The molecular basis of lung carcinogenesis must be understood more fully and exploited to enhance survival rates of patients suffering from lung cancer. In this review we will discuss the major molecular alterations that occur in lung cancer. Emphasis is placed on alterations that occur early during carcinogenesis since they might be relevant for future screening programs. Finally we will shortly review new approaches that are used to study the molecular pathology of lung cancer and how they can be applied in a clinical setting.

1.
Greenlee RT, Hill-Harmon MB, Murray T, Thun M: Cancer statistics, 2001. CA Cancer J Clin 2001;51:15–36.
2.
Brambilla E, Travis WD, Colby TV, Corrin B, Shimosato Y: The new World Health Organization classification of lung tumours. Eur Respir J 2001;18:1059–1068.
3.
Janssen-Heijnen ML, Coebergh JW: The changing epidemiology of lung cancer in Europe. Lung Cancer 2003;41:245–258.
4.
Auerbach O, Hammond EC, Garfinkel L: Changes in bronchial epithelium in relation to cigarette smoking, 1955–1960 vs. 1970–1977. N Engl J Med 1979;300:381–385.
5.
Loeb LA: A mutator phenotype in cancer. Cancer Res 2001;61:3230–3239.
6.
Li D, Firozi PF, Wang LE, Bosken CH, Spitz MR, Hong WK, Wei Q: Sensitivity to DNA damage induced by benzo(a)pyrene diol epoxide and risk of lung cancer: A case-control analysis. Cancer Res 2001;61:1445–1450.
7.
Shen H, Spitz MR, Qiao Y, Guo Z, Wang LE, Bosken CH, et al: Smoking, DNA repair capacity and risk of nonsmall cell lung cancer. Int J Cancer 2003;107:84–88.
8.
Wei Q, Cheng L, Hong WK, Spitz MR: Reduced DNA repair capacity in lung cancer patients. Cancer Res 1996;56:4103–4107.
9.
Wei Q, Cheng L, Amos CI, Wang LE, Guo Z, Hong WK, et al: Repair of tobacco carcinogen-induced DNA adducts and lung cancer risk: A molecular epidemiologic study. J Natl Cancer Inst 2000;92:1764–1772.
10.
Wu X, Gu J, Amos CI, Jiang H, Hong WK, Spitz MR: A parallel study of in vitro sensitivity to benzo[a]pyrene diol epoxide and bleomycin in lung carcinoma cases and controls. Cancer 1998;83:1118–1127.
11.
Hecht SS: Cigarette smoking and lung cancer: Chemical mechanisms and approaches to prevention. Lancet Oncol 2002;3:461–469.
12.
Houlston RS: CYP1A1 polymorphisms and lung cancer risk: A meta-analysis. Pharmacogenetics 2000;10:105–114.
13.
Houlston RS: Glutathione S-transferase M1 status and lung cancer risk: A meta-analysis. Cancer Epidemiol Biomarkers Prev 1999;8:675–682.
14.
Chang JW, Chen YC, Chen CY, Chen JT, Chen SK, Wang YC: Correlation of genetic instability with mismatch repair protein expression and p53 mutations in non-small cell lung cancer. Clin Cancer Res 2000;6:1639–1646.
15.
Peltomaki P, Lothe RA, Aaltonen LA, Pylkkanen L, Nystrom-Lahti M, Seruca R, et al: Microsatellite instability is associated with tumors that characterize the hereditary non-polyposis colorectal carcinoma syndrome. Cancer Res 1993;53:5853–5855.
16.
Mao L, Lee DJ, Tockman MS, Erozan YS, Askin F, Sidransky D: Microsatellite alterations as clonal markers for the detection of human cancer. Proc Natl Acad Sci USA 1994;91:9871–9875.
17.
Rosell R, Pifarre A, Monzo M, Astudillo J, Lopez-Cabrerizo MP, Calvo R, et al: Reduced survival in patients with stage-I non-small-cell lung cancer associated with DNA-replication errors. Int J Cancer 1997;74:330–334.
18.
Miozzo M, Sozzi G, Musso K, Pilotti S, Incarbone M, Pastorino U, et al: Microsatellite alterations in bronchial and sputum specimens of lung cancer patients. Cancer Res 1996;56:2285–2288.
19.
Kok K, Osinga J, Carritt B, Davis MB, van der Hout AH, van der Veen AY, et al: Deletion of a DNA sequence at the chromosomal region 3p21 in all major types of lung cancer. Nature 1987;330:578–581.
20.
Chung GT, Sundaresan V, Hasleton P, Rudd R, Taylor R, Rabbitts PH: Sequential molecular genetic changes in lung cancer development. Oncogene 1995;11:2591–2598.
21.
Wistuba II, Behrens C, Milchgrub S, Bryant D, Hung J, Minna JD, et al: Sequential molecular abnormalities are involved in the multistage development of squamous cell lung carcinoma. Oncogene 1999;18:643–650.
22.
Wistuba II, Behrens C, Virmani AK, Mele G, Milchgrub S, Girard L, et al: High resolution chromosome 3p allelotyping of human lung cancer and preneoplastic/preinvasive bronchial epithelium reveals multiple, discontinuous sites of 3p allele loss and three regions of frequent breakpoints. Cancer Res 2000;60:1949–1960.
23.
Sekido Y, Bader S, Latif F, Gnarra JR, Gazdar AF, Linehan WM, et al: Molecular analysis of the von Hippel-Lindau disease tumor suppressor gene in human lung cancer cell lines. Oncogene 1994;9:1599–1604.
24.
Hibi K, Takahashi T, Yamakawa K, Ueda R, Sekido Y, Ariyoshi Y, et al: Three distinct regions involved in 3p deletion in human lung cancer. Oncogene 1992;7:445–449.
25.
Knudson AG Jr: The ninth Gordon Hamilton-Fairley memorial lecture. Hereditary cancers: Clues to mechanisms of carcinogenesis. Br J Cancer 1989;59:661–666.
26.
Pomerantz J, Schreiber-Agus N, Liegeois NJ, Silverman A, Alland L, Chin L, et al: The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2’s inhibition of p53. Cell 1998;92:713–723.
27.
Zhang Y, Xiong Y, Yarbrough WG: ARF promotes MDM2 degradation and stabilizes p53:ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell 1998;92:725–734.
28.
Hollstein M, Sidransky D, Vogelstein B, Harris CC: p53 mutations in human cancers. Science 1991;253:49–53.
29.
Gao HG, Chen JK, Stewart J, Song B, Rayappa C, Whong WZ, et al: Distribution of p53 and K-ras mutations in human lung cancer tissues. Carcinogenesis 1997;18:473–478.
30.
Toyooka S, Tsuda T, Gazdar AF: The TP53 gene, tobacco exposure, and lung cancer. Hum Mutat 2003;21:229–239.
31.
Bennett WP, Colby TV, Travis WD, Borkowski A, Jones RT, Lane DP, et al: p53 protein accumulates frequently in early bronchial neoplasia. Cancer Res 1993;53:4817–4822.
32.
Boers JE, ten Velde GP, Thunnissen FB: P53 in squamous metaplasia: A marker for risk of respiratory tract carcinoma. Am J Respir Crit Care Med 1996;153:411–416.
33.
Brambilla E, Gazzeri S, Lantuejoul S, Coll JL, Moro D, Negoescu A, et al: p53 mutant immunophenotype and deregulation of p53 transcription pathway (Bcl2, Bax, and Waf1) in precursor bronchial lesions of lung cancer. Clin Cancer Res 1998;4:1609–1618.
34.
Breuer RH, Snijders PJ, Sutedja TG, Linden H, Risse EK, Meijer CJ, et al: Suprabasal p53 immunostaining in premalignant endobronchial lesions in combination with histology is associated with bronchial cancer. Lung Cancer 2003;40:165–172.
35.
Fontanini G, Vignati S, Bigini D, Merlo GR, Ribecchini A, Angeletti CA, et al: Human non-small cell lung cancer: p53 protein accumulation is an early event and persists during metastatic progression. J Pathol 1994;174:23–31.
36.
Jeanmart M, Lantuejoul S, Fievet F, Moro D, Sturm N, Brambilla C, et al: Value of immunohistochemical markers in preinvasive bronchial lesions in risk assessment of lung cancer. Clin Cancer Res 2003;9:2195–2203.
37.
Kohno H, Hiroshima K, Toyozaki T, Fujisawa T, Ohwada H: p53 mutation and allelic loss of chromosome 3p, 9p of preneoplastic lesions in patients with nonsmall cell lung carcinoma. Cancer 1999;85:341–347.
38.
Li ZH, Zheng J, Weiss LM, Shibata D: c-k-ras and p53 mutations occur very early in adenocarcinoma of the lung. Am J Pathol 1994;144:303–309.
39.
Ponticiello A, Barra E, Giani U, Bocchino M, Sanduzzi A: p53 immunohistochemistry can identify bronchial dysplastic lesions proceeding to lung cancer: A prospective study. Eur Respir J 2000;15:547–552.
40.
Rusch V, Klimstra D, Linkov I, Dmitrovsky E: Aberrant expression of p53 or the epidermal growth factor receptor is frequent in early bronchial neoplasia and coexpression precedes squamous cell carcinoma development. Cancer Res 1995;55:1365–1372.
41.
Sozzi G, Miozzo M, Donghi R, Pilotti S, Cariani CT, Pastorino U, et al: Deletions of 17p and p53 mutations in preneoplastic lesions of the lung. Cancer Res 1992;52:6079–6082.
42.
Sundaresan V, Ganly P, Hasleton P, Rudd R, Sinha G, Bleehen NM, et al: p53 and chromosome 3 abnormalities, characteristic of malignant lung tumours, are detectable in preinvasive lesions of the bronchus. Oncogene 1992;7:1989–1997.
43.
Walker C, Dixon GR, Myskow M: Human non-small cell lung cancer: p53 protein accumulation is an early event and persists during metastatic progression. J Pathol 1995;176:319–320.
44.
Zheng J, Shu Q, Li ZH, Tsao JI, Weiss LM, Shibata D: Patterns of p53 mutations in squamous cell carcinoma of the lung. Acquisition at a relatively early age. Am J Pathol 1994;145:1444–1449.
45.
Serrano M, Hannon GJ, Beach D: A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 1993;366:704–707.
46.
Harbour JW, Lai SL, Whang-Peng J, Gazdar AF, Minna JD, Kaye FJ: Abnormalities in structure and expression of the human retinoblastoma gene in SCLC. Science 1988;241:353–357.
47.
Reissmann PT, Koga H, Takahashi R, Figlin RA, Holmes EC, Piantadosi S, et al: Inactivation of the retinoblastoma susceptibility gene in non-small-cell lung cancer. The Lung Cancer Study Group. Oncogene 1993;8:1913–1919.
48.
Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K, Tavtigian SV, et al: A cell cycle regulator potentially involved in genesis of many tumor types. Science 1994;264:436–440.
49.
Belinsky SA, Nikula KJ, Palmisano WA, Michels R, Saccomanno G, Gabrielson E, et al: Aberrant methylation of p16(INK4a) is an early event in lung cancer and a potential biomarker for early diagnosis. Proc Natl Acad Sci USA 1998;95:11891–11896.
50.
Brambilla E, Gazzeri S, Moro D, Lantuejoul S, Veyrenc S, Brambilla C: Alterations of Rb pathway (Rb-p16INK4-cyclin D1) in preinvasive bronchial lesions. Clin Cancer Res 1999;5:243–250.
51.
Brambilla E, Moro D, Gazzeri S, Brambilla C: Alterations of expression of Rb, p16(INK4A) and cyclin D1 in non-small cell lung carcinoma and their clinical significance. J Pathol 1999;188:351–360.
52.
Kersting M, Friedl C, Kraus A, Behn M, Pankow W, Schuermann M: Differential frequencies of p16(INK4a) promoter hypermethylation, p53 mutation, and K-ras mutation in exfoliative material mark the development of lung cancer in symptomatic chronic smokers. J Clin Oncol 2000;18:3221–3229.
53.
Lamy A, Sesboue R, Bourguignon J, Dautreaux B, Metayer J, Frebourg T, et al: Aberrant methylation of the CDKN2a/p16INK4a gene promoter region in preinvasive bronchial lesions: A prospective study in high-risk patients without invasive cancer. Int J Cancer 2002;100:189–193.
54.
Nuovo GJ, Plaia TW, Belinsky SA, Baylin SB, Herman JG: In situ detection of the hypermethylation-induced inactivation of the p16 gene as an early event in oncogenesis. Proc Natl Acad Sci USA 1999;96:12754–12759.
55.
Gazzeri S, Gouyer V, Vour’ch C, Brambilla C, Brambilla E: Mechanisms of p16INK4A inactivation in nonsmall-cell lung cancers. Oncogene 1998;16:497–504.
56.
Esteller M, Herman JG: Cancer as an epigenetic disease: DNA methylation and chromatin alterations in human tumours. J Pathol 2002;196:1–7.
57.
Jacobs JJ, Kieboom K, Marino S, DePinho RA, van Lohuizen M: The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 1999;397:164–168.
58.
Vonlanthen S, Heighway J, Altermatt HJ, Gugger M, Kappeler A, Borner MM, et al: The bmi-1 oncoprotein is differentially expressed in non-small cell lung cancer and correlates with INK4A-ARF locus expression. Br J Cancer 2001;84:1372–1376.
59.
Betticher DC, Heighway J, Hasleton PS, Altermatt HJ, Ryder WD, Cerny T, et al: Prognostic significance of CCND1 (cyclin D1) overexpression in primary resected non-small-cell lung cancer. Br J Cancer 1996;73:294–300.
60.
Lonardo F, Rusch V, Langenfeld J, Dmitrovsky E, Klimstra DS: Overexpression of cyclins D1 and E is frequent in bronchial preneoplasia and precedes squamous cell carcinoma development. Cancer Res 1999;59:2470–2476.
61.
Ratschiller D, Heighway J, Gugger M, Kappeler A, Pirnia F, Schmid RA, et al: Cyclin D1 overexpression in bronchial epithelia of patients with lung cancer is associated with smoking and predicts survival. J Clin Oncol 2003;21:2085–2093.
62.
Reissmann PT, Koga H, Figlin RA, Holmes EC, Slamon DJ: Amplification and overexpression of the cyclin D1 and epidermal growth factor receptor genes in non-small-cell lung cancer. Lung Cancer Study Group. J Cancer Res Clin Oncol 1999;125:61–70.
63.
Schauer IE, Siriwardana S, Langan TA, Sclafani RA: Cyclin D1 overexpression vs. retinoblastoma inactivation: Implications for growth control evasion in non-small cell and small cell lung cancer. Proc Natl Acad Sci USA 1994;91:7827–7831.
64.
Sozzi G, Veronese ML, Negrini M, Baffa R, Cotticelli MG, Inoue H, et al: The FHIT gene 3p14.2 is abnormal in lung cancer. Cell 1996;85:17–26.
65.
Yanagisawa K, Kondo M, Osada H, Uchida K, Takagi K, Masuda A, et al: Molecular analysis of the FHIT gene at 3p14.2 in lung cancer cell lines. Cancer Res 1996;56:5579–5582.
66.
Otterson GA, Xiao GH, Geradts J, Jin F, Chen WD, Niklinska W, Kaye FJ, Yeung RS: Protein expression and functional analysis of the FHIT gene in human tumor cells. J Natl Cancer Inst 1998;90:426–432.
67.
Siprashvili Z, Sozzi G, Barnes LD, McCue P, Robinson AK, Eryomin V, et al: Replacement of FHIT in cancer cells suppresses tumorigenicity. Proc Natl Acad Sci USA 1997;94:13771–13776.
68.
Ortiz-Vega S, Khokhlatchev A, Nedwidek M, Zhang XF, Dammann R, Pfeifer GP, et al: The putative tumor suppressor RASSF1A homodimerizes and heterodimerizes with the Ras-GTP binding protein Nore1. Oncogene 2002;21:1381–1390.
69.
Agathanggelou A, Honorio S, Macartney DP, Martinez A, Dallol A, Rader J, et al: Methylation associated inactivation of RASSF1A from region 3p21.3 in lung, breast and ovarian tumours. Oncogene 2001;20:1509–1518.
70.
Burbee DG, Forgacs E, Zochbauer-Muller S, Shivakumar L, Fong K, Gao B, et al: Epigenetic inactivation of RASSF1A in lung and breast cancers and malignant phenotype suppression. J Natl Cancer Inst 2001;93:691–699.
71.
Dammann R, Li C, Yoon JH, Chin PL, Bates S, Pfeifer GP: Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3. Nat Genet 2000;25:315–319.
72.
Tomizawa Y, Kohno T, Kondo H, Otsuka A, Nishioka M, Niki T, et al: Clinicopathological significance of epigenetic inactivation of RASSF1A at 3p21.3 in stage I lung adenocarcinoma. Clin Cancer Res 2002;8:2362–2368.
73.
Leid M, Kastner P, Chambon P: Multiplicity generates diversity in the retinoic acid signalling pathways. Trends Biochem Sci 1992;17:427–433.
74.
Toulouse A, Morin J, Dion PA, Houle B, Bradley WE: RARbeta2 specificity in mediating RA inhibition of growth of lung cancer-derived cells. Lung Cancer 2000;28:127–137.
75.
Berard J, Laboune F, Mukuna M, Masse S, Kothary R, Bradley WE: Lung tumors in mice expressing an antisense RARbeta2 transgene. FASEB J 1996;10:1091–1097.
76.
Xu XC, Sozzi G, Lee JS, Lee JJ, Pastorino U, Pilotti S, et al: Suppression of retinoic acid receptor beta in non-small-cell lung cancer in vivo: Implications for lung cancer development. J Natl Cancer Inst 1997;89:624–629.
77.
Zochbauer-Muller S, Fong KM, Virmani AK, Geradts J, Gazdar AF, Minna JD: Aberrant promoter methylation of multiple genes in non-small cell lung cancers. Cancer Res 2001;61:249–255.
78.
Kurie JM, Lotan R, Lee JJ, Lee JS, Morice RC, Liu DD, et al: Treatment of former smokers with 9-cis-retinoic acid reverses loss of retinoic acid receptor-beta expression in the bronchial epithelium: Results from a randomized placebo-controlled trial. J Natl Cancer Inst 2003;95:206–214.
79.
Martinet N, Alla F, Farre G, Labib T, Drouot H, Vidili R, et al: Retinoic acid receptor and retinoid X receptor alterations in lung cancer precursor lesions. Cancer Res 2000;60:2869–2875.
80.
Picard E, Seguin C, Monhoven N, Rochette-Egly C, Siat J, Borrelly J, et al: Expression of retinoid receptor genes and proteins in non-small-cell lung cancer. J Natl Cancer Inst 1999;91:1059–1066.
81.
Soria JC, Xu X, Liu DD, Lee JJ, Kurie J, Morice RC, et al: Retinoic acid receptor beta and telomerase catalytic subunit expression in bronchial epithelium of heavy smokers. J Natl Cancer Inst 2003;95:165–168.
82.
Kurie JM, Lee JS, Khuri FR, Mao L, Morice RC, Lee JJ, et al: N-(4-hydroxyphenyl)retinamide in the chemoprevention of squamous metaplasia and dysplasia of the bronchial epithelium. Clin Cancer Res 2000;6:2973–2979.
83.
McLarty JW, Holiday DB, Girard WM, Yanagihara RH, Kummet TD, Greenberg SD: β-Carotene, vitamin A, and lung cancer chemoprevention: Results of an intermediate endpoint study. Am J Clin Nutr 1995;62(6 Suppl):1431S–1438S.
84.
Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A, et al: Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996;334:1150–1155.
85.
Kolodkin AL, Levengood DV, Rowe EG, Tai YT, Giger RJ, Ginty DD: Neuropilin is a semaphorin III receptor. Cell 1997;90:753–762.
86.
Lantuejoul S, Constantin B, Drabkin H, Brambilla C, Roche J, Brambilla E: Expression of VEGF, semaphorin SEMA3F, and their common receptors neuropilins NP1 and NP2 in preinvasive bronchial lesions, lung tumours, and cell lines. J Pathol 2003;200:336–347.
87.
Brambilla E, Constantin B, Drabkin H, Roche J: Semaphorin SEMA3F localization in malignant human lung and cell lines: A suggested role in cell adhesion and cell migration. Am J Pathol 2000;156:939–950.
88.
Vermeulen S, Van Marck V, Van Hoorde L, Van Roy F, Bracke M, Mareel M: Regulation of the invasion suppressor function of the cadherin/catenin complex. Pathol Res Pract 1996;192:694–707.
89.
Pirinen RT, Hirvikoski P, Johansson RT, Hollmen S, Kosma VM: Reduced expression of alpha-catenin, beta-catenin, and gamma-catenin is associated with high cell proliferative activity and poor differentiation in non-small cell lung cancer. J Clin Pathol 2001;54:391–395.
90.
Retera JM, Leers MP, Sulzer MA, Theunissen PH: The expression of beta-catenin in non-small-cell lung cancer: A clinicopathological study. J Clin Pathol 1998;51:891–894.
91.
Kuramochi M, Fukuhara H, Nobukuni T, Kanbe T, Maruyama T, Ghosh HP, et al: TSLC1 is a tumor-suppressor gene in human non-small-cell lung cancer. Nat Genet 2001;27:427–430.
92.
Masuda M, Yageta M, Fukuhara H, Kuramochi M, Maruyama T, Nomoto A, et al: The tumor suppressor protein TSLC1 is involved in cell-cell adhesion. J Biol Chem 2002;277:31014–31019.
93.
Ito A, Okada M, Uchino K, Wakayama T, Koma Y, Iseki S, et al: Expression of the TSLC1 adhesion molecule in pulmonary epithelium and its down-regulation in pulmonary adenocarcinoma other than bronchioloalveolar carcinoma. Lab Invest 2003;83:1175–1183.
94.
Fukami T, Fukuhara H, Kuramochi M, Maruyama T, Isogai K, Sakamoto M, et al: Promoter methylation of the TSLC1 gene in advanced lung tumors and various cancer cell lines. Int J Cancer 2003;107:53–59.
95.
Uchino K, Ito A, Wakayama T, Koma Y, Okada T, Ohbayashi C, et al: Clinical implication and prognostic significance of the tumor suppressor TSLC1 gene detected in adenocarcinoma of the lung. Cancer 2003;98:1002–1007.
96.
Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, et al: PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997;275:1943–1947.
97.
Di Cristofano A, Pesce B, Cordon-Cardo C, Pandolfi PP: Pten is essential for embryonic development and tumour suppression. Nat Genet 1998;19:348–355.
98.
Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T, et al: Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 1998;95:29–39.
99.
Girard L, Zochbauer-Muller S, Virmani AK, Gazdar AF, Minna JD: Genome-wide allelotyping of lung cancer identifies new regions of allelic loss, differences between small cell lung cancer and non-small cell lung cancer, and loci clustering. Cancer Res 2000;60:4894–4906.
100.
Okami K, Wu L, Riggins G, Cairns P, Goggins M, Evron E, et al: Analysis of PTEN/MMAC1 alterations in aerodigestive tract tumors. Cancer Res 1998;58:509–511.
101.
Forgacs E, Biesterveld EJ, Sekido Y, Fong K, Muneer S, Wistuba II, et al: Mutation analysis of the PTEN/MMAC1 gene in lung cancer. Oncogene 1998;17:1557–1565.
102.
Hosoya Y, Gemma A, Seike M, Kurimoto F, Uematsu K, Hibino S, et al: Alteration of the PTEN/MMAC1 gene locus in primary lung cancer with distant metastasis. Lung Cancer 1999;25:87–93.
103.
Kohno T, Takahashi M, Manda R, Yokota J: Inactivation of the PTEN/MMAC1/TEP1 gene in human lung cancers. Genes Chromosom Cancer 1998;22:152–156.
104.
Yokomizo A, Tindall DJ, Drabkin H, Gemmill R, Franklin W, Yang P, et al: PTEN/MMAC1 mutations identified in small cell, but not in non-small cell lung cancers. Oncogene 1998;17:475–479.
105.
Soria JC, Lee HY, Lee JI, Wang L, Issa JP, Kemp BL, et al: Lack of PTEN expression in non-small cell lung cancer could be related to promoter methylation. Clin Cancer Res 2002;8:1178–1184.
106.
Torres J, Navarro S, Rogla I, Ripoll F, Lluch A, Garcia-Conde J, et al: Heterogeneous lack of expression of the tumour suppressor PTEN protein in human neoplastic tissues. Eur J Cancer 2001;37:114–121.
107.
Chun KH, Kosmeder JW, Sun S, Pezzuto JM, Lotan R, Hong WK, Lee HY: Effects of deguelin on the phosphatidylinositol 3-kinase/Akt pathway and apoptosis in premalignant human bronchial epithelial cells. J Natl Cancer Inst 2003;95:291–302.
108.
Wang Y, Minoshima S, Shimizu N: Precise mapping of the EGF receptor gene on the human chromosome 7p12 using an improved fish technique. Jpn J Hum Genet 1993;38:399–406.
109.
Graus-Porta D, Beerli RR, Daly JM, Hynes NE: ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J 1997;16:1647–1655.
110.
Lenferink AE, Busse D, Flanagan WM, Yakes FM, Arteaga CL: ErbB2/neu kinase modulates cellular p27(Kip1) and cyclin D1 through multiple signaling pathways. Cancer Res 2001;61:6583–6591.
111.
Franklin WA, Veve R, Hirsch FR, Helfrich BA, Bunn PA Jr: Epidermal growth factor receptor family in lung cancer and premalignancy. Semin Oncol 2002;29(1 suppl 4):3–14.
112.
Kurie JM, Shin HJ, Lee JS, Morice RC, Ro JY, Lippman SM, et al: Increased epidermal growth factor receptor expression in metaplastic bronchial epithelium. Clin Cancer Res 1996;2:1787–1793.
113.
Piyathilake CJ, Frost AR, Manne U, Weiss H, Bell WC, Heimburger DC, et al: Differential expression of growth factors in squamous cell carcinoma and precancerous lesions of the lung. Clin Cancer Res 2002;8:734–744.
114.
Rusch V, Baselga J, Cordon-Cardo C, Orazem J, Zaman M, Hoda S, et al: Differential expression of the epidermal growth factor receptor and its ligands in primary non-small cell lung cancers and adjacent benign lung. Cancer Res 1993;53(10 suppl):2379–2385.
115.
Tateishi M, Ishida T, Mitsudomi T, Kaneko S, Sugimachi K: Immunohistochemical evidence of autocrine growth factors in adenocarcinoma of the human lung. Cancer Res 1990;50:7077–7080.
116.
Schechter AL, Stern DF, Vaidyanathan L, Decker SJ, Drebin JA, Greene MI, et al: The neu oncogene: An erb-B-related gene encoding a 185,000-Mr tumour antigen. Nature 1984;312:513–516.
117.
Scheurle D, Jahanzeb M, Aronsohn RS, Watzek L, Narayanan R: HER-2/neu expression in archival non-small cell lung carcinomas using FDA-approved Hercep test. Anticancer Res 2000;20:2091–2096.
118.
Schneider PM, Hung MC, Chiocca SM, Manning J, Zhao XY, Fang K, et al: Differential expression of the c-erbB-2 gene in human small cell and non-small cell lung cancer. Cancer Res 1989;49:4968–4971.
119.
Meert AP, Martin B, Paesmans M, Berghmans T, Mascaux C, Verdebout JM, et al: The role of HER-2/neu expression on the survival of patients with lung cancer: A systematic review of the literature. Br J Cancer 2003;89:959–965.
120.
Hilbe W, Dlaska M, Duba HC, Dirnhofer S, Eisterer W, Oberwasserlechner F, et al: Automated real-time PCR to determine K-ras codon 12 mutations in non-small cell lung cancer: Comparison with immunohistochemistry and clinico-pathological features. Int J Oncol 2003;23:1121–1126.
121.
Rodenhuis S, van de Wetering ML, Mooi WJ, Evers SG, van Zandwijk N, Bos JL: Mutational activation of the K-ras oncogene. A possible pathogenetic factor in adenocarcinoma of the lung. N Engl J Med 1987;317:929–935.
122.
Rodenhuis S, Slebos RJ, Boot AJ, Evers SG, Mooi WJ, Wagenaar SS, et al: Incidence and possible clinical significance of K-ras oncogene activation in adenocarcinoma of the human lung. Cancer Res 1988;48:5738–5741.
123.
Noda N, Matsuzoe D, Konno T, Kawahara K, Yamashita Y, Shirakusa T: K-ras gene mutations in non-small cell lung cancer in Japanese. Oncol Rep 2001;8:889–892.
124.
Slebos RJ, Hruban RH, Dalesio O, Mooi WJ, Offerhaus GJ, Rodenhuis S: Relationship between K-ras oncogene activation and smoking in adenocarcinoma of the human lung. J Natl Cancer Inst 1991;83:1024–1027.
125.
Harada M, Dosaka-Akita H, Miyamoto H, Kuzumaki N, Kawakami Y: Prognostic significance of the expression of ras oncogene product in non-small cell lung cancer. Cancer 1992;69:72–77.
126.
Miyamoto H, Harada M, Isobe H, Akita HD, Haneda H, Yamaguchi E, et al: Prognostic value of nuclear DNA content and expression of the ras oncogene product in lung cancer. Cancer Res 1991;51:6346–6350.
127.
Schiller JH, Adak S, Feins RH, Keller SM, Fry WA, Livingston RB, Hammond ME, Wolf B, Sabatini L, Jett J, Kohman L, Johnson DH: Lack of prognostic significance of p53 and K-ras mutations in primary resected non-small-cell lung cancer on E4592: A Laboratory Ancillary Study on an Eastern Cooperative Oncology Group Prospective Randomized Trial of Postoperative Adjuvant Therapy. J Clin Oncol 2001;19:448–457.
128.
Broers JL, Viallet J, Jensen SM, Pass H, Travis WD, Minna JD, et al: Expression of c-myc in progenitor cells of the bronchopulmonary epithelium and in a large number of non-small cell lung cancers. Am J Respir Cell Mol Biol 1993;9:33–43.
129.
Albanell J, Lonardo F, Rusch V, Engelhardt M, Langenfeld J, Han W, et al: High telomerase activity in primary lung cancers: Association with increased cell proliferation rates and advanced pathologic stage. J Natl Cancer Inst 1997;89:1609–1615.
130.
Hara H, Yamashita K, Shinada J, Yoshimura H, Kameya T: Clinicopathologic significance of telomerase activity and hTERT mRNA expression in non-small cell lung cancer. Lung Cancer 2001;34:219–226.
131.
Hiyama K, Hiyama E, Ishioka S, Yamakido M, Inai K, Gazdar AF, et al: Telomerase activity in small-cell and non-small-cell lung cancers. J Natl Cancer Inst 1995;87:895–902.
132.
Kumaki F, Kawai T, Hiroi S, Shinomiya N, Ozeki Y, Ferrans VJ, et al: Telomerase activity and expression of human telomerase RNA component and human telomerase reverse transcriptase in lung carcinomas. Hum Pathol 2001;32:188–195.
133.
Xinarianos G, Scott FM, Liloglou T, Prime W, Callaghan J, Gosney JR, et al: Telomerase activity in non-small cell lung carcinomas correlates with smoking status. Int J Oncol 1999;15:961–965.
134.
Shibuya K, Fujisawa T, Hoshino H, Baba M, Saitoh Y, Iizasa T, et al: Increased telomerase activity and elevated hTERT mRNA expression during multistage carcinogenesis of squamous cell carcinoma of the lung. Cancer 2001;92:849–855.
135.
Yashima K, Litzky LA, Kaiser L, Rogers T, Lam S, Wistuba II, et al: Telomerase expression in respiratory epithelium during the multistage pathogenesis of lung carcinomas. Cancer Res 1997;57:2373–2377.
136.
Feng J, Funk WD, Wang SS, Weinrich SL, Avilion AA, Chiu CP, et al: The RNA component of human telomerase. Science 1995;269:1236–1241.
137.
Meyerson M, Counter CM, Eaton EN, Ellisen LW, Steiner P, Caddle SD, et al: hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell 1997;90:785–795.
138.
Nakayama J, Tahara H, Tahara E, Saito M, Ito K, Nakamura H, et al: Telomerase activation by hTRT in human normal fibroblasts and hepatocellular carcinomas. Nat Genet 1998;18:65–68.
139.
Steenbergen RD, Kramer D, Meijer CJ, Walboomers JM, Trott DA, Cuthbert AP, et al: Telomerase suppression by chromosome 6 in a human papillomavirus type 16-immortalized keratinocyte cell line and in a cervical cancer cell line. J Natl Cancer Inst 2001;93:865–872.
140.
Snijders PJ, Breuer RH, Sutedja TG, Egging M, Voorhorst FJ, Steenbergen RD, et al: Elevated hTERT mRNA levels: A potential determinant of bronchial squamous cell carcinoma (in situ). Int J Cancer 2004;109:412–417.
141.
Marchetti A, Bertacca G, Buttitta F, Chella A, Quattrocolo G, Angeletti CA, et al: Telomerase activity as a prognostic indicator in stage I non-small cell lung cancer. Clin Cancer Res 1999;5:2077–2081.
142.
Wang L, Soria JC, Kemp BL, Liu DD, Mao L, Khuri FR: hTERT expression is a prognostic factor of survival in patients with stage I non-small cell lung cancer. Clin Cancer Res 2002;8:2883–2889.
143.
Evan GI, Wyllie AH, Gilbert CS, Littlewood TD, Land H, Brooks M, et al: Induction of apoptosis in fibroblasts by c-myc protein. Cell 1992;69:119–128.
144.
Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW, et al: Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 1996;379:88–91.
145.
Hockenbery D, Nunez G, Milliman C, Schreiber RD, Korsmeyer SJ: Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 1990;348:334–336.
146.
Oltvai ZN, Milliman CL, Korsmeyer SJ: Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 1993;74:609–619.
147.
Apte SS, Mattei MG, Olsen BR: Mapping of the human BAX gene to chromosome 19q13.3-q13.4 and isolation of a novel alternatively spliced transcript, BAX delta. Genomics 1995;26:592–594.
148.
Apolinario RM, van der Valk P, de Jong JS, Deville W, van Ark-Otte J, Dingemans AM, van Mourik JC, Postmus PE, Pinedo HM, Giaccone G: Prognostic value of the expression of p53, bcl-2, and bax oncoproteins, and neovascularization in patients with radically resected non-small-cell lung cancer. J Clin Oncol 1997;15:2456–2466.
149.
Pezzella F, Turley H, Kuzu I, Tungekar MF, Dunnill MS, Pierce CB, et al: bcl-2 protein in non-small-cell lung carcinoma. N Engl J Med 1993;329:690–694.
150.
Chen Y, Sato M, Fujimura S, Endo C, Sakurada A, Aikawa H, et al: Expression of Bcl-2, Bax, and p53 proteins in carcinogenesis of squamous cell lung cancer. Anticancer Res 1999;19:1351–1356.
151.
Walker C, Robertson L, Myskow M, Dixon G: Expression of the BCL-2 protein in normal and dysplastic bronchial epithelium and in lung carcinomas. Br J Cancer 1995;72:164–169.
152.
Martin B, Paesmans M, Berghmans T, Branle F, Ghisdal L, Mascaux C, et al: Role of Bcl-2 as a prognostic factor for survival in lung cancer: A systematic review of the literature with meta-analysis. Br J Cancer 2003;89:55–64.
153.
Pastorino U, Andreola S, Tagliabue E, Pezzella F, Incarbone M, Sozzi G, et al: Immunocytochemical markers in stage I lung cancer: Relevance to prognosis. J Clin Oncol 1997;15:2858–2865.
154.
Tock B, Zwiebel JA, Schoenfeldt M: Clinical trials referral resource. Current clinical trials of G3139. Oncology (Huntingt) 2003;17:1244–1258.
155.
Ambrosini G, Adida C, Altieri DC: A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 1997;3:917–921.
156.
Deveraux QL, Roy N, Stennicke HR, Van Arsdale T, Zhou Q, Srinivasula SM, et al: IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. EMBO J 1998;17:2215–2223.
157.
Falleni M, Pellegrini C, Marchetti A, Oprandi B, Buttitta F, Barassi F, et al: Survivin gene expression in early-stage non-small cell lung cancer. J Pathol 2003;200:620–626.
158.
Hofmann HS, Simm A, Hammer A, Silber RE, Bartling B: Expression of inhibitors of apoptosis (IAP) proteins in non-small cell human lung cancer. J Cancer Res Clin Oncol 2002;128:554–560.
159.
Ikehara M, Oshita F, Kameda Y, Ito H, Ohgane N, Suzuki R, Saito H, Yamada K, Noda K, Mitsuda A: Expression of survivin correlated with vessel invasion is a marker of poor prognosis in small adenocarcinoma of the lung. Oncol Rep 2002;9:835–838.
160.
Monzo M, Rosell R, Felip E, Astudillo J, Sanchez JJ, Maestre J, et al: A novel anti-apoptosis gene: Re-expression of survivin messenger RNA as a prognosis marker in non-small-cell lung cancers. J Clin Oncol 1999;17:2100–2104.
161.
Achiwa H, Yatabe Y, Hida T, Kuroishi T, Kozaki K, Nakamura S, et al: Prognostic significance of elevated cyclooxygenase 2 expression in primary, resected lung adenocarcinomas. Clin Cancer Res 1999;5:1001–1005.
162.
Hasturk S, Kemp B, Kalapurakal SK, Kurie JM, Hong WK, Lee JS: Expression of cyclooxygenase-1 and cyclooxygenase-2 in bronchial epithelium and nonsmall cell lung carcinoma. Cancer 2002;94:1023–1031.
163.
Hida T, Yatabe Y, Achiwa H, Muramatsu H, Kozaki K, Nakamura S, et al: Increased expression of cyclooxygenase 2 occurs frequently in human lung cancers, specifically in adenocarcinomas. Cancer Res 1998;58:3761–3764.
164.
Khuri FR, Wu H, Lee JJ, Kemp BL, Lotan R, Lippman SM, et al: Cyclooxygenase-2 overexpression is a marker of poor prognosis in stage I non-small cell lung cancer. Clin Cancer Res 2001;7:861–867.
165.
Takahashi T, Kozaki K, Yatabe Y, Achiwa H, Hida T: Increased expression of COX-2 in the development of human lung cancers. J Environ Pathol Toxicol Oncol 2002;21:177–181.
166.
Wolff H, Saukkonen K, Anttila S, Karjalainen A, Vainio H, Ristimaki A: Expression of cyclooxygenase-2 in human lung carcinoma. Cancer Res 1998;58:4997–5001.
167.
El Bayoumy K, Iatropoulos M, Amin S, Hoffmann D, Wynder EL: Increased expression of cyclooxygenase-2 in rat lung tumors induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-4-(3-pyridyl)-1-butanone: The impact of a high-fat diet. Cancer Res 1999;59:1400–1403.
168.
Kelley DJ, Mestre JR, Subbaramaiah K, Sacks PG, Schantz SP, Tanabe T, et al: Benzo[a]pyrene up-regulates cyclooxygenase-2 gene expression in oral epithelial cells. Carcinogenesis 1997;18:795–799.
169.
Tsujii M, DuBois RN: Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell 1995;83:493–501.
170.
Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, DuBois RN: Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 1998;93:705–716.
171.
Tsujii M, Kawano S, DuBois RN: Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc Natl Acad Sci USA 1997;94:3336–3340.
172.
Sanchez-Alcazar JA, Bradbury DA, Pang L, Knox AJ: Cyclooxygenase (COX) inhibitors induce apoptosis in non-small cell lung cancer through cyclooxygenase independent pathways. Lung Cancer 2003;40:33–44.
173.
Altorki NK, Keresztes RS, Port JL, Libby DM, Korst RJ, Flieder DB, et al: Celecoxib, a selective cyclo-oxygenase-2 inhibitor, enhances the response to preoperative paclitaxel and carboplatin in early-stage non-small-cell lung cancer. J Clin Oncol 2003;21:2645–2650.
174.
Schreinemachers DM, Everson RB: Aspirin use and lung, colon, and breast cancer incidence in a prospective study. Epidemiology 1994;5:138–146.
175.
Sorensen HT, Friis S, Norgard B, Mellemkjaer L, Blot WJ, McLaughlin JK, et al: Risk of cancer in a large cohort of nonaspirin NSAID users: A population-based study. Br J Cancer 2003;88:1687–1692.
176.
Fontanini G, Lucchi M, Vignati S, Mussi A, Ciardiello F, De Laurentiis M, et al: Angiogenesis as a prognostic indicator of survival in non-small-cell lung carcinoma: A prospective study. J Natl Cancer Inst 1997;89:881–886.
177.
Fontanini G, Faviana P, Lucchi M, Boldrini L, Mussi A, Camacci T, et al: A high vascular count and overexpression of vascular endothelial growth factor are associated with unfavourable prognosis in operated small cell lung carcinoma. Br J Cancer 2002;86:558–563.
178.
Shweiki D, Itin A, Soffer D, Keshet E: Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 1992;359:843–845.
179.
Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z: Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 1999;13:9–22.
180.
Rak J, Mitsuhashi Y, Bayko L, Filmus J, Shirasawa S, Sasazuki T, et al: Mutant ras oncogenes upregulate VEGF/VPF expression: Implications for induction and inhibition of tumor angiogenesis. Cancer Res 1995;55:4575–4580.
181.
Shibusa T, Shijubo N, Abe S: Tumor angiogenesis and vascular endothelial growth factor expression in stage I lung adenocarcinoma. Clin Cancer Res 1998;4:1483–1487.
182.
Shijubo N, Uede T, Kon S, Maeda M, Segawa T, Imada A, et al: Vascular endothelial growth factor and osteopontin in stage I lung adenocarcinoma. Am J Respir Crit Care Med 1999;160:1269–1273.
183.
Volm M, Koomagi R, Mattern J: Prognostic value of vascular endothelial growth factor and its receptor Flt-1 in squamous cell lung cancer. Int J Cancer 1997;74:64–68.
184.
Ohta Y, Watanabe Y, Murakami S, Oda M, Hayashi Y, Nonomura A, et al: Vascular endothelial growth factor and lymph node metastasis in primary lung cancer. Br J Cancer 1997;76:1041–1045.
185.
Fontanini G, Calcinai A, Boldrini L, Lucchi M, Mussi A, Angeletti CA, et al: Modulation of neoangiogenesis in bronchial preneoplastic lesions. Oncol Rep 1999;6:813–817.
186.
Keith RL, Miller YE, Gemmill RM, Drabkin HA, Dempsey EC, Kennedy TC, et al: Angiogenic squamous dysplasia in bronchi of individuals at high risk for lung cancer. Clin Cancer Res 2000;6:1616–1625.
187.
Sporn MB: The war on cancer. Lancet 1996;347:1377–1381.
188.
John A, Tuszynski G: The role of matrix metalloproteinases in tumor angiogenesis and tumor metastasis. Pathol Oncol Res 2001;7:14–23.
189.
Kanno N, Nonomura N, Miki T, Kojima Y, Takahara S, Nozaki M, et al: Effects of epidermal growth factor on the invasion activity of the bladder cancer cell line. J Urol 1998;159:586–590.
190.
Lamoreaux WJ, Fitzgerald ME, Reiner A, Hasty KA, Charles ST: Vascular endothelial growth factor increases release of gelatinase A and decreases release of tissue inhibitor of metalloproteinases by microvascular endothelial cells in vitro. Microvasc Res 1998;55:29–42.
191.
Giordano TJ, Shedden KA, Schwartz DR, Kuick R, Taylor JM, Lee N, et al: Organ-specific molecular classification of primary lung, colon, and ovarian adenocarcinomas using gene expression profiles. Am J Pathol 2001;159:1231–1238.
192.
Bhattacharjee A, Richards WG, Staunton J, Li C, Monti S, Vasa P, et al: Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proc Natl Acad Sci USA 2001;98:13790–13795.
193.
Garber ME, Troyanskaya OG, Schluens K, Petersen S, Thaesler Z, Pacyna-Gengelbach M, et al: Diversity of gene expression in adenocarcinoma of the lung. Proc Natl Acad Sci USA 2001;98:13784–13789.
194.
Kikuchi T, Daigo Y, Katagiri T, Tsunoda T, Okada K, Kakiuchi S, et al: Expression profiles of non-small cell lung cancers on cDNA microarrays: Identification of genes for prediction of lymph-node metastasis and sensitivity to anti-cancer drugs. Oncogene 2003;22:2192–2205.
195.
Virtanen C, Ishikawa Y, Honjoh D, Kimura M, Shimane M, Miyoshi T, et al: Integrated classification of lung tumors and cell lines by expression profiling. Proc Natl Acad Sci USA 2002;99:12357–12362.
196.
Li C, Chen Z, Xiao Z, Wu X, Zhan X, Zhang X, et al: Comparative proteomics analysis of human lung squamous carcinoma. Biochem Biophys Res Commun 2003;309:253–260.
197.
Yanagisawa K, Shyr Y, Xu BJ, Massion PP, Larsen PH, White BC, et al: Proteomic patterns of tumour subsets in non-small-cell lung cancer. Lancet 2003;362:433–439.
198.
Zhukov TA, Johanson RA, Cantor AB, Clark RA, Tockman MS: Discovery of distinct protein profiles specific for lung tumors and pre-malignant lung lesions by SELDI mass spectrometry. Lung Cancer 2003;40:267–279.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.