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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2009, Vol. 3 Issue (3) : 245-255     DOI: 10.1007/s11684-009-0044-3
Research articles |
Molecular markers and pathogenically targeted therapy in non-small cell lung cancer
Bo PENG BA 1, Jinnong ZHANG MD 2, Jamile S. WOODS MD 3, Wei PENG MD, PhD 3, 4,
1.College of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA; 2.Pulmonary Division of Union Hospital, Huazhong University of Science and Technology, Wuhan 430022, China; 3.Department of Pulmonary and Critical Care Medicine, Salt Lake Regional Medical Center, Iasis Healthcare, UT 84102, USA; 4.2009-10-29 14:44:41;
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Abstract  Lung cancer is one of the most common human cancers and the number one cancer killer in the United States. In general, lung cancer includes small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), but NSCLC accounts for approximately 90% of lung cancer. The early diagnosis and therapy of lung cancer still presents a big challenge because validated screening tools, which can improve current early detection to reduce mortality from lung cancer, do not exist. Over the last decade, molecular genetic abnormalities have been described in NSCLC, including chromosomal aberrations, overexpression of oncogenes, and deletion and/or mutations in tumor suppressor genes. These molecular markers in NSCLC demonstrated close associations with the development of lung cancer such as Ras, the epidermal growth factor receptor (EGFR, or c-erbB-1), HER2 (c-erbB-2), c-Met, and Bcl-2. Therefore, this information may be applied for early cancer detection, classification, novel targeted therapy, and prognosis in NSCLC. Recent clinical data have revealed that targeted therapy might be the second-line therapy as an alternative approach. Currently, the targeted therapies are mainly focused on two lung cancer pathways, the EGFR and the vascular endothelial growth factor (VEGF) pathways. Some clinical trials are very encouraging, but some of them are not. However, these trials have not identified a subgroup of NSCLC with biomarkers. Therefore, it is very important to select NSCLC patients with biomarkers to match targeted agents so that we can further identify effectiveness of targeted therapy in the future.
Keywords lung cancer      carcinoma, non-small cell lung cancer      molecular markers      targeted therapy      
Issue Date: 05 September 2009
URL:     OR
Parkin D M, Bray F, Ferlay J, Pisani P. Globalcancer statistics, 2002. CA Cancer J Clin, 2005, 55(2): 74―108

doi: 10.3322/canjclin.55.2.74
Alberg A J, Samet J M. Epidemiology of lung cancer. Chest, 2003, 123: 21S

doi: 10.1378/chest.123.1_suppl.21S
Zang E A, Wynder E L. Differences in lung cancerrisk between men and women: examination of the evidence. J Natl Cancer Inst, 1996, 88(34): 183―192

doi: 10.1093/jnci/88.3-4.183
Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun M J. Cancer statistics, 2008. CA Cancer J Clin, 2008, 58(2): 71―96

doi: 10.3322/CA.2007.0010
Molina J R, Adjei A A, Jett J R. Advances in chemotherapy of non-small cell lung cancer. Chest, 2006, 130(4): 1211―1219

doi: 10.1378/chest.130.4.1211
Mariadason J M, Augenlicht L H, Arango D. Microarray analysis in the clinical management of cancer. Hematol Oncol Clin North Am, 2003, 17(2): 377―387

doi: 10.1016/S0889-8588(03)00006-6
Anglim P P, Alonzo T A, Laird-Offringa I A. DNA methylation-based biomarkers forearly detection of non-small cell lung cancer: an update. Mol Cancer, 2008, 7: 81

doi: 10.1186/1476-4598-7-81
Mountain C F. New prognostic factors in lung cancer. Biologic prophets of cancercell aggression. Chest, 1995, 108(1): 246―254

doi: 10.1378/chest.108.1.246
Salgia R, Skarin A T. Molecular abnormalities inlung cancer. J Clin Oncol, 1998, 16(3): 1207―1217
Strauss G M, Kwiatkowski D J, Harpole D H, Lynch T J, Skarin A T, Sugarbaker D J. Molecular and pathologic markers in stage I non-small cell carcinomaof the lung. J Clin Oncol, 1995, 13(5): 1265―1279
Rosell R, Felip E, Garcia-Campelo R, Balana C. Thebiology of non-small-cell lung cancer: identifying new targets forrational therapy. Lung Cancer, 2004, 46(2): 135―148

doi: 10.1016/j.lungcan.2004.04.031
Devereux T R, Taylor J A, Barrett J C. Molecular mechanisms of lung cancer. Interaction of environmentaland genetic factors. Giles F. Filley Lecture.Chest, 1996, 109(3 Suppl): 14S―19S

doi: 10.1378/chest.109.3_Supplement.14S
Killary A M, Wolf M E, Giambernardi T A, Naylor S L. Definition of a tumor suppressor locus within human chromosome 3p21-p22. Proc Natl Acad Sci USA, 1992, 89(22): 10877―10881

doi: 10.1073/pnas.89.22.10877
Otterson G, Lin A, Kay F. Genetic etiology of lung cancer. Oncology (Huntingt), 1992, 6(9): 97―104, 107; discussion 108,111―112
Hirao T, Nelson H H, Ashok T D, Wain J C, Mark E J, Christiani D C, Wiencke J K, Kelsey K T. Tobacco smoke-induced DNA damage and an early age ofsmoking initiation induce chromosome loss at 3p21 in lung cancer. Cancer Res, 2001, 61(2): 612―615
Hibi, K, Takahashi, T, Yamakawa, K, Ueda R, Sekido Y, Ariyoshi Y, Suyama M, Takagi H, Nakamura Y, Takahashi T. Three distinct regions involvedin 3p deletion in human lung cancer. Oncogene, 1992, 7: 445―449
Hibi K, Takahashi T, Yamakawa K, Ueda R, Sekido Y, Ariyoshi Y, Suyama M, Takagi H, Nakamura Y, Takahashi T. Deletion mapping of the shortarm of chromosome 8 in non-small cell lung carcinoma. Genes Chromosomes Cancer, 1993, 7(3): 85―88
Nakachi K, Imai K, Hayashi S, Watanabe J, Kawajiri K. Genetic susceptibility tosquamous cell carcinoma of the lung in relation to cigarette smokingdose. Cancer Res, 1991, 51(19): 5177―5180
Ambrosone C B, Rao U, Michalek A M, Cummings K M, Mettlin C J. Lung cancer histologic typesand family history of cancer. Analysis of histologic subtypes of 872patients with primary lung cancer. Cancer, 1993, 72(4): 1192―1198

doi: 10.1002/1097-0142(19930815)72:4<1192::AID-CNCR2820720410>3.0.CO;2-S
Slebos R J, Kibbelaar R E, Dalesio O, Kooistra A, Stam J, Meijer C J, Wagenaar S S, Vanderschueren RG, van Zandwijk N, Mooi W J. K-ras oncogene activation as a prognostic marker in adenocarcinomaof the lung. N Engl J Med, 1990, 323(9): 561―565
Rodenhuis S, Slebos R J. Clinical significance ofras oncogene activation in human lung cancer. Cancer Res, 1992, 52(Suppl): 2665―2669
Graziano S L, Gamble G P, Newman N B, Abbott L Z, Rooney M, Mookherjee S, Lamb M L, Kohman L J, Poiesz B J. Prognostic significance of K-ras codon 12 mutations in patients withresected stage I and II non-small-cell lung cancer. J Clin Oncol, 1999, 17(2): 668―675
Graziano S L, Gamble G P, Newman N B, Abbott L Z, Rooney M, Mookherjee S, Lamb M L, Kohman L J, Poiesz B J. Cigarette smoking is strongly associated with mutation of the k-rasgene in patients with primary adenocarcinomaof the lung. Cancer, 2001, 92(6): 1525―1530

doi: 10.1002/1097-0142(20010915)92:6<1525::AID-CNCR1478>3.0.CO;2-H
Velu T J, Beguinot L, Vass W C, Willingham M C, Merlino G T, Pastan I, Lowy D R. Epidermal-growth-factor-dependenttransformation by a human EGF receptor proto-oncogene. Science, 1987, 238(4832): 1408―1410

doi: 10.1126/science.3500513
To C T, Tsao M S. The roles of hepatocyte growthfactor/scatter factor and met receptor in human cancers (Review). Oncol Rep, 1998, 5(5): 1013―1024
Ichimura, E, Maeshima, A, Nakajima, T, Nakamura, T. Expressionof c-met/HGF receptor in human non-small cell lung carcinomas in vitroand in vivo and its prognostic significance. Jpn J Cancer Res, 1996, 87(10): 1063―1069
Hockenbery D, Nuñez G, Milliman C, Schreiber R D, Korsmeyer S J. Bcl-2 is an inner mitochondrialmembrane protein that blocks programmed cell death. Nature, 1990, 348(6299): 334―336

doi: 10.1038/348334a0
Anton R C, Brown R W, Younes M, Gondo M M, Stephenson M A, Cagle P T. Absence of prognostic significance of bcl-2 immunopositivityin non-small cell lung cancer: analysis of 427 cases. Hum Pathol, 1997, 28(9): 1079―1082

doi: 10.1016/S0046-8177(97)90062-9
Ohmura Y, Aoe M, Andou A, Shimizu N. Telomeraseactivity and Bcl-2 expression in non-small cell lung cancer. Clin Cancer Res, 2000, 6(8): 2980―2987
Laudanski J, Chyczewski L, Niklinska W E, Kretowska M, Furman M, Sawicki B, Niklinski J. Expressionof bcl-2 protein in non-small cell lung cancer: correlation with clinicopathologyand patient survival. Neoplasma, 1999, 46(1): 25―30
Groeger A M, Caputi M, Esposito V, De Luca A, Salat A, Murabito M, Giordano G G, Baldi F, Giordano A, Wolner E. Bcl-2protein expression correlates with nodal status in non small celllung cancer. Anticancer Res, 1999, 19(1B): 821―824
Pezzella F, Turley H, Kuzu I, Tungekar M F, Dunnill M S, Pierce C B, Harris A, Gatter K C, Mason D Y. bcl-2 protein in non-small cell lung carcinoma. N Engl J Med, 1993, 329(10): 690―694

doi: 10.1056/NEJM199309023291003
Silvestrini R, Costa A, Lequaglie C, Mochen C, Veneroni S, Leutner M, Ravasi G. Bcl-2protein and prognosis in patients with potentially curable non-small-celllung cancer. Virchows Arch, 1998, 432(5): 441―444

doi: 10.1007/s004280050188
Huang C I, Neuberg D, Johnson B E, Wei J Y, Christiani D C. Expression of bcl-2 proteinis associated with shorter survival in nonsmall cell lung carcinoma. Cancer, 2003, 98(1): 135―143

doi: 10.1002/cncr.11461
Sharp T V, Munoz F, Bourboulia D, Presneau N, Darai E, Wang H W, Cannon M, Butcher D N, Nicholson A G, Klein G, Imreh S, Boshoff C. LIMdomains-containing protein 1 (LIMD1), a tumor suppressor encoded atchromosome 3p21.3, binds pRB and represses E2F-driven transcription. Proc Natl Acad Sci USA, 2004, 101(47): 16531―16536

doi: 10.1073/pnas.0407123101
Zhang S Y, Liu S C, Johnson D G, Klein-Szanto A J. E2F-1 gene transfer enhances invasiveness of human head and neckcarcinoma cell lines. Cancer Res, 2000, 60(21): 5972―5976
Banerjee D, Gorlick R, Liefshitz A, Danenberg K, Danenberg P C, Danenberg P V, Klimstra D, Jhanwar S, Cordon-Cardo C, Fong Y, Kemeny N, Bertino J R. Levels of E2F-1 expression are higher in lung metastasis of coloncancer as compared with hepatic metastasis and correlate with levelsof thymidylate synthase. Cancer Res, 2000, 60(9): 2365―2367
Lane D P. Cancer. p53, guardian of the genome. Nature, 1992, 358(6381): 15―16

doi: 10.1038/358015a0
Tsao M S, Aviel-Ronen S, Ding K, Lau D, Liu N, Sakurada A, Whitehead M, Zhu C Q, Livingston R, Johnson D H, Rigas J, Seymour L, Winton T, Shepherd F A. Prognostic and predictive importance of p53 and RAS foradjuvant chemotherapy in non small-cell lung cancer. J Clin Oncol, 2007, 25(33): 5240―5247

doi: 10.1200/JCO.2007.12.6953
Knudson A G Jr. The ninth Gordon Hamilton-Fairley memorial lecture. Hereditary cancers:clues to mechanisms of carcinogenesis. Br J Cancer, 1989, 59(5): 661―666
Xu H J, Quinlan D C, Davidson A G, Hu S X, Summers C L, Li J, Benedict W F. Altered retinoblastoma proteinexpression and prognosis in early-stage non-small-cell lung carcinoma. J Natl Cancer Inst, 1994, 86(9): 695―699

doi: 10.1093/jnci/86.9.695
Xu H J, Cagle P T, Hu S X, Li J, Benedict W F. Altered retinoblastoma andp53 protein status in non-small cell carcinoma of the lung: potentialsynergistic effects on prognosis. ClinCancer Res, 1996, 2(7): 1169―1176
Shapiro G I, Rollins B J. p16INK4A as a human tumorsuppressor. Biochim Biophys Acta, 1996, 18; 1242(3): 165―169
Hannon G J, Beach D. p15INK4B is a potential effectorof TGF-beta-induced cell cycle arrest. Nature, 1994, 371(6494): 257―261

doi: 10.1038/371257a0
Shapiro G I, Edwards C D, Kobzik L, Godleski J, Richards W, Sugarbaker D J, Rollins B J. Reciprocal Rb inactivation and p16INK4 expression in primary lungcancers and cell lines. Cancer Res, 1995, 55(3): 505―509
Kratzke R A, Greatens T M, Rubins J B, Maddaus M A, Niewoehner D E, Niehans G A, Geradts J. Rband p16INK4a expression in resected non-small cell lung tumors. Cancer Res, 1996, 56(15): 3415―3420
Gonzalez-Quevedo R, Iniesta P, Moran A, de Juan C, Sanchez-Pernaute A, Fernandez C, Torres A, Diaz-Rubio E, Balibrea J L, Benito M. Cooperativerole of telomerase activity and p16 expression in the prognosis ofnon-small-cell lung cancer. J Clin Oncol, 2002, 20(1): 254―262

doi: 10.1200/JCO.20.1.254
Gautam A, Li Z R, Bepler G. RRM1-induced metastasis suppression through PTEN-regulatedpathways. Oncogene, 2003, 22(14): 2135―2142

doi: 10.1038/sj.onc.1206232
Zheng Z, Chen T, Li X, Haura E, Sharma A, Bepler G. DNAsynthesis and repair genes RRM1 and ERCC1 in lung cancer. N Engl J Med, 2007, 356(8): 800―808

doi: 10.1056/NEJMoa065411
Ohta Y, Nozaki Z, Nozawa H, Kamesui T, Tsunezuka Y, Oda M, Watanabe G. Thepredictive value of vascular endothelial growth factor and nm23 forthe diagnosis of occult metastasis in non-small cell lung cancer. Jpn J Cancer Res, 2001, 92(3): 361―366
Tomita M, Ayabe T, Matsuzaki Y, Onitsuka T. Immunohistochemicalanalysis of nm23-H1 gene product in node-positive lung cancer andlymph nodes. Lung Cancer, 1999, 24(1): 11―16

doi: 10.1016/S0169-5002(99)00018-5
Higashiyama M, Taki T, Ieki Y, Adachi M, Huang C L, Koh T, Kodama K, Doi O, Miyake M. Reduced motility related protein-1 (MRP-1/CD9) gene expressionas a factor of poor prognosis in non-small cell lung cancer. Cancer Res, 1995, 55(24): 6040―6044
Lau L F, Lam S C. The CCN family of angiogenicregulators: the integrin connection. ExpCell Res, 1999, 248(1): 44―57

doi: 10.1006/excr.1999.4456
Chen N, Leu S J, Todorovic V, Lam S C, Lau L F. Identification of a novel integrin alphavbeta3binding site in CCN1 (CYR61) critical for pro-angiogenic activitiesin vascular endothelial cells. J Biol Chem, 2004, 279(42): 44166―44176

doi: 10.1074/jbc.M406813200
Xie D, Yin D, Wang H J, Liu G T, Elashoff R, Black K, Koeffler H P. Levels of expression of CYR61and CTGF are prognostic for tumor progression and survival of individualswith gliomas. Clin Cancer Res, 2004, 10(6): 2072―2081

doi: 10.1158/1078-0432.CCR-0659-03
Chen C C, Chen N, Lau L F. The angiogenic factors Cyr61 and connective tissue growthfactor induce adhesive signaling in primary human skin fibroblasts. J Biol Chem, 2001, 276(13): 10443―10452

doi: 10.1074/jbc.M008087200
Tong X, Xie D, O'Kelly J, Miller C W, Muller-Tidow C, Koeffler H P. Cyr61, a member of CCN family, is a tumor suppressorin non-small cell lung cancer. J Biol Chem, 2001, 276(50): 47709―47714

doi: 10.1074/jbc.M107878200
Chang C C, Shih J Y, Jeng Y M, Su J L, Lin B Z, Chen S T, Chau Y P, Yang P C, Kuo M L. Connectivetissue growth factor and its role in lung adenocarcinoma invasionand metastasis. J Natl Cancer Inst, 2004, 96(5): 364―375
Shih J Y, Yang S C, Hong T M, Yuan A, Chen J J, Yu C J, Chang Y L, Lee Y C, Peck K, Wu C W, Yang P C. Collapsin response mediator protein-1 and the invasion and metastasisof cancer cells. J Natl Cancer Inst, 2001, 93(18): 1392―1400

doi: 10.1093/jnci/93.18.1392
Pérez-Soler R, Chachoua A, Hammond L A, Rowinsky E K, Huberman M, Karp D, Rigas J, Clark G M, Santabárbara P, Bonomi P. Determinants of tumor responseand survival with erlotinib in patients with non-small-cell lung cancer. J Clin Oncol, 2004, 22(16), 3238―3247

doi: 10.1200/JCO.2004.11.057
Jackman D M, Yeap B Y, Lindeman N I, Fidias P, Rabin M S, Temel J, Skarin A T, Meyerson M, Holmes A J, Borras A M, Freidlin B, Ostler P A, Lucca J, Lynch T J, Johnson B E, Jänne P A. Phase II clinical trial ofchemotherapy-naive patients>or= 70 years of age treated with erlotinibfor advanced non-small-cell lung cancer. J Clin Oncol, 2007, 25(7): 760―766

doi: 10.1200/JCO.2006.07.5754
Shepherd F A, Rodrigues Pereira J, Ciuleanu T, Tan E H, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, van Kooten M, Dediu M, Findlay B, Tu D, Johnston D, Bezjak A, Clark G, Santabárbara P, Seymour L; NationalCancer Institute of Canada Clinical Trials Group. Erlotinib in previouslytreated non-small-cell lung cancer. N EnglJ Med, 2005, 353(2): 123―132

doi: 10.1056/NEJMoa050753
Herbst R S, Prager D, Hermann R, Fehrenbacher L, Johnson B E, Sandler A, Kris M G, Tran H T, Klein P, Li X, Ramies D, Johnson D H, Miller V A; TRIBUTE Investigator Group.TRIBUTE: A phase III trial of erlotinib hydrochloride (OSI-774) combinedwith carboplatin and paclitaxel chemotherapy in advanced non-small-celllung cancer. J Clin Oncol, 2005, 23(25): 5892―5899

doi: 10.1200/JCO.2005.02.840
Gatzemeier U, Pluzanska A, Szczesna Aet al. Results of a phase III trial of erlotinib(OSI-774) combined with cisplatin and GC chemotherapy in advancednon-small cell lung cancer (NSCLC). J ClinOncol, 2004, 22(suppl 14): 619s
Giaccone G, Herbst R S, Manegold C, Scagliotti G, Rosell R, Miller V, Natale R B, Schiller J H, Von Pawel J, Pluzanska A, Gatzemeier U, Grous J, Ochs J S, Averbuch S D, Wolf M K, Rennie P, Fandi A, Johnson D H. Gefitinib in combination with gemcitabine and cisplatinin advanced non-small-cell lung cancer: a phase III trial--INTACT1. J Clin Oncol, 2004, 22(5): 777―784

doi: 10.1200/JCO.2004.08.001
Herbst R S, Giaccone G, Schiller J H, Natale R B, Miller V, Manegold C, Scagliotti G, Rosell R, Oliff I, Reeves J A, Wolf M K, Krebs A D, Averbuch S D, Ochs J S, Grous J, Fandi A, Johnson D H. Gefitinib in combination with paclitaxeland carboplatin in advanced non-small-cell lung cancer: A phase IIItrial–INTACT 2. J Clin Oncol, 2004, 22(5): 785―794

doi: 10.1200/JCO.2004.07.215
Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard J Y, Nishiwaki Y, Vansteenkiste J, Kudoh S, Rischin D, Eek R, Horai T, Noda K, Takata I, Smit E, Averbuch S, Macleod A, Feyereislova A, Dong R P, Baselga J. Multi-institutional randomized Phase II trial of gefitinibfor previously treated patients with advanced nonsmall-cell lung cancer(The IDEAL 1 Trial) [corrected]. J ClinOncol, 2003, 21(12): 2237―2246

doi: 10.1200/JCO.2003.10.038
Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, Thongprasert S, Tan E H, Pemberton K, Archer V, Carroll K. Gefitinib plus best supportivecare in previously treated patients with refractory advanced non-small-celllung cancer: results from a randomized, placebo-controlled, multicentrestudy (Iressa Survival Evaluation in Lung Cancer). Lancet, 2005, 366(6496): 1527―1537

doi: 10.1016/S0140-6736(05)67625-8
Hanna N, Lilenbaum R, Ansari R, Lynch T, Govindan R, Jänne P A, Bonomi P. Phase II trial of cetuximabin patients with previously treated non-small-cell lung cancer. J Clin Oncol, 2006, 24(33): 5253―5258

doi: 10.1200/JCO.2006.08.2263
Pirker R, Szczesna A, von Pawel J, Krzakowski M, Ramlau R, Park K, Gatzemeier U, Bajeta E, Emig M, Pereira J R. A randomized, multicenter, phase III study of cetuximab in combinationwith cisplatin/vinorelbine (CV) versus CV alone in the first-linetreatment of patients with advanced non-small cell lung cancer (NSCLC). J Clin Oncol (Suppl), 2008, 26(15S): 3
Socinski M A. Antibodies to the epidermal growth factor receptor in non–smallcell lung cancer: current status of matuzumab and panitumumab. Clinical Cancer Research, 2007, (13): 4597s―4601s

doi: 10.1158/1078-0432.CCR-07-0335
Sandler A, Gray R, Perry M C, Brahmer J, Schiller J H, Dowlati A, Lilenbaum R, Johnson D H. Paclitaxel-carboplatin aloneor with bevacizumab for non-small-cell lung cancer. N Engl J Med, 2006, 355(24): 2542―2550

doi: 10.1056/NEJMoa061884
Johnson D H, Fehrenbacher L, Novotny W F, Herbst R S, Nemunaitis J J, Jablons D M, Langer C J, DeVore R F 3rd, Gaudreault J, Damico L A, Holmgren E, Kabbinavar F. Randomized phase II trial comparing bevacizumab pluscarboplatin and paclitaxel with carboplatin and paclitaxel alone inpreviously untreated locally advanced or metastatic non-small-celllung cancer. J Clin Oncol, 2004, 22(11): 2184―2191

doi: 10.1200/JCO.2004.11.022
Socinski M A, Novello S, Sanchez J M. Efficacy and safety of sunitinib in previously treated,advanced non-small cell lung cancer (NSCLC): Preliminary results ofa multicenter phase II trial. J Clin Oncol, 2006, 24(18S): 7001
Tateishi M, Ishida T, Mitsudomi T, Kaneko S, Sugimachi K. Prognostic value of c-erbB-2protein expression in human lung adenocarcinoma and squamous cellcarcinoma. Eur J Cancer, 1991, 27(11): 1372―1375
Shi D, He G, Cao S, Pan W, Zhang H Z, Yu D, Hung M C. Overexpression of the c-erbB-2/neu-encodedp185 protein in primary lung cancer. MolCarcinog, 1992, 5(3): 213―218

doi: 10.1002/mc.2940050308
Harpole D H Jr, Herndon J E 2nd, Wolfe W G, Iglehart J D, Marks J R. A prognostic model of recurrenceand death in stage I non-small cell lung cancer utilizing presentation,histopathology, and oncoprotein expression. Cancer Res, 1995, 55(1): 51―56
Hsieh C C, Chow K C, Fahn H J, Tsai C M, Li W Y, Huang M H, Wang L S. Prognostic significance ofHER-2/neu overexpression in stage I adenocarcinoma of lung. Ann Thorac Surg, 1998, 66(4): 1159―1163

doi: 10.1016/S0003-4975(98)00792-9
Cantero R, Torres A J, Maestro M L, Hernando F, Sanz M T, Del Barco V, Gomez A, Fernandez C, Balibrea J L. Prognostic value of the quantified expression of p185 in non-smallcell lung cancer. J Thorac Cardiovasc Surg, 2000, 119(6): 1119―1125

doi: 10.1067/mtc.2000.105211
Ardizzoni A, Cafferata M A, Paganuzzi M, Filiberti R, Marroni P, Neri M, Fontana V, Nicolo G, Perdelli L, Stampino C G, Rosso R, Puntoni R. Study of pretreatment serum levels of HER-2/neu oncoproteinas a prognostic and predictive factor in patients with advanced nonsmallcell lung carcinoma. Cancer, 2001, 92(7): 1896―1904

doi: 10.1002/1097-0142(20011001)92:7<1896::AID-CNCR1707>3.0.CO;2-0
Kase S, Sugio K, Yamazaki K, Okamoto T, Yano T, Sugimachi K. Expression of E-cadherin and beta-catenin in human non-smallcell lung cancer and the clinical significance. Clin Cancer Res, 2000, 6(12): 4789―4796
Hommura F, Furuuchi K, Yamazaki K, Ogura S, Kinoshita I, Shimizu M, Moriuchi T, Katoh H, Nishimura M, Dosaka-Akita H. Increased expression of beta-cateninpredicts better prognosis in nonsmall cell lung carcinomas. Cancer, 2002, 94(3): 752―758

doi: 10.1002/cncr.10213
Bremnes R M, Veve R, Gabrielson E, Hirsch F R, Baron A, Bemis L, Gemmill R M, Drabkin H A, Franklin W A. High-throughput tissue microarray analysis used to evaluatebiology and prognostic significance of the E-cadherin pathway in non-small-celllung cancer. J Clin Oncol, 2002, 20(10): 2417―2428

doi: 10.1200/JCO.2002.08.159
Burbee D G, Forgacs E, Zochbauer-Muller S, Shivakumar L, Fong K, Gao B, Randle D, Kondo M, Virmani A, Bader S, Sekido Y, Latif F, Milchgrub S, Toyooka S, Gazdar A F, Lerman M I, Zabarovsky E, White M, Minna J D. Epigenetic inactivation of RASSF1A inlung and breast cancers and malignant phenotype suppression. J Natl Cancer Inst, 2001, 93(9): 691―699

doi: 10.1093/jnci/93.9.691
Dammann R, Li C, Yoon J H, Chin P L, Bates S, Pfeifer G P. Epigenetic inactivation of a RAS association domain family proteinfrom the lung tumour suppressor locus 3p21.3. Nat Genet, 2000, 25(3): 315―319

doi: 10.1038/77083
Maruyama R, Sugio K, Yoshino I, Maehara Y, Gazdar A F. Hypermethylation of FHITas a prognostic marker in nonsmall cell lung carcinoma. Cancer, 2004, 100(7): 1472―1477

doi: 10.1002/cncr.20144
Huncharek M, Muscat J, Geschwind J F. K-ras oncogene mutation as a prognostic marker in non-smallcell lung cancer: a combined analysis of 881 cases. Carcinogenesis, 1999, 20: 1507―1510

doi: 10.1093/carcin/20.8.1507
Higashiyama M, Kodama K, Yokouchi H, Takami K, Adachi M, Taki T, Ishiguro S, Nakamori S, Yoshie O, Miyake M. KAI1/CD82expression in nonsmall cell lung carcinoma is a novel, favorable prognosticfactor: an immunohistochemical analysis. Cancer, 1998, 83(3): 466―474

doi: 10.1002/(SICI)1097-0142(19980801)83:3<466::AID-CNCR15>3.0.CO;2-U
Takaoka A, Hinoda Y, Satoh S, Adachi Y, Itoh F, Adachi M, Imai K. Suppressionof invasive properties of colon cancer cells by a metastasis suppressorKAI1 gene. Oncogene, 1998, 16(11): 1443―1453

doi: 10.1038/sj.onc.1201648
[1] Alexandra Urman,H. Dean Hosgood. Curbing the burden of lung cancer[J]. Front. Med., 2016, 10(2): 228-232.
[2] Li Bian,Yonghua Ruan,Liju Ma,Hairong Hua,Li Zhou,Xiaoyu Tuo,Zheyan Zhou,Ting Li,Shiyue Liu,Kewei Jin. Pathogenesis sequences in Gejiu miners with lung cancer: an introduction[J]. Front. Med., 2015, 9(3): 344-349.
[3] Peter B. Alexander,Xiao-Fan Wang. Resistance to receptor tyrosine kinase inhibition in cancer: molecular mechanisms and therapeutic strategies[J]. Front. Med., 2015, 9(2): 134-138.
[4] Douglas D. Fang, Joan Cao, Jitesh P. Jani, Konstantinos Tsaparikos, Alessandra Blasina, Jill Kornmann, Maruja E. Lira, Jianying Wang, Zuzana Jirout, Justin Bingham, Zhou Zhu, Yin Gu, Gerrit Los, Zdenek Hostomsky, Todd VanArsdale. Combined gemcitabine and CHK1 inhibitor treatment induces apoptosis resistance in cancer stem cell-like cells enriched with tumor spheroids from a non-small cell lung cancer cell line[J]. Front Med, 2013, 7(4): 462-476.
[5] Li Shang, Mingrong Wang. Molecular alterations and clinical relevance in esophageal squamous cell carcinoma[J]. Front Med, 2013, 7(4): 401-410.
[6] Yue Yu, Jie He. Molecular classification of non-small-cell lung cancer: diagnosis, individualized treatment, and prognosis[J]. Front Med, 2013, 7(2): 157-171.
[7] Yize Xiao, Ying Shao, Xianjun Yu, Guangbiao Zhou. The epidemic status and risk factors of lung cancer in Xuanwei City, Yunnan Province, China[J]. Front Med, 2012, 6(4): 388-394.
[8] Ji Qi, David Mu. MicroRNAs and lung cancers: from pathogenesis to clinical implications[J]. Front Med, 2012, 6(2): 134-155.
[9] Liangqian Tong, Ming Zhao, Shu Zhu, Jing Chen. Synthesis and application of superparamagnetic iron oxide nanoparticles in targeted therapy and imaging of cancer[J]. Front Med, 2011, 5(4): 379-387.
[10] Min ZHU, Xiang-Ning FU, Xiao-Ping CHEN. Lobectomy by video-assisted thoracoscopic surgery (VATS) for early stage of non-small cell lung cancer[J]. Front Med, 2011, 5(1): 53-60.
[11] Dian-Ke YU PhD, Chen WU MD, Wen TAN MD, Dong-Xin LIN MD, . Functional XPF polymorphisms associated with lung cancer susceptibility in a Chinese population[J]. Front. Med., 2010, 4(1): 82-89.
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