红,许凯黎.肺癌标志物研究进展[J].实用肿瘤杂志,2002,17(5)：295-297.
6 Buccheri G.Tumor Markers:Clinical Meaning and Use.In:Brambilla C,Brambilla E. Lung Tumors[J]. New York:Marcel Dekker 1999:435-452.
7 Nawata S, Sugino N, Kato H. Squamous cell carcinoma antigen[J]. Nippon Rinsho,2005,63(Suppl8):684-686.
8 Oremek GM, Sauer-eppel H, Bruzdziak TH. Value of tumour and inflammatory markers in lung cancer[J]. Anticancer Res,2007,27(4A):1911-1915.
9 Chishing CW. Potentially useful biomarkers for the diagnosis, treatment and prognosis of lung cancer[J]. Biom Pharm,2007,61(9):515-519.
10 Ebem W, Muley T, Trainer R, et al. Comparision of changes in the NSE levels with clinical assessment in the therapy monitoring of patients with small cell lung cancer[J]. Anticancer Res,2002,22(28):1083.
11 Shihayma T, Veoka H, Nishiik B, et al. Complementary roles of progastrin-releasing peptide(proGRP)and neuron specific enolase(NSE)in diagnosis and prognosis of small cell lung cancer(SCLC) [J]. Lung Cancer,2001,32(1):61.
12 Bates F, Esteller M, Rose R, et al. Detection of aberrant promoter hypermetnylation of tumor suppressor gene in scrota DNA from non-small cell lung cancer patients[J]. Cancer Res,2002,59(1):67-70.
13 Spaulding DC, Spaulding BO. Epidermal growth factor receptor expression and measurement in solid tumors[J]. SEMIN Oncol,2002,29(5 Suppl 14):45-54.
14 Saski H, Yukiue H, Mizumo K.et al. Elevated serum epidermal factor receptor level is correlated with lymph node metastasis in lung cancer [J]. Int J Clin Oncol,2003,8(2):79-82.
15 Clared LE, Leitzel K, Smith J, et al. Epidermal growth factor receptor mRNA in peripheral blood of patients with pancreatic, lung, and colon carcinomas detected by RT-PCR[J]. Int J Clin Oncol,2003,22(2):425-430.
16 Wang XJ, Yu JJ, Sreekumar A, et al. Autoantibedy signatures in prostate cancer[J]. The New England Journal of Medicine,2005,353(16):1224-1235.
17 Goldenberg DM, Sharkey RM, Primus FJ. Immuno cytochemical detection of carcinoembryonic antigen in conventional histopathology specimens[J]. Cancer,1978,42(16):1546-1553.
18 Seemann MD, Einerl T, Furst H, et al. An evaluation of the tumor markers carcinoembryonic antigen(CEA), cytokerotin tumor markers, carcinoembryonic antigen(CEA), cytokeratin marker(CYFRA21-1)and neuron-specific enolase(NSE)in the differentiation of malignant from benign solitary pulmonary lesions[J]. Lung Cancer,1999,26(3):149.
19 HasholznerL, Stieber P, Reiter W, et al. CA242 incomparison with established tumor markers in colorectal, pancreatic and lung cancer[J]. Anti Cancer Res,1999,19(4A):2477-2480.
20 Peon RT, Fan ST, Wong J. Clinical implications of circulating angiogenic factors in cancer patients[J]. J Cin Oncol,2001,19(4):1207.
21 Kimura Y, Fujii T, Hamamoto K, et al. Serum CA125 level is a good prognostic indicator in lung cancer[J]. Br J Cancer,1990,62(7):676-678.
22 Barradas PA, Cristorao MM, Costa AM, et al. Comparison of three serum (cyfra21-1, NSE and CEA) in lung cancer:diagnosis efficacy prognostic importance value in chemotherapy monitoring and in early prediction of relapse[J].Chest,1998,114(3):250-255.
23 Nisman B,Lafair J,Heching N,et al. Evaluation of tissue specific antigen,CYFRA21-1,and carcinoembryonic antigen in non-small cell lung carcinoma:does the combined use of cytokeratin markers give any addition information[J]. Cancer,1998,82(10):1850-1859
24 Schneider J. Tumor markers in detection of lung cancer[J]. Adv Clin Chem, 2006,42(1):1-41.
25 Seemann MD, Einerl T, Furst H, et al. An evaluation of the tumor markers, carcinoembryonic antigen(CEA), cytokeratin marker(Cyfra21-1) and neuron-specific enolase (NSE) in the differentiation of malignant from benign solitary pulmonary lesions[J]. Lung Cancer,1999,26(3):149.
26 Muley T, Dienemann H, Ebert W. CYFRA 21-1 and CEA are independent prognostic factors in 153 operated stage I NSCLC patients[J]. Anticancer Res,2004,24(3b):1953-1956.
27 Pujol JL, Molinier O, Ebert W, et al. CYFRA 21-1 is a progn ostic determinant in non-small cell lung cancer:resuhs of a meta-analysis in 2063 patients[J]. Br J Cancer,2004,90(11):2097-2105.
28 Galligioni E, Fem A. Angiogenesis and antiangiogenic agents in non-small cell lung cancer[J]. Lung Cancer,2001,34(4):S3-7.
29 Body JJ, Sculier JP, Raymakers N, el al. Evaluation of squamous cell carcinoma antigen as a new marker for lung cancer[J]. Cancer,1990,65(7):1552-1556.
30 Mall JW, Schwenk W, Philipp AW, et al. Serum vascular endothelial growth factor levels correlate better with tumour stage in small cell lung cancer than albumin, neuron-specific enolase or lactate dehydrogenase[J]. Respirology,2002,7(2):99-102.
31 Hantapet P, Riantawan P, Lebnak P, et al. Utility of selflm cytokeratin 19 fragment(CYFAR21-1)and carcinoembryonie antigen(CEA)as tumor markers for non-small cell lung cancer[J]. Med Assoco,2000,83(4):383-391.
32 Molina R, Filella X, Auge JM, et al. Tumor markers(CEA, CA 125, CYFRA 21-1, SCC and NSE)in patients with non-small cell lung cancer as an aid in histological diagnosis and prognosis comparison with the main clinical and pathological prognostic factors[J]. Tumour Biol,2003,24(4):209-218.
33舒仁明,何思春,焦鑫,等.CEA在肺癌和其它肺部疾病的表达[J].四川省卫生管理干部学院学报,2004,2(31)：43.
34邵海燕,毛文炜,曾爱平.组织多肽特异性抗原和癌胚抗原在肺癌诊断中价值[J].浙江临床医学,2004,6(9)：754-752.
35 Matsuoka K, Sumitomo S, Nakashima N, et al. Prognostic value of carcinoembryonic antigen and CYFRA21-1 in patients with pathological stage I non-small cell lung cancer[J]. Eur J Cardiothorac Surg,2007,32(3):435-439.
36 Buecheri G and Ferrigno D. Identifying patients at risk of early postoperative recurrence of lung cancer:a new use of the old CEA test[J]. Ann Thomc stag,2003,75(3):973-980.
37 Stieber P, Dinemann H, Schalhom A, et al. Pro-gastrin-rel easing Peptide(ProGRP), A useful marker in small-cell lung carcinomas[J]. Anticancer Res,1999,19(24):2673-2678.
38 Molina R, Filella X, Auge JM. ProGRP:a new biomarker for small cell lung cancer[J]. Clin Biochem,2004,37(6):505-511.
39 Takada M, Kusunoki Y, Masuda N, et al. Pro-gastrin-releasing peptide(31-98)as a tumour marker of small cell lung cancer:comparative evaluation with neuron specific enolase[J]. Br J Cancer,1996,73(10):1227-1232.
40 Vandepol M, Twiinstra A, Tenvelde GP, et al. NSE as a marker of brain metastasis in patients with SCLC[J]. J Neurooncol,1994,19(2):149-150.
41 Plebani M, Basso D, Navaglia F, et al. Clinic evaluation of seven tumor markers in lung cancer diagnosis:can any combination improve the result[J], Br J Cancer,1995,72(1):170-173.
42 Poola I, Graziano SL.Expression of neuron-specific enolase, chromo-granin A, synaptophysin and Leu-7 in lung cancer cell lines[J]. J Exp Clin Cancer Res,1998,17(2):165.
43 Pinson P, Joos G, Watripont P, et al. Serum neuron-specific enolase as A tumor marker in the diagnosis and follow-up of small-cell lung cancer[J]. Respiration 1997,64(1):102.
44 Castaldo G, Tomaiuolo R, Sanduzzi A, et al. Carcinoembryonic antigen mRNA analysis detects micrometastatic cells in blood from lung cancer patients[J]. Eur Respir J,2003,22(3):418-421.
45 Schneider J, Velcovsky HG, Morr H, et al. Comparison of the tumormarkers tumorM2-PK, CEA,CYFRA 21-1, NSE and SCC in the diagnosis of lung cancer[J].Anticancer Res,2000,20(6D):50532-50581.
46 Toshihhiko I, Takerhik F, MakotoS, et al. Elevated levels of circulating plasma MMPs-9 in non-small cell lung cancer patients[J]. Clin Cancer Ras,1999,5(2):149-152.
47 Pujol JL, Grenier J, Parrat E, et al. Cytokeratins as serum markers in lung cancer: a comparison of CYFRA 21-1 and TPS[J]. Am J Respir Crit Care Med,1996,154(3Ptl):725-733.
48 Ho YJ, Hsieh JF, Tasi SC, et al. Tissue polypeptide specific antigen and squamous cell carcinoma antigen for early prediction of recurrence in lung squamous cell carcinoma[J]. Lung,2000,178(2):75-80.
49 Kennedy TC,Hirsch FR. Using molecular markers in sputum for the early detection of lung cancer:a review[J]. Lung Cancer,2004,45(2):S21-27.
50 Muller-Tidow C,Diederichs S,Thomas M. Ge-nome-wide screening for prognosis-predicting genes in early-stage non-small-cell lung cancer[J].2004,45 Suppl 2:145-150.
51 Yamamoto A,Shimizu E,Sumitomo K,et al. Lmyc overexpression and detection of auto-anti-bodies against L-myc in both the serum and pleural effusion from a patients with non-Small cell lung cancer[J].Intern Med,1997,36(10):724-727.
52 Playioye MA,Neve RM,Lane HA,et al. The erbB signaling network:receptor heterodimerization in development and cancer[J]. EMBO J,2000,19(13):3159-3167.
53赵元军,张世明,刘思令,等.ras和erbB-2基因在肺癌中的表达及意义[J].癌症,1998,17(2)：99-161.
54 Keohavong P,Demichele MA,Melocrinos AC,et al. Detection of K-ras mutations in lung carcinomas:relations to prognosis[J]. Clin Cancer Res,1996,2(21):411-418.
55 Yakubovskaya MS, Spiegelman V, Luo FC, et al. High frequency of K-ras mutation in normal appearing lung tissue and sputum of patients with lung cancer[J]. Int J Callcer,1995,63(9):810.
56 Mills NE, Hshman CL, Scholes J, et al. Detection of k-ras oncogene mutation in broncholveolar alvage fluid for lung cancer diagnosis[J]. J Natel Cancer Insti,1995,87(4):1056.
57 Cho JK, Kim JH, Lee YH, et al. Corrc lation between K-ras gene mutation andprognosis of patients with non-small cell lung eardnorna[J]. Cancer, 1997,79(3):462.
58 Diez M, Pbllan M, Masestro M, et al. Prediction of recurrence by quantifiation of p185 protein in non-sraall cell lung tissue[J]. Br J cancer,1997,75(5):684.
59李小华,陈德基,江曼,等.实验性肺癌癌变过程中p53、mdm2、k-ras及PCNA蛋白的表达[J].癌症杂志,2001,20(9)：921.
60 Mitsudomi T, Takahashi T. Genetic abnormalities in lung call and their prognostic implications[J]. Gan To Kagaku Ryoho,1996,23(8):990.
61来茂德.医学分子生物学[M][J].人民卫生出版社,1998：324.
62 Ahrendt SA, Hu Y, Buta M, et al. p53 mutations and survival in stage I non-small cell lung cancer:results of a prospective study[J]. J Natl Cancer Inst,2003,95(13):961-970.
63 Gonzaie ZR, Silva JM, Sanchez A, et al. Microsatellite alterations and TP53 mutations in plasma DNA of small cell lung cancer patients:follow-up study and prognostie significance[J]. Ann Oncol,2000,11(9):1097-1104.
64 Takahashi T, Carbone D, et al. Wild-type but mutant p53 soppresses the growth of human lung cancer cells bearing multiple genetic lessions[J]. Cancer Res,1992,52(23):2340.
65 Soussi T. p53 an tibodies in the sera of patiens with various type of cancer:a review[J]. Cancer Res,2000,60(18):1777-1788.
66 Andriani F, Conte D, Mastrangelo T, et al. Detecting lung cancer in plasm a with the use of multiple genetic markers[J]. Int J Cancer,2004,108(1):91-96.
67彭猛青,王绪,刘德林,等.非小细胞肺癌p16基因甲基化及缺失的研究[J].中国肺癌杂志,2002,5(4)：250-253.
68 Kawabuchi B, Moriyama S, Hirohaka M. P16 inactivition in small-sized lung adenocarcinoma:its association with poor prognosis[J]. Int J Cancer,1999,84(1):49-53.
69 Belinsky SA, Nikula KJ, Palmisano WA, et al. Aberrant methylation of p16(INK4a)is an early event in lung cancer and a potential biomarker for carly diagnosis[J]. Proc Natl Acad Sci USA,1998,95(20):11891-11896.
70 Samgimura T, Vahijima T. Genetic ansd epigenetie alterations in carciogenesis[J]. Mutation Res,2000,462(2-3):235.
71杨德昌,杨拴盈.肺癌诊断及治疗进展[J].中华结核呼吸杂志,2004,1(1)：18-19.
72 Rohayem J, Diestelkoetter P, Weigle B, et al. Antibody response to the tumor associated inhibitor of apoptosis protein survivin in cancer patients[J]. Cancer Res,2000,60(19):1815-1817.
73 Sozzi G, MUSSO K, Ratclffe H, et al.Detection of micro-satellite alterations in plasma DNA of non-small cell lung cancer patients:a prospect for early diagnosis[J]. Clin Cancer Res,1999,5(27):2689-2692.
74 Fielding P, Turabull L, Prime W, et al.hnRNP A2/B1 upregulation in bronchial lavage specimens:a clinical marker of early lung cancer detection[J]. Clin Cancer Res,1999,5(5A):4048-4052.
75 Fleischhacker M, Beinert T, Emitsch M, et al. Detection of amplifiable messenger RNA in serum of patients with lung cancer[J]. Ann NY Acad Sci, 2001,9(2):178-188.
76 Hiyama K, Ishioka S, Shirotani Y, et al[J]. Oncogene,1995,10(5):937-944.
77 Soder A, Going J, Kaye S, et al[J]. Oncogene,1998,16(8):979-983.
78 Metso T, Haahtela T, Seveus L.Identification of intracellular markers in induced sputum and bronchoalveolar lavage samples in patients with respiratory disorders and healthy persons[J]. Respir Med,2002,96(11):918-926.
79 Sen S,Reddy VG,Khanna A,et al.A comparative study of telomerase activity in sputum, bronchial washing and biopsy specimens of lung cancer[J].Lung Cancer.2001,33(1):41-49.
80 Kim NW, Piatyszek MA, Prowse K, et al.Specific association of human telomerase activity with immortal cells and cancer[J]. Science,1994, 266(17):2011-2015.
81 Gauthier LR, Granotier C,Soria J,et al.Detection of circulation carcinoma cell by telomerase activity[J]. Br J Cancer,2001,84(7):631-635.
82 Sen S,Reddy VG,Khanna N,et al.A comparative study of telomera activity in putama, bronchial washing and biopsy specimens of lung cancer[J]. Lung Cancer,2001,33(1):41-49.
83 Usadel H, Brabender J, Danenberg K, et al.Quantitative adenomatous polypsis coli promoter methylation analysis in tumor tissue, serum and plasma DNA of patients with lung cance[J]r. Cancer Res,2002,62(4):371-375.
84周清华,陈军,刘伦旭,等.人肺癌中FHIT等位基因异常的研究[J].中国肺癌杂志,2002,5(2)：6-12.
85周清华,陈军,刘伦旭,等.人非小细胞肺癌中FHIT等位基因缺失和突变研究[J].中国肺癌杂志,2001,4(1)：10-14.
2 Sun Z, Fu X, Zhang L, et al. A protein chip system for parallel analysis of multi-tumor markers and its application in cancerdetection[J].Anticancer Res,2004,24(2C):1159-1165.
3 Ahrendt SA, Hu Y, Buta M, et al. p53 mutations and survival in stage I non-small-cell lung cancer:results of a prospective study[J]. J Natl Cancer Inst, 2003,95(13):961-970.
4 Coulet F, Blons H, Cabelguenne A, et al. Detection of plasma tumour DNA in head and neck squamous cell carcinoma by microsatellite typing and p53 mutation analysis[J]. Cancer Res,2000,60(3):707-711.
5 Mack U, Ukena D, Montenarh M, et al. Serum anti-p53 antibodies in patiens with lung cancer[J]. Oncol Rep,2000,7(3):669-674.
6 Phatak P, Burger AM. Telomerase and its potential for therapeutic intervention[J]. Br J Pharmacol,2007,152(7):1003-1011.
7 Li X, Niddzuka H, Tsutsumi K, et al. Slructure, interactions and effects on activity ofthe 5'terminal region of human telomerase RNA[J]. J Bio chem, 2007,141(5):755-765.
8 Soder, AI, Hoare S, Muir S, et al. Amplification,increased dosage and in situ expression of the telomerase RNA gene in human cancer[J]. Oncogene,1997,14(19):1013-1021.
9 Hsu CP, Miawa J, Shai SE, et al. Correlation between telomerase expression and terminal restriction fragment length ratio in non-small cel lung cancer-an adjusted measurement and its clinical significance[J]. Eur J Cardiothoracic Surgery,2004,26(2):425-431.
10 Gauthier LR, Granotier C, Soria J, et al. Detection of circulation carcinoma cell by telomerase activity[J]. Br J Cancer,2001,84(7):631-635.
11 Scott E, Dessain H, Roger R, et al. Methylation of human telomerase gene CPG island in blood[J]. Cancer Res,2000,60(6):537-541.
12 Garcia M,Jemal A,Ward EM,et al.Global Cancer Facts&Figures 2007 (M).Atlanta,GA:American Cancer Society,2007.
13 Farber E. The multistep nature of cancer development[J]. Cancer Res, 1984,44(27):4214-4223.
14 Leea JH, Hongb YS, Jeong SR, et al. p53 and FHIT mutations and micro satellite alterations in malignancy-associated pleural effusion[J]. Lung Cancer,2004,44(1):33-42.
15 Sozzi G, Conte D, Mariani L, et al. Analysis of circulating tumor DNA in plasmat diagnosis and during follow-up of lung cancer patients[J]. Cancer Res, 2001,61(12):4675-4678.
16 Takehisa H, Yoshio T, Moriaki H, et al. p53 null mutations undetected by imm-unohistochemical staining predict a poor outcome with early-stage non-small cell lung carcinomas[J]. Cancer Res,1999,59(21):5572-5577.
17 Silva JM, Dominguez G, Garcia JM. Presence of tumor DNA in plasma of breast cancer patients[J]. Cancer Res,1999,59(13):3251-3256.
18白莉,孙燕,李申德.肺癌组织抑癌基固p53异常分析借变.畸变、突变[J].1996,8(6)：321-326.
19 Sapio A, Morra I, Pradotto L, et al. Molecular genetic changes in a series of neuroepithelial tumors of childhood[J]. J Neuro oncol,2002,59(2):117-122.
20 Navada S, Lai P, Schwartz AG, et al. Temporal trends in small-cell lung cancer: analysis of the national surveillance epidemiology and end results (SEER)database[J]. J Clin Oncol,2006,24(18Suppl):S384.
21 Visser O, Belderbos J, Kwa H, et al. Improved stage specific survival of NSCLC in northern Holland Flevoland, the netherland effect of intensified treatment or stage migration[J]. Lung Cancer,2005,49(Suppl 2):S198.
22 Samgimura T, Vahijima T. Genetic and epigenetie alterations in carciogenesis[J]. Mutation Res,2000,462(2-3):235.
23李小华,陈德基,江曼,等.实验性肺癌癌变过程中p53、mdm2、k-ras及PCNA蛋白的表达[J].癌症杂志,2001,20(9)：921.
24 Soussi T. p53 antibodies in the sera of patiens with various type of cancer:a review[J]. Cancer Res,2000,60(19):1777-1788.
25郭雪君,邓伟吾,黄绍光.肺癌基因和抑制基因的研究进展[J].中华结核和呼吸杂志,1995,18(3)：267.
26 Takahashi T, Carbone D, etal. Wild-type but mutant p53 soppresses the growth of human lung cancer cells bearing multiple genetic lesions[J]. Cancer Res,1992,52(5):2340.
27 Mitsudomi T, Takahashi T, Genetic abnormalities in lung call and their prognostic implications[J]. Gan To Kagaku Ryoho,1996,23(8):990.
28张振峰.p53与人类肺癌研究进展[J].国外医学内科学分册,1999,26(6)：255.
29 Chen PL, Chen YM, Bookstein R, et al. Genetic mechanisms of tumor suppression by the human p53 gene[J]. Science,1990,250(4987):1576.
30 Soussi T, Loano G. p53 mutation heterogenety in cancer[J]. Biochem Biophysier Commun,2005,331(3):834.
31 Laudanski J, Burzykowski T, Niklinska W, et al. Prognostic value of serum p53 an tibodies in patiens with resected non-small cell lung cancer[J]. Lung Cancer, 1998,22(3):191-200.
32 Andriani F, Conte D, Mastrangelo T, et al. Detecting lung cancer in plasma with the use of multiple genetic markers[J]. Int J Cancer,2004,108(1):91-96.
33 Gonzaiez R, Silva JM, Sanchez A, et al. Microsatellite alterations and p53 mutations in plasma DNA of small-cell lung cancer patients:follow-up study and prognostie significance[J]. Ann Oncol,2000,11(9):1097-1104.
34 Mao L, Hruban RH, Boyle JO, et al. Detection of one-gene mutationsin sputum precedes diagnosis of lung cancer[J]. Cancer Res,1994,54(12):1634-1637.
35 Li Mao, Hruben RH,Boyle JO, et al. Detection of oncogene mutations in sputum procedes diagnosis of lung cancer[J]. Cancer Res,1994, No(3):1663.
36 Mitsudomi T, Oyama T, Kusano T, et al.Mutation of the p53 gene as a predictor of poor prognosis in patients with non-small cell lung cancer[J]. J Natl Cancer Int,1993,No(4):2018.
37 Dai Y, Morishita Y, Mase K, et al. Application of the p53 and K-ras gene mutation patterns for cytologle diagnosis of recurrent lung carcinomas[J]. Cancer,2000,90(4):258-263.
38 Tocknan MS, Gupta PK, Myers JD, et al. Sensitive and specific monoclonal antibody recognition of human lung cancer antigen on observed sputum cell:a new approach to early lung cancer detection[J]. J Clin Oneol,1988,No(11):1685.
39 Jacobson DR, Fishman CL, Mills NE. Molecular genetic tumor markers in the early diagnosis and screening of non-small cell lung cancer[J]. Ann Oncol,1995,6(Suppl 3):S3-8.
40 Hu Y, McDermott MP, Ahrendt SA. The p53 codon 72 proline allele is associated with p53 gene mutation in non-small cell lung cancer[J]. Clin Cancer Res.2005,11(7):2502.
41 Fouquet C, Antoine M, Tisserand P, el al. Rapid and sensitive p53 alteration analysis in biopsies from lung canoer patients using a functional assay and a universal oligonucleotide array prospective study[J]. Clin Cancer Res. 2004,10(10):3479.
42 Mitsudomi T, lam S, Shirakusa T, et al. Detection and sequencing of the p53 gene mutations in bronchial biopsy samples in patients with lung cancer[J]. Chest,1993,104(5):362.
43郭雪君,倪培华,李莉,等.可疑肺癌病人纤支镜检查标本的p53基因突变检测[J].癌症杂志,2000,19(3)：216.
44.赖百塘.端粒酶在肺癌诊断和治疗中的价值[J].中国肺癌杂志,2000,3(2)：81-83.
45.陈鲁琦,陈鲁豫,王宁,等.肺癌支气管肺泡灌洗液细胞端粒酶测定的临床意义[J].中华结核和呼吸杂志,1998,21(12)：730-732.
46.王勇,胡杰贵,江丰收,等.端粒酶活性在肺癌患者外周血中的表达研究[J].现代肿瘤医学,2008,16(7)：1142-1144.
47. Yang C T, Lee M H, Lan R S,et al. Telomerase activity inpleural effusions. Diagnostic significance[J]. Clin Oneol,1998,16(2):567-573.
48.王金亮,王嘉祺,安真光,等.端粒酶活性在肺癌患者痰脱落细胞中表达的临床价值[J].中国肺癌杂志,2002,5(1)：38-40.
49. Yahata N,ohyashiki K,Ohyashiki JH,et al.Telomerase activity in lung cancer cells obtained From bronchial washings[J]. J Nalt Cancer Inst,1998,90(9):84-90.
50. Tockman MS. Advances in sputum analysis for screening and early detection of lung cancer[J]. Cancer Control,2000,7(11):19-24.
51.成柏君,陆舜,冯久贤,等.端粒酶与p53、p16基因在非小细胞肺癌中的表达及其意义[J].中国癌症杂志,2001,11(5)：437-440.
52.刘华,温志震,王嘉祺,等.肺癌痰液p53和Kras基因及端粒酶联合检测的临床研究[J].临床研究,2006,13(17)：1304-1307.
53.姚珂 余祖滨 闭家新,等.肺癌组织中端粒酶活性检测及临床意义[J].中国肺癌杂志2003,6(5)：364-366.
54. Gauthier LR, Granotier C,Soria J,et al.Detection of circulation carcinoma cell by telomerase activity[J]. Br J Cancer,2001,84(7):631-635.
55.韦尉东,黄植蕃,戎铁华,等.端粒酶活性表达及p53异常在非小细胞肺癌中表 达及临床意义[J].癌症,2001,20(3)：301-304.
56. Kim NW, Piatyszek MA, Prowse K, et al. Specific association of human telomerase activity with immortal cells and cancer[J]. Science,1994, 266(27):2011-2015.
57 Dejmek A. Yahata N, Ohyashiki K. et al.[J]. Cancer,2000,90 (2):117-125.
58刘瑾,杨青,亚佳.等[J].中国肺癌杂志,2001,4(4)：299-302.
59 Arai T, Yasuda Y, Takaya T. et al [J]. Oncol Rep.1998,5(4):405-408.
60 Sen S, Reddy VG, Khanna N, et al. A comparative study of telomerase activity in sputum, bronchial washing and biopsy specimens of lung cancer[J]. Lung Cancer,2001,33(1):41-49.
61 Petty TL. The early identification of lung carcinoma by sputum cytology[J]. Cancer,2000,89(15):2461-2466.
62 Metso T, Haahtela T, Seveus L. Identification of intracellular markers in induced sputum and bronchoalveolar lavage samples in patients with respiratory disorders and healthy persons[J]. Respir Med,2002,96(11):918-926.
63申社林,李兵.血液基因组DNA的快速提取方法[J].生物技术通报2007,12(4)：146-147.
64于世寰,霍建民,石玉枝,等.纤维支气管镜活组织端粒酶活性检测对肺癌的诊断价值[J].中国内镜杂志,2004,10(8)：15-17.
65张月,康健,等.端粒酶及端粒酶逆转录酶在良、恶性胸腔积液中的表达及意义[J].山东医药,2008,48(40)：40-41.
66王强修,刘杜先,仲伟霞,等.端粒酶的检测与肿瘤诊治进展[J].肿瘤防治杂志,2000,7(5)：515-517.
67 Yahata N, Ohyashiki K, Ohyashiki JH, et al. Telomerase activity in lung cancer cells obtained from bronchial washings[J]. J Natl Cancer Inst, 1998,90(9):684-690.
68 Hiyama K, Hiyama E, Ishioka S, et al. Telomerase activity in small cell and non-small cell lung cancer[J]. J Natl Cancer Inst,1995,87(10):895-902.
69王安潮,黄礼年,陈余清,等.支气管活检标本的端粒酶活性检测对肺癌的诊断价值[J].中华结核和呼吸杂志,2000,23(8)：475-477.
70 Xinarianoa G, Scott FM, Litoglou T, et al. Evaluation of tetomerase activity in bronchial lavage as a potential diagnostic marker for malignant lung disease[J]. Lung Cancer,2000,28(1):37.
71 Shayjw, Gazdar AF. Telomerase in the early detection of cancer[J]. Clin Pathol,1997,50(2):106.
72 Gauthier LR. Detection of circulating carcinoma cells by telomerase activity[J]. Br J Cancer,2001,84(5):631-635.
73何平,闫灵,吴宝刚,等.肺癌患者外周血单个核细胞TERT基因表达在诊断中的价值[J].中国实用内科杂志,2005,25(8)：708-709.
74 Sen S, Reddy VG, Khanna N. et al. A comparative study of telomera activity in putama,bronchial washing and biopsy specimens of lung Cancer[J]. Lung Cancer,2001,33(1):41-49.
75刘东海,王丰民,冯伟云等.孤立性肺部结节肺泡灌洗液端粒酶活性测定对肺癌早期诊断的研究[J].江西医学检验,2005,23(10)：443.
76 Oremek GM, Sauer-eppel H, Bruzdziak TH. Value of tumour and inflammatory markers in lungcancer[J]. Anticancer Res,2007,27(4A):1911-1915.
77 Liu YQ, Liu JM, Lan X, et al. Tumor markers in differential diagnosis of the hydrothorax[J]. Clinical Medicine of China,2006,22(3):235-237.
78 Shi GL, Hu XL, Yue SD, et al. The value of serum tumor marker in the diagnosis of lung cancer[J]. Chin J Oncol,2005,27(5):299-301.
79 Gauthier LR, Granotier C, Soria J, et al. Detection of circulation carcinoma cell by telomerase activity[J]. Br J Cancer,2001,84(7):631-635.
80 Scott E, Dessain H, Roger R, et al. Methylation of human telomerase gene CPG island in blood[J]. Cancer Res,2000,60(7):537-541.
81姚连昌.痰标本中肺癌相关基因检测用于肺癌早期诊断的研究进展[J].中国肺癌杂志,2000,3(3)：239-243.
82郑永咏,王茹,尹帆.端粒、端粒酶及p16、p53基因在肺癌早期诊断中的研究进展[J].医学综述,2002,8(1)：4-5.
83 Nishio Y, Nakanishi K, Ozeki Y, et al. Telomere length, telomerase activity, and expressions of human telomerase mRNA component(hTERC)and hunmn telomerase reverse transcriptase(hTERT)mRNA in pulmonary neuroendocrine tumors[J]. Jpn J Clin Oncol,2007,37(1):16-22.
84 Dikmen G, Dikmen E, Kara M, et al. Diagnostic implications of telomerase activity in pleural effusions[J]. Eur Respir J,2003,22(3):422-426.
1 Jemal A,Tiwaei RC,Murray T, et al. Cancer Statistics[J]. CA Cancer J Clin, 2004,54(2):92-119.
2顾宗元,胡宏,王磊,等.影响肺癌相关肿瘤标志物因素分析临床[J].肺科杂志,2003,8(1)：11-12.
3陆舜,蔡映云.肺癌与端粒酶[J].国外医学呼吸系统分册,2002,22：4-5.
4中华医学会检验医学分会肿瘤标志物专家委员会.肿瘤标志物临床检测的基本原则[J].中华检验医学杂志,2004,27(6)：393.
5李红,许凯黎.肺癌标志物研究进展[J].实用肿瘤杂志,2002,17(5)：295-297.
6 Buccheri G.Tumor Markers:Clinical Meaning and Use.In:Brambilla C,Brambilla E. Lung Tumors[J]. New York:Marcel Dekker 1999:435-452.
7 Nawata S, Sugino N, Kato H. Squamous cell carcinoma antigen[J]. Nippon Rinsho,2005,63(Suppl8):684-686.
8 Oremek GM, Sauer-eppel H, Bruzdziak TH. Value of tumour and inflammatory markers in lung cancer[J]. Anticancer Res,2007,27(4A):1911-1915.
9 Chishing CW. Potentially useful biomarkers for the diagnosis, treatment and prognosis of lung cancer[J]. Biom Pharm,2007,61(9):515-519.
10 Ebem W, Muley T, Trainer R, et al. Comparision of changes in the NSE levels with clinical assessment in the therapy monitoring of patients with small cell lung cancer[J]. Anticancer Res,2002,22(28):1083.
11 Shihayma T, Veoka H, Nishiik B, et al. Complementary roles of progastrin-releasing peptide(proGRP)and neuron specific enolase(NSE)in diagnosis and prognosis of small cell lung cancer(SCLC) [J]. Lung Cancer,2001,32(1):61.
12 Bates F, Esteller M, Rose R, et al. Detection of aberrant promoter hypermetnylation of tumor suppressor gene in scrota DNA from non-small cell lung cancer patients[J]. Cancer Res,2002,59(1):67-70.
13 Spaulding DC, Spaulding BO. Epidermal growth factor receptor expression and measurement in solid tumors[J]. SEMIN Oncol,2002,29(5 Suppl 14):45-54.
14 Saski H, Yukiue H, Mizumo K.et al. Elevated serum epidermal factor receptor level is correlated with lymph node metastasis in lung cancer [J]. Int J Clin Oncol,2003,8(2):79-82.
15 Clared LE, Leitzel K, Smith J, et al. Epidermal growth factor receptor mRNA in peripheral blood of patients with pancreatic, lung, and colon carcinomas detected by RT-PCR[J]. Int J Clin Oncol,2003,22(2):425-430.
16 Wang XJ, Yu JJ, Sreekumar A, et al. Autoantibedy signatures in prostate cancer[J]. The New England Journal of Medicine,2005,353(16):1224-1235.
17 Goldenberg DM, Sharkey RM, Primus FJ. Immuno cytochemical detection of carcinoembryonic antigen in conventional histopathology specimens[J]. Cancer,1978,42(16):1546-1553.
18 Seemann MD, Einerl T, Furst H, et al. An evaluation of the tumor markers carcinoembryonic antigen(CEA), cytokerotin tumor markers, carcinoembryonic antigen(CEA), cytokeratin marker(CYFRA21-1)and neuron-specific enolase(NSE)in the differentiation of malignant from benign solitary pulmonary lesions[J]. Lung Cancer,1999,26(3):149.
19 HasholznerL, Stieber P, Reiter W, et al. CA242 incomparison with established tumor markers in colorectal, pancreatic and lung cancer[J]. Anti Cancer Res,1999,19(4A):2477-2480.
20 Peon RT, Fan ST, Wong J. Clinical implications of circulating angiogenic factors in cancer patients[J]. J Cin Oncol,2001,19(4):1207.
21 Kimura Y, Fujii T, Hamamoto K, et al. Serum CA125 level is a good prognostic indicator in lung cancer[J]. Br J Cancer,1990,62(7):676-678.
22 Barradas PA, Cristorao MM, Costa AM, et al. Comparison of three serum (cyfra21-1, NSE and CEA) in lung cancer:diagnosis efficacy prognostic importance value in chemotherapy monitoring and in early prediction of relapse[J].Chest,1998,114(3):250-255.
23 Nisman B,Lafair J,Heching N,et al. Evaluation of tissue specific antigen,CYFRA21-1,and carcinoembryonic antigen in non-small cell lung carcinoma:does the combined use of cytokeratin markers give any addition information[J]. Cancer,1998,82(10):1850-1859
24 Schneider J. Tumor markers in detection of lung cancer[J]. Adv Clin Chem, 2006,42(1):1-41.
25 Seemann MD, Einerl T, Furst H, et al. An evaluation of the tumor markers, carcinoembryonic antigen(CEA), cytokeratin marker(Cyfra21-1) and neuron-specific enolase (NSE) in the differentiation of malignant from benign solitary pulmonary lesions[J]. Lung Cancer,1999,26(3):149.
26 Muley T, Dienemann H, Ebert W. CYFRA 21-1 and CEA are independent prognostic factors in 153 operated stage I NSCLC patients[J]. Anticancer Res,2004,24(3b):1953-1956.
27 Pujol JL, Molinier O, Ebert W, et al. CYFRA 21-1 is a progn ostic determinant in non-small cell lung cancer:resuhs of a meta-analysis in 2063 patients[J]. Br J Cancer,2004,90(11):2097-2105.
28 Galligioni E, Fem A. Angiogenesis and antiangiogenic agents in non-small cell lung cancer[J]. Lung Cancer,2001,34(4):S3-7.
29 Body JJ, Sculier JP, Raymakers N, el al. Evaluation of squamous cell carcinoma antigen as a new marker for lung cancer[J]. Cancer,1990,65(7):1552-1556.
30 Mall JW, Schwenk W, Philipp AW, et al. Serum vascular endothelial growth factor levels correlate better with tumour stage in small cell lung cancer than albumin, neuron-specific enolase or lactate dehydrogenase[J]. Respirology,2002,7(2):99-102.
31 Hantapet P, Riantawan P, Lebnak P, et al. Utility of selflm cytokeratin 19 fragment(CYFAR21-1)and carcinoembryonie antigen(CEA)as tumor markers for non-small cell lung cancer[J]. Med Assoco,2000,83(4):383-391.
32 Molina R, Filella X, Auge JM, et al. Tumor markers(CEA, CA 125, CYFRA 21-1, SCC and NSE)in patients with non-small cell lung cancer as an aid in histological diagnosis and prognosis comparison with the main clinical and pathological prognostic factors[J]. Tumour Biol,2003,24(4):209-218.
33舒仁明,何思春,焦鑫,等.CEA在肺癌和其它肺部疾病的表达[J].四川省卫生管理干部学院学报,2004,2(31)：43.
34邵海燕,毛文炜,曾爱平.组织多肽特异性抗原和癌胚抗原在肺癌诊断中价值[J].浙江临床医学,2004,6(9)：754-752.
35 Matsuoka K, Sumitomo S, Nakashima N, et al. Prognostic value of carcinoembryonic antigen and CYFRA21-1 in patients with pathological stage I non-small cell lung cancer[J]. Eur J Cardiothorac Surg,2007,32(3):435-439.
36 Buecheri G and Ferrigno D. Identifying patients at risk of early postoperative recurrence of lung cancer:a new use of the old CEA test[J]. Ann Thomc stag,2003,75(3):973-980.
37 Stieber P, Dinemann H, Schalhom A, et al. Pro-gastrin-rel easing Peptide(ProGRP), A useful marker in small-cell lung carcinomas[J]. Anticancer Res,1999,19(24):2673-2678.
38 Molina R, Filella X, Auge JM. ProGRP:a new biomarker for small cell lung cancer[J]. Clin Biochem,2004,37(6):505-511.
39 Takada M, Kusunoki Y, Masuda N, et al. Pro-gastrin-releasing peptide(31-98)as a tumour marker of small cell lung cancer:comparative evaluation with neuron specific enolase[J]. Br J Cancer,1996,73(10):1227-1232.
40 Vandepol M, Twiinstra A, Tenvelde GP, et al. NSE as a marker of brain metastasis in patients with SCLC[J]. J Neurooncol,1994,19(2):149-150.
41 Plebani M, Basso D, Navaglia F, et al. Clinic evaluation of seven tumor markers in lung cancer diagnosis:can any combination improve the result[J], Br J Cancer,1995,72(1):170-173.
42 Poola I, Graziano SL.Expression of neuron-specific enolase, chromo-granin A, synaptophysin and Leu-7 in lung cancer cell lines[J]. J Exp Clin Cancer Res,1998,17(2):165.
43 Pinson P, Joos G, Watripont P, et al. Serum neuron-specific enolase as A tumor marker in the diagnosis and follow-up of small-cell lung cancer[J]. Respiration 1997,64(1):102.
44 Castaldo G, Tomaiuolo R, Sanduzzi A, et al. Carcinoembryonic antigen mRNA analysis detects micrometastatic cells in blood from lung cancer patients[J]. Eur Respir J,2003,22(3):418-421.
45 Schneider J, Velcovsky HG, Morr H, et al. Comparison of the tumormarkers tumorM2-PK, CEA,CYFRA 21-1, NSE and SCC in the diagnosis of lung cancer[J].Anticancer Res,2000,20(6D):50532-50581.
46 Toshihhiko I, Takerhik F, MakotoS, et al. Elevated levels of circulating plasma MMPs-9 in non-small cell lung cancer patients[J]. Clin Cancer Ras,1999,5(2):149-152.
47 Pujol JL, Grenier J, Parrat E, et al. Cytokeratins as serum markers in lung cancer: a comparison of CYFRA 21-1 and TPS[J]. Am J Respir Crit Care Med,1996,154(3Ptl):725-733.
48 Ho YJ, Hsieh JF, Tasi SC, et al. Tissue polypeptide specific antigen and squamous cell carcinoma antigen for early prediction of recurrence in lung squamous cell carcinoma[J]. Lung,2000,178(2):75-80.
49 Kennedy TC,Hirsch FR. Using molecular markers in sputum for the early detection of lung cancer:a review[J]. Lung Cancer,2004,45(2):S21-27.
50 Muller-Tidow C,Diederichs S,Thomas M. Ge-nome-wide screening for prognosis-predicting genes in early-stage non-small-cell lung cancer[J].2004,45 Suppl 2:145-150.
51 Yamamoto A,Shimizu E,Sumitomo K,et al. Lmyc overexpression and detection of auto-anti-bodies against L-myc in both the serum and pleural effusion from a patients with non-Small cell lung cancer[J].Intern Med,1997,36(10):724-727.
52 Playioye MA,Neve RM,Lane HA,et al. The erbB signaling network:receptor heterodimerization in development and cancer[J]. EMBO J,2000,19(13):3159-3167.
53赵元军,张世明,刘思令,等.ras和erbB-2基因在肺癌中的表达及意义[J].癌症,1998,17(2)：99-161.
54 Keohavong P,Demichele MA,Melocrinos AC,et al. Detection of K-ras mutations in lung carcinomas:relations to prognosis[J]. Clin Cancer Res,1996,2(21):411-418.
55 Yakubovskaya MS, Spiegelman V, Luo FC, et al. High frequency of K-ras mutation in normal appearing lung tissue and sputum of patients with lung cancer[J]. Int J Callcer,1995,63(9):810.
56 Mills NE, Hshman CL, Scholes J, et al. Detection of k-ras oncogene mutation in broncholveolar alvage fluid for lung cancer diagnosis[J]. J Natel Cancer Insti,1995,87(4):1056.
57 Cho JK, Kim JH, Lee YH, et al. Corrc lation between K-ras gene mutation andprognosis of patients with non-small cell lung eardnorna[J]. Cancer, 1997,79(3):462.
58 Diez M, Pbllan M, Masestro M, et al. Prediction of recurrence by quantifiation of p185 protein in non-sraall cell lung tissue[J]. Br J cancer,1997,75(5):684.
59李小华,陈德基,江曼,等.实验性肺癌癌变过程中p53、mdm2、k-ras及PCNA蛋白的表达[J].癌症杂志,2001,20(9)：921.
60 Mitsudomi T, Takahashi T. Genetic abnormalities in lung call and their prognostic implications[J]. Gan To Kagaku Ryoho,1996,23(8):990.
61来茂德.医学分子生物学[M][J].人民卫生出版社,1998：324.
62 Ahrendt SA, Hu Y, Buta M, et al. p53 mutations and survival in stage I non-small cell lung cancer:results of a prospective study[J]. J Natl Cancer Inst,2003,95(13):961-970.
63 Gonzaie ZR, Silva JM, Sanchez A, et al. Microsatellite alterations and TP53 mutations in plasma DNA of small cell lung cancer patients:follow-up study and prognostie significance[J]. Ann Oncol,2000,11(9):1097-1104.
64 Takahashi T, Carbone D, et al. Wild-type but mutant p53 soppresses the growth of human lung cancer cells bearing multiple genetic lessions[J]. Cancer Res,1992,52(23):2340.
65 Soussi T. p53 an tibodies in the sera of patiens with various type of cancer:a review[J]. Cancer Res,2000,60(18):1777-1788.
66 Andriani F, Conte D, Mastrangelo T, et al. Detecting lung cancer in plasm a with the use of multiple genetic markers[J]. Int J Cancer,2004,108(1):91-96.
67彭猛青,王绪,刘德林,等.非小细胞肺癌p16基因甲基化及缺失的研究[J].中国肺癌杂志,2002,5(4)：250-253.
68 Kawabuchi B, Moriyama S, Hirohaka M. P16 inactivition in small-sized lung adenocarcinoma:its association with poor prognosis[J]. Int J Cancer,1999,84(1):49-53.
69 Belinsky SA, Nikula KJ, Palmisano WA, et al. Aberrant methylation of p16(INK4a)is an early event in lung cancer and a potential biomarker for carly diagnosis[J]. Proc Natl Acad Sci USA,1998,95(20):11891-11896.
70 Samgimura T, Vahijima T. Genetic ansd epigenetie alterations in carciogenesis[J]. Mutation Res,2000,462(2-3):235.
71杨德昌,杨拴盈.肺癌诊断及治疗进展[J].中华结核呼吸杂志,2004,1(1)：18-19.
72 Rohayem J, Diestelkoetter P, Weigle B, et al. Antibody response to the tumor associated inhibitor of apoptosis protein survivin in cancer patients[J]. Cancer Res,2000,60(19):1815-1817.
73 Sozzi G, MUSSO K, Ratclffe H, et al.Detection of micro-satellite alterations in plasma DNA of non-small cell lung cancer patients:a prospect for early diagnosis[J]. Clin Cancer Res,1999,5(27):2689-2692.
74 Fielding P, Turabull L, Prime W, et al.hnRNP A2/B1 upregulation in bronchial lavage specimens:a clinical marker of early lung cancer detection[J]. Clin Cancer Res,1999,5(5A):4048-4052.
75 Fleischhacker M, Beinert T, Emitsch M, et al. Detection of amplifiable messenger RNA in serum of patients with lung cancer[J]. Ann NY Acad Sci, 2001,9(2):178-188.
76 Hiyama K, Ishioka S, Shirotani Y, et al[J]. Oncogene,1995,10(5):937-944.
77 Soder A, Going J, Kaye S, et al[J]. Oncogene,1998,16(8):979-983.
78 Metso T, Haahtela T, Seveus L.Identification of intracellular markers in induced sputum and bronchoalveolar lavage samples in patients with respiratory disorders and healthy persons[J]. Respir Med,2002,96(11):918-926.
79 Sen S,Reddy VG,Khanna A,et al.A comparative study of telomerase activity in sputum, bronchial washing and biopsy specimens of lung cancer[J].Lung Cancer.2001,33(1):41-49.
80 Kim NW, Piatyszek MA, Prowse K, et al.Specific association of human telomerase activity with immortal cells and cancer[J]. Science,1994, 266(17):2011-2015.
81 Gauthier LR, Granotier C,Soria J,et al.Detection of circulation carcinoma cell by telomerase activity[J]. Br J Cancer,2001,84(7):631-635.
82 Sen S,Reddy VG,Khanna N,et al.A comparative study of telomera activity in putama, bronchial washing and biopsy specimens of lung cancer[J]. Lung Cancer,2001,33(1):41-49.
83 Usadel H, Brabender J, Danenberg K, et al.Quantitative adenomatous polypsis coli promoter methylation analysis in tumor tissue, serum and plasma DNA of patients with lung cance[J]r. Cancer Res,2002,62(4):371-375.
84周清华,陈军,刘伦旭,等.人肺癌中FHIT等位基因异常的研究[J].中国肺癌杂志,2002,5(2)：6-12.
85周清华,陈军,刘伦旭,等.人非小细胞肺癌中FHIT等位基因缺失和突变研究[J].中国肺癌杂志,2001,4(1)：10-14.