Finding biomarkers for non-small cell lung cancer diagnosis and prognosis

Abstract

Despite of several decades of efforts, lung cancer remains one of most deadly diseases, with a 5-year survival rate approximately 15% worldwide. In China, the situation is even worse. Although there is no official data released yet, the 5-year survival rate is estimated to be around 10%. In past 30 years, there was a dramatic increase of lung cancer related death about 465% in mainland China. Annually, about 400000 people die of lung cancer and the number is still climbing. At the same time, the number of new lung cancer cases also increase rapidly. The high mortality of lung cancer is mainly ascribed to two factors: the lack of effective ways to identify early diagnostic biomarkers and to treat metastatic cancer. Lung cancer can be pathologically divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), among which NSCLC accounts for about 80% of all cases. In this review, we will focus on the recent efforts and progress in finding biomarkers in NSCLC. Since biomarkers are derived from both invasive and non-invasive ways, we divide them into these two categories and review them separately. We hope the discovery of biomarkers will eventually change the current clinical practice in NSCLC patients and improve their quality of life.

Keywords

non-small cell lung cancer / biomarkers / diagnosis / prognosis

References

[1] Amos C I, Wu X, Broderick P, Gorlov I P, Gu J, Eisen T, Dong Q, Zhang Q, Gu X, Vijayakrishnan J, Sullivan K, Matakidou A, Wang Y, Mills G, Doheny K, Tsai Y Y, Chen W V, Shete S, Spitz M R, Houlston R S (2008). Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet, 40(5): 616-622

[2] Angelopoulou K, Diamandis E P, Sutherland D J, Kellen J A, Bunting P S (1994). Prevalence of serum antibodies against the p53 tumor suppressor gene protein in various cancers. Int J Cancer, 58(4): 480-487

[3] Aruga A, Koizumi M, Hotta R, Takahashi S, Ogata E (1997). Usefulness of bone metabolic markers in the diagnosis and follow-up of bone metastasis from lung cancer. Br J Cancer, 76(6): 760-764

[4] Ayesh R, Idle J R, Ritchie J C, Crothers M J, Hetzel M R (1984). Metabolic oxidation phenotypes as markers for susceptibility to lung cancer. Nature, 312(5990): 169-170

[5] Baron A T, Wilken J A, Haggstrom D E, Goodrich S T, Maihle N J (2009). Clinical implementation of soluble EGFR (sEGFR) as a theragnostic serum biomarker of breast, lung and ovarian cancer. IDrugs, 12(5): 302-308

[6] Bass A J, Watanabe H, Mermel C H, Yu S, Perner S, Verhaak R G, Kim S Y, Wardwell L, Tamayo P, Gat-Viks I, Ramos A H, Woo M S, Weir B A, Getz G, Beroukhim R, O’Kelly M, Dutt A, Rozenblatt-Rosen O, Dziunycz P, Komisarof J, Chirieac L R, Lafargue C J, Scheble V, Wilbertz T, Ma C, Rao S, Nakagawa H, Stairs D B, Lin L, Giordano T J, Wagner P, Minna J D, Gazdar A F, Zhu C Q, Brose M S, Cecconello I, Jr U R, Marie S K, Dahl O, Shivdasani R A, Tsao M S, Rubin M A, Wong K K, Regev A, Hahn W C, Beer D G, Rustgi A K, Meyerson M (2009). SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas. Nat Genet, 41(11): 1238-1242

[7] Bates J, Rutherford R, Divilly M, Finn J, Grimes H, O’Muircheartaigh I, Gilmartin J J (1997). Clinical value of CYFRA 21.1, carcinoembryonic antigen, neurone-specific enolase, tissue polypeptide specific antigen and tissue polypeptide antigen in the diagnosis of lung cancer. Eur Respir J, 10(11): 2535-2538

[8] Baty F, Facompré M, Kaiser S, Schumacher M, Pless M, Bubendorf L, Savic S, Marrer E, Budach W, Buess M, Kehren J, Tamm M, Brutsche M H (2010). Gene profiling of clinical routine biopsies and prediction of survival in non-small cell lung cancer. Am J Respir Crit Care Med, 181(2): 181-188

[9] Beer D G, Kardia S L, Huang C C, Giordano T J, Levin A M, Misek D E, Lin L, Chen G, Gharib T G, Thomas D G, Lizyness M L, Kuick R, Hayasaka S, Taylor J M, Iannettoni M D, Orringer M B, Hanash S (2002). Gene-expression profiles predict survival of patients with lung adenocarcinoma. Nat Med, 8(8): 816-824

[10] Berger A H, Niki M, Morotti A, Taylor B S, Socci N D, Viale A, Brennan C, Szoke J, Motoi N, Rothman P B, Teruya-Feldstein J, Gerald W L, Ladanyi M, Pandolfi P P (2010). Identification of DOK genes as lung tumor suppressors. Nat Genet, 42(3): 216-223

[11] Bhattacharjee A, Richards W G, Staunton J, Li C, Monti S, Vasa P, Ladd C, Beheshti J, Bueno R, Gillette M, Loda M, Weber G, Mark E J, Lander E S, Wong W, Johnson B E, Golub T R, Sugarbaker D J, Meyerson M (2001). Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proc Natl Acad Sci USA, 98(24): 13790-13795

[12] Borgia J A, Basu S, Faber L P, Kim A W, Coon J S, Kaiser-Walters K A, Fhied C, Thomas S, Rouhi O, Warren W H, Bonomi P, Liptay M J (2009). Establishment of a multi-analyte serum biomarker panel to identify lymph node metastases in non-small cell lung cancer. J Thorac Oncol, 4(3): 338-347

[13] Brandt-Rauf P W, Smith S, Hemminki K, Koskinen H, Vainio H, Niman H, Ford J (1992). Serum oncoproteins and growth factors in asbestosis and silicosis patients. Int J Cancer, 50(6): 881-885

[14] Bremnes R M, Sirera R, Camps C (2005). Circulating tumour-derived DNA and RNA markers in blood: a tool for early detection, diagnostics, and follow-up? Lung Cancer, 49(1): 1-12

[15] Caporaso N E, Tucker M A, Hoover R N, Hayes R B, Pickle L W, Issaq H J, Muschik G M, Green-Gallo L, Buivys D, Aisner S, Resau J H, Trump B F, Tollerud D, Weston A, Harris C C (1990). Lung cancer and the debrisoquine metabolic phenotype. J Natl Cancer Inst, 82(15): 1264-1272

[16] Carrola J, Rocha C M, Barros A S, Gil A M, Goodfellow B J, Carreira I M, Bernardo J, Gomes A, Sousa V, Carvalho L, Duarte I F (2011). Metabolic signatures of lung cancer in biofluids: NMR-based metabonomics of urine. J Proteome Res, 10(1): 221-230

[17] Castillo S D, Angulo B, Suarez-Gauthier A, Melchor L, Medina P P, Sanchez-Verde L, Torres-Lanzas J, Pita G, Benitez J, Sanchez-Cespedes M (2010). Gene amplification of the transcription factor DP1 and CTNND1 in human lung cancer. J Pathol, 222(1): 89-98

[18] Chen H Y, Yu S L, Chen C H, Chang G C, Chen C Y, Yuan A, Cheng C L, Wang C H, Terng H J, Kao S F, Chan W K, Li H N, Liu C C, Singh S, Chen W J, Chen J J, Yang P C (2007). A five-gene signature and clinical outcome in non-small-cell lung cancer. N Engl J Med, 356(1): 11-20

[19] Chen X, Ba Y, Ma L, Cai X, Yin Y, Wang K, Guo J, Zhang Y, Chen J, Guo X, Li Q, Li X, Wang W, Zhang Y, Wang J, Jiang X, Xiang Y, Xu C, Zheng P, Zhang J, Li R, Zhang H, Shang X, Gong T, Ning G, Wang J, Zen K, Zhang J, Zhang C Y (2008). Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res, 18(10): 997-1006

[20] Chen X, Hu Z, Wang W, Ba Y, Ma L, Zhang C, Wang C, Ren Z, Zhao Y, Wu S,Zhuang R, Zhang Y, Hu H, Liu C, Xu L, Wang J, Shen H, Zhang J, Zen K, Zhang C Y (2011). Identification of ten serum microRNAs from a genome-wide serum microRNA expression profile as novel non-invasive biomarkers for non-small cell lung cancer diagnosis. Int J Cancer,

[21] Cheng T L, Chang M Y, Huang S Y, Sheu C C, Kao E L, Cheng Y J, Chong I W (2005). Overexpression of circulating c-met messenger RNA is significantly correlated with nodal stage and early recurrence in non-small cell lung cancer. Chest, 128(3): 1453-1460

[22] Chitale D, Gong Y, Taylor B S, Broderick S, Brennan C, Somwar R, Golas B, Wang L, Motoi N, Szoke J, Reinersman J M, Major J, Sander C, Seshan V E, Zakowski M F, Rusch V, Pao W, Gerald W, Ladanyi M (2009). An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors. Oncogene, 28(31): 2773-2783

[23] Chung C C, Magalhaes W C, Gonzalez-Bosquet J, Chanock S J (2010). Genome-wide association studies in cancer—current and future directions. Carcinogenesis, 31(1): 111-120

[24] Chung J H, Park M S, Kim Y S, Chang J, Kim J H, Kim S K, Kim S K (2005). Usefulness of bone metabolic markers in the diagnosis of bone metastasis from lung cancer. Yonsei Med J, 46(3): 388-393

[25] Duche J C, Joanne C, Barre J, de Cremoux H, Dalphin J C, Depierre A, Brochard P, Tillement J P, Bechtel P (1991). Lack of a relationship between the polymorphism of debrisoquine oxidation and lung cancer. Br J Clin Pharmacol, 31(5): 533-536

[26] Egloff A M, Weissfeld J, Land S R, Finn O J (2005). Evaluation of anticyclin B1 serum antibody as a diagnostic and prognostic biomarker for lung cancer. Ann N Y Acad Sci, 1062(1): 29-40

[27] Endoh H, Tomida S, Yatabe Y, Konishi H, Osada H, Tajima K, Kuwano H, Takahashi T, Mitsudomi T (2004). Prognostic model of pulmonary adenocarcinoma by expression profiling of eight genes as determined by quantitative real-time reverse transcriptase polymerase chain reaction. J Clin Oncol, 22(5): 811-819

[28] Fleischhacker M, Beinert T, Ermitsch M, Seferi D, Possinger K, Engelmann C, Jandrig B (2001). Detection of amplifiable messenger RNA in the serum of patients with lung cancer. Ann N Y Acad Sci, 945(1): 179-188

[29] Foss K M, Sima C, Ugolini D, Neri M, Allen K E, Weiss G J (2011). miR-1254 and miR-574-5p: serum-based microRNA biomarkers for early-stage non-small cell lung cancer. J Thorac Oncol, 6(3): 482-488

[30] Gallegos Ruiz M I, Floor K, Roepman P, Rodriguez J A, Meijer G A, Mooi W J, Jassem E, Niklinski J, Muley T, van Zandwijk N, Smit E F, Beebe K, Neckers L, Ylstra B, Giaccone G (2008). Integration of gene dosage and gene expression in non-small cell lung cancer, identification of HSP90 as potential target. PLoS ONE, 3(3): e0001722

[31] Galvan A, Falvella F S, Frullanti E, Spinola M, Incarbone M, Nosotti M, Santambrogio L, Conti B, Pastorino U, Gonzalez-Neira A, Dragani T A (2010). Genome-wide association study in discordant sibships identifies multiple inherited susceptibility alleles linked to lung cancer. Carcinogenesis, 31(3): 462-465

[32] Gao Y, Xiao Q, Ma H, Li L, Liu J, Feng Y, Fang Z, Wu J, Han X, Zhang J, Sun Y, Wu G, Padera R, Chen H, Wong K K, Ge G, Ji H (2010). LKB1 inhibits lung cancer progression through lysyl oxidase and extracellular matrix remodeling. Proc Natl Acad Sci USA, 107(44): 18892-18897

[33] Garber M E, Troyanskaya O G, Schluens K, Petersen S, Thaesler Z, Pacyna-Gengelbach M, van de Rijn M, Rosen G D, Perou C M, Whyte R I, Altman R B, Brown P O, Botstein D, Petersen I (2001). Diversity of gene expression in adenocarcinoma of the lung. Proc Natl Acad Sci USA, 98(24): 13784-13789

[34] Gilad S, Meiri E, Yogev Y, Benjamin S, Lebanony D, Yerushalmi N, Benjamin H, Kushnir M, Cholakh H, Melamed N, Bentwich Z, Hod M, Goren Y, Chajut A (2008). Serum microRNAs are promising novel biomarkers. PLoS ONE, 3(9): e3148

[35] Giovanella L, Ceriani L, Bandera M, Rimoldi R, Beghé B, Roncari G (1995). Tissue polypeptide specific antigen (tps) and cytokeratin 19 fragment (CYFRA 21.1) immunoradiometric assay in non small cell lung cancer evaluation. Q J Nucl Med, 39(4): 285-289

[36] He L, He X, Lim L P, de Stanchina E, Xuan Z, Liang Y, Xue W, Zender L, Magnus J, Ridzon D, Jackson A L, Linsley P S, Chen C, Lowe S W, Cleary M A, Hannon G J (2007). A microRNA component of the p53 tumour suppressor network. Nature, 447(7148): 1130-1134

[37] Helmig S, Schneider J (2007). Oncogene and tumor-suppressor gene products as serum biomarkers in occupational-derived lung cancer. Expert Rev Mol Diagn, 7(5): 555-568

[38] Hoagland L F IV, Campa M J, Gottlin E B, Herndon J E 2nd, Patz E F Jr (2007). Haptoglobin and posttranslational glycan-modified derivatives as serum biomarkers for the diagnosis of nonsmall cell lung cancer. Cancer, 110(10): 2260-2268

[39] Hsiung C A, Lan Q, Hong Y C, Chen C J, Hosgood H D, Chang I S, Chatterjee N, Brennan P, Wu C, Zheng W, Chang G C, Wu T, Park J Y, Hsiao C F, Kim Y H, Shen H, Seow A, Yeager M, Tsai Y H, Kim Y T, Chow W H, Guo H, Wang W C, Sung S W, Hu Z, Chen K Y, Kim J H, Chen Y, Huang L, Lee K M, Lo Y L, Gao Y T, Kim J H, Liu L, Huang M S, Jung T H, Jin G, Caporaso N, Yu D, Kim C H, Su W C, Shu X O, Xu P, Kim I S, Chen Y M, Ma H, Shen M, Cha S I, Tan W, Chang C H, Sung J S, Zhang M, Yang T Y, Park K H, Yuenger J, Wang C L, Ryu J S, Xiang Y, Deng Q, Hutchinson A, Kim J S, Cai Q, Landi M T, Yu C J, Park J Y, Tucker M, Hung J Y, Lin C C, Perng R P, Boffetta P, Chen C Y, Chen K C, Yang S Y, Hu C Y, Chang C K, Fraumeni J F Jr, Chanock S, Yang P C, Rothman N, Lin D (2010). The 5p15.33 locus is associated with risk of lung adenocarcinoma in never-smoking females in Asia. PLoS Genet, 6(8): e1001051

[40] Hu Z, Chen X, Zhao Y, Tian T, Jin G, Shu Y, Chen Y, Xu L, Zen K, Zhang C, Shen H (2010). Serum microRNA signatures identified in a genome-wide serum microRNA expression profiling predict survival of non-small-cell lung cancer. J Clin Oncol, 28(10): 1721-1726

[41] Huang Y T, Heist R S, Chirieac L R, Lin X, Skaug V, Zienolddiny S, Haugen A, Wu M C, Wang Z, Su L, Asomaning K, Christiani D C (2009). Genome-wide analysis of survival in early-stage non-small-cell lung cancer. J Clin Oncol, 27(16): 2660-2667

[42] Hung R J, Christiani D C, Risch A, Popanda O, Haugen A, Zienolddiny S, Benhamou S, Bouchardy C, Lan Q, Spitz M R, Wichmann H E, LeMarchand L, Vineis P, Matullo G, Kiyohara C, Zhang Z F, Pezeshki B, Harris C, Mechanic L, Seow A, Ng D P, Szeszenia-Dabrowska N, Zaridze D, Lissowska J, Rudnai P, Fabianova E, Mates D, Foretova L, Janout V, Bencko V, Caporaso N, Chen C, Duell E J, Goodman G, Field J K, Houlston R S, Hong Y C, Landi M T, Lazarus P, Muscat J, McLaughlin J, Schwartz A G, Shen H, Stucker I, Tajima K, Matsuo K, Thun M, Yang P, Wiencke J, Andrew A S, Monnier S, Boffetta P, Brennan P (2008a). International Lung Cancer Consortium: pooled analysis of sequence variants in DNA repair and cell cycle pathways. Cancer Epidemiol Biomarkers Prev, 17(11): 3081-3089

[43] Hung R J, McKay J D, Gaborieau V, Boffetta P, Hashibe M, Zaridze D, Mukeria A, Szeszenia-Dabrowska N, Lissowska J, Rudnai P, Fabianova E, Mates D, Bencko V, Foretova L, Janout V, Chen C, Goodman G, Field J K, Liloglou T, Xinarianos G, Cassidy A, McLaughlin J, Liu G, Narod S, Krokan H E, Skorpen F, Elvestad M B, Hveem K, Vatten L, Linseisen J, Clavel-Chapelon F, Vineis P, Bueno-de-Mesquita H B, Lund E, Martinez C, Bingham S, Rasmuson T, Hainaut P, Riboli E, Ahrens W, Benhamou S, Lagiou P, Trichopoulos D, Holcátová I, Merletti F, Kjaerheim K, Agudo A, Macfarlane G, Talamini R, Simonato L, Lowry R, Conway D I, Znaor A, Healy C, Zelenika D, Boland A, Delepine M, Foglio M, Lechner D, Matsuda F, Blanche H, Gut I, Heath S, Lathrop M, Brennan P (2008b). A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature, 452(7187): 633-637

[44] Jagadeeswaran R, Surawska H, Krishnaswamy S, Janamanchi V, Mackinnon A C, Seiwert T Y, Loganathan S, Kanteti R, Reichman T, Nallasura V, Schwartz S, Faoro L, Wang Y C, Girard L, Tretiakova M S, Ahmed S, Zumba O, Soulii L, Bindokas V P, Szeto L L, Gordon G J, Bueno R, Sugarbaker D, Lingen M W, Sattler M, Krausz T, Vigneswaran W, Natarajan V, Minna J, Vokes E E, Ferguson M K, Husain A N, Salgia R (2008). Paxillin is a target for somatic mutations in lung cancer: implications for cell growth and invasion. Cancer Res, 68(1): 132-142

[45] Johnson S M, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, Labourier E, Reinert K L, Brown D, Slack F J (2005). RAS is regulated by the let-7 microRNA family. Cell, 120(5): 635-647

[46] Kang J U, Koo S H, Kwon K C, Park J W (2010). Frequent silence of chromosome 9p, homozygous DOCK8, DMRT1 and DMRT3 deletion at 9p24.3 in squamous cell carcinoma of the lung. Int J Oncol, 37(2): 327-335

[47] Kopreski M S, Benko F A, Gocke C D (2001). Circulating RNA as a tumor marker: detection of 5T4 mRNA in breast and lung cancer patient serum. Ann N Y Acad Sci, 945(1): 172-178

[48] Krolikowski F J, Reuter K, Waalkes T P, Sieber S M, Adamson R H (1976). Serum sialic acid levels in lung cancer patients. Pharmacology, 14(1): 47-51

[49] Kumar M S, Pester R E, Chen C Y, Lane K, Chin C, Lu J, Kirsch D G, Golub T R, Jacks T (2009). Dicer1 functions as a haploinsufficient tumor suppressor. Genes Dev, 23(23): 2700-2704

[50] Lawrie C H, Gal S, Dunlop H M, Pushkaran B, Liggins A P, Pulford K, Banham A H, Pezzella F, Boultwood J, Wainscoat J S, Hatton C S, Harris A L (2008). Detection of elevated levels of tumour-associated microRNAs in serum of patients with diffuse large B-cell lymphoma. Br J Haematol, 141(5): 672-675

[51] Li D, Shimamura T, Ji H, Chen L, Haringsma H J, McNamara K, Liang M C, Perera S A, Zaghlul S, Borgman C L, Kubo S, Takahashi M, Sun Y, Chirieac L R, Padera R F, Lindeman N I, Jänne P A, Thomas R K, Meyerson M L, Eck M J, Engelman J A, Shapiro G I, Wong K K (2007). Bronchial and peripheral murine lung carcinomas induced by T790M-L858R mutant EGFR respond to HKI-272 and rapamycin combination therapy. Cancer Cell, 12(1): 81-93

[52] Li Y, Sheu C C, Ye Y, de Andrade M, Wang L, Chang S C, Aubry M C, Aakre J A, Allen M S, Chen F, Cunningham J M, Deschamps C, Jiang R, Lin J, Marks R S, Pankratz V S, Su L, Li Y, Sun Z, Tang H, Vasmatzis G, Harris C C, Spitz M R, Jen J, Wang R, Zhang Z F, Christiani D C, Wu X, Yang P (2010). Genetic variants and risk of lung cancer in never smokers: a genome-wide association study. Lancet Oncol, 11(4): 321-330

[53] Liu L, Sun S, Liu J, Wu S, Dai S, Wang X, Huang L, Xiao X, He D (2009). A new serum biomarker for lung cancer-transthyretin. J Lung Cancer, 12(4): 300-305

[54] Luo J C, Zehab R, Anttila S, Ridanpaa M, Husgafvel-Pursiainen K, Vainio H, Carney W, De Vivo I, Milling C, Brandt-Rauf P W (1994). Detection of serum p53 protein in lung cancer patients. J Occup Med, 36(2): 155-160

[55] Ma C, Quesnelle K M, Sparano A, Rao S, Park M S, Cohen M A, Wang Y, Samanta M, Kumar M S, Aziz M U, Naylor T L, Weber B L, Fakharzadeh S S, Weinstein G S, Vachani A, Feldman M D, Brose M S (2009). Characterization CSMD1 in a large set of primary lung, head and neck, breast and skin cancer tissues. Cancer Biol Ther, 8(10): 907-916

[56] McCaughan F, Pole J C, Bankier A T, Konfortov B A, Carroll B, Falzon M, Rabbitts T H, George P J, Dear P H, Rabbitts P H (2010). Progressive 3q amplification consistently targets SOX2 in preinvasive squamous lung cancer. Am J Respir Crit Care Med, 182(1): 83-91

[57] McKay J D, Hung R J, Gaborieau V, Boffetta P, Chabrier A, Byrnes G, Zaridze D, Mukeria A, Szeszenia-Dabrowska N, Lissowska J, Rudnai P, Fabianova E, Mates D, Bencko V, Foretova L, Janout V, McLaughlin J, Shepherd F, Montpetit A, Narod S, Krokan H E, Skorpen F, Elvestad M B, Vatten L, Njølstad I, Axelsson T, Chen C, Goodman G, Barnett M, Loomis M M, Lubiñski J, Matyjasik J, Lener M, Oszutowska D, Field J, Liloglou T, Xinarianos G, Cassidy A, Vineis P, Clavel-Chapelon F, Palli D, Tumino R, Krogh V, Panico S, González C A, Ramón Quirós J, Martínez C, Navarro C, Ardanaz E, Larrañaga N, Kham K T, Key T, Bueno-de-Mesquita H B, Peeters P H, Trichopoulou A, Linseisen J, Boeing H, Hallmans G, Overvad K, Tjønneland A, Kumle M, Riboli E, Zelenika D, Boland A, Delepine M, Foglio M, Lechner D, Matsuda F, Blanche H, Gut I, Heath S, Lathrop M, Brennan P, the EPIC Study (2008). Lung cancer susceptibility locus at 5p15.33. Nat Genet, 40(12): 1404-1406

[58] Medina P P, Castillo S D, Blanco S, Sanz-Garcia M, Largo C, Alvarez S, Yokota J, Gonzalez-Neira A, Benitez J, Clevers H C, Cigudosa J C, Lazo P A, Sanchez-Cespedes M (2009). The SRY-HMG box gene, SOX4, is a target of gene amplification at chromosome 6p in lung cancer. Hum Mol Genet, 18(7): 1343-1352

[59] Miki D, Kubo M, Takahashi A, Yoon K A, Kim J, Lee G K, Zo J I, Lee J S, Hosono N, Morizono T, Tsunoda T, Kamatani N, Chayama K, Takahashi T, Inazawa J, Nakamura Y, Daigo Y (2010). Variation in TP63 is associated with lung adenocarcinoma susceptibility in Japanese and Korean populations. Nat Genet, 42(10): 893-896

[60] Mitchell P S, Parkin R K, Kroh E M, Fritz B R, Wyman S K, Pogosova-Agadjanyan E L, Peterson A, Noteboom J, O’Briant K C, Allen A, Lin D W, Urban N, Drescher C W, Knudsen B S, Stirewalt D L, Gentleman R, Vessella R L, Nelson P S, Martin D B, Tewari M (2008). Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci USA, 105(30): 10513-10518

[61] Miura N, Nakamura H, Sato R, Tsukamoto T, Harada T, Takahashi S, Adachi Y, Shomori K, Sano A, Kishimoto Y, Ito H, Hasegawa J, Shiota G (2006). Clinical usefulness of serum telomerase reverse transcriptase (hTERT) mRNA and epidermal growth factor receptor (EGFR) mRNA as a novel tumor marker for lung cancer. Cancer Sci, 97(12): 1366-1373

[62] Newnham G M, Thomas D M, McLachlan S A, Wright G, Conron M (2008). Molecular profiling of non-small cell lung cancer: of what value in clinical practice? Heart Lung Circ, 17(6): 451-462

[63] Patel K, Farlow E C, Kim A W, Lee B S, Basu S, Coon J S, Decresce D, Thimothy L, Walters K A, Fhied C, Chang C, Chen S H, Faber L P, Bonomi P, Liptay M J, Borgia J A(2011). Enhancement of a multianalyte serum biomarker panel to identify lymph node metastases in non-small cell lung cancer with circulating autoantibody biomarkers. Int J Cancer, 129(1): 133-142

[64] Patz E F Jr, Campa M J, Gottlin E B, Kusmartseva I, Guan X R, Herndon J E II (2007). Panel of serum biomarkers for the diagnosis of lung cancer. J Clin Oncol, 25(35): 5578-5583

[65] Petty R D, Nicolson M C, Kerr K M, Collie-Duguid E, Murray G I (2004). Gene expression profiling in non-small cell lung cancer: from molecular mechanisms to clinical application. Clin Cancer Res, 10(10): 3237-3248

[66] Potti A, Mukherjee S, Petersen R, Dressman H K, Bild A, Koontz J, Kratzke R, Watson M A, Kelley M, Ginsburg G S, West M, Harpole D H Jr, Nevins J R (2006). A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer. N Engl J Med, 355(6): 570-580

[67] Pujol J L, Cooper E H, Grenier J, Purves D A, Lehmann M, Ray P, Aouta M D, Bashir M, Godard P, Michel F B (1994). Clinical evaluation of serum tissue polypeptide-specific antigen (TPS) in non-small cell lung cancer. Eur J Cancer, 30A(12): 1768-1774

[68] Rodríguez-Piñeiro A M, Blanco-Prieto S, Sánchez-Otero N, Rodríguez-Berrocal F J, de la Cadena M P (2010). On the identification of biomarkers for non-small cell lung cancer in serum and pleural effusion. J Proteomics, 73(8): 1511-1522

[69] Rokicki M, Rokicki W, Czyzewski K, Wojcieszek E (1987). Usefulness of determining the levels of sialic acid in the blood serum, pulmonary homogenates and urine of patients with lung cancer. Nowotwory, 37(3): 226-231

[70] Salvati F, Antilli A, Cruciani A R, Pau F, Flore F, Munno R, De Angelis G, Cipri A, Pigorini F (1985). Plasma carcinoembryonic antigen and tissue polypeptide antigen levels in lung cancer: correlation with cell types and stage. Cancer Detect Prev, 8(1-2): 111-114

[71] Sanchez-Palencia A, Gomez-Morales M, Gomez-Capilla J A, Pedraza V, Boyero L, Rosell R, Farez-Vidal M E (2011). Gene expression profiling reveals novel biomarkers in nonsmall cell lung cancer. Int J Cancer, 129(2): 355-364

[72] Sato Y, Yamamoto N, Kunitoh H, Ohe Y, Minami H, Laird N M, Katori N, Saito Y, Ohnami S, Sakamoto H, Sawada J, Saijo N, Yoshida T, Tamura T (2011). Genome-wide association study on overall survival of advanced non-small cell lung cancer patients treated with carboplatin and paclitaxel. J Thorac Oncol, 6(1): 132-138

[73] Sen E, Ulger F, Kaya A, Akar N, Gonullu U (2008). Serum endothelial monocyte-activating polypeptide-II: a novel biomarker in patients with non-small-cell lung cancer. Clin Lung Cancer, 9(3): 166-170

[74] Shaw G L, Falk R T, Deslauriers J, Frame J N, Nesbitt J C, Pass H I, Issaq H J, Hoover R N, Tucker M A (1995). Debrisoquine metabolism and lung cancer risk. Cancer Epidemiol Biomarkers Prev, 4(1): 41-48

[75] Shedden K, Taylor J M, Enkemann S A, Tsao M S, Yeatman T J, Gerald W L, Eschrich S, Jurisica I, Giordano T J, Misek D E, Chang A C, Zhu C Q, Strumpf D, Hanash S, Shepherd F A, Ding K, Seymour L, Naoki K, Pennell N, Weir B, Verhaak R, Ladd-Acosta C, Golub T, Gruidl M, Sharma A, Szoke J, Zakowski M, Rusch V, Kris M, Viale A, Motoi N, Travis W, Conley B, Seshan V E, Meyerson M, Kuick R, Dobbin K K, Lively T, Jacobson J W, Beer D G, Shedden K, Taylor J M G, Enkemann S A, Tsao M S, Yeatman T J, Gerald W L, Eschrich S, Jurisica I, Giordano T J, Misek D E, Chang A C, Zhu C Q, Strumpf D, Hanash S, Shepherd F A, Ding K, Seymour L, Naoki K, Pennell N, Weir B, Verhaak R, Ladd-Acosta C, Golub T, Gruidl M, Sharma A, Szoke J, Zakowski M, Rusch V, Kris M, Viale A, Motoi N, Travis W, Conley B, Seshan V E, Meyerson M, Kuick R, Dobbin K K, Lively T, Jacobson J W, Beer D G, he Director’s Challenge Consortium for the Molecular Classification of Lung Adenocarcinoma (2008). Gene expression-based survival prediction in lung adenocarcinoma: a multi-site, blinded validation study. Nat Med, 14(8): 822-827

[76] Smirnova K D, Lazarev N I (1970). Adrenal cortex steroid hormone metabolites in the urine of patients with cancer of the lung. Vestn Akad Med Nauk SSSR, 25(2): 35-38

[77] Speirs C J, Murray S, Davies D S, Biola Mabadeje A F, Boobis A R (1990). Debrisoquine oxidation phenotype and susceptibility to lung cancer. Br J Clin Pharmacol, 29(1): 101-109

[78] Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada H, Endoh H, Harano T, Yatabe Y, Nagino M, Nimura Y, Mitsudomi T, Takahashi T (2004). Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res, 64(11): 3753-3756

[79] Thöm I, Andritzky B, Schuch G, Burkholder I, Edler L, Johansen J S, Bokemeyer C, Schumacher U, Laack E (2010). Elevated pretreatment serum concentration of YKL-40-An independent prognostic biomarker for poor survival in patients with metastatic nonsmall cell lung cancer. Cancer, 116(17): 4114-4121

[80] Toschi L, Cappuzzo F (2010). Clinical implications of MET gene copy number in lung cancer. Future Oncol, 6(2): 239-247

[81] Ulivi P, Mercatali L, Zoli W, Dell’amore D, Poletti V, Casoni G L, Scarpi E, Flamini E, Amadori D, Silvestrini R (2008). Serum free DNA and COX-2 mRNA expression in peripheral blood for lung cancer detection. Thorax, 63(9): 843-844

[82] Vollebergh M A, Kappers I, Klomp H M, Buning-Kager J C, Korse C M, Hauptmann M, de Visser K E, van den Heuvel M M, Linn S C (2010). Ligands of epidermal growth factor receptor and the insulin-like growth factor family as serum biomarkers for response to epidermal growth factor receptor inhibitors in patients with advanced non-small cell lung cancer. J Thorac Oncol, 5(12): 1939-1948

[83] Wang Y, Broderick P, Webb E, Wu X, Vijayakrishnan J, Matakidou A, Qureshi M, Dong Q, Gu X, Chen W V, Spitz M R, Eisen T, Amos C I, Houlston R S (2008). Common 5p15.33 and 6p21.33 variants influence lung cancer risk. Nat Genet, 40(12): 1407-1409

[84] Weir B A, Woo M S, Getz G, Perner S, Ding L, Beroukhim R, Lin W M, Province M A, Kraja A, Johnson L A, Shah K, Sato M, Thomas R K, Barletta J A, Borecki I B, Broderick S, Chang A C, Chiang D Y, Chirieac L R, Cho J, Fujii Y, Gazdar A F, Giordano T, Greulich H, Hanna M, Johnson B E, Kris M G, Lash A, Lin L, Lindeman N, Mardis E R, McPherson J D, Minna J D, Morgan M B, Nadel M, Orringer M B, Osborne J R, Ozenberger B, Ramos A H, Robinson J, Roth J A, Rusch V, Sasaki H, Shepherd F, Sougnez C, Spitz M R, Tsao M S, Twomey D, Verhaak R G, Weinstock G M, Wheeler D A, Winckler W, Yoshizawa A, Yu S, Zakowski M F, Zhang Q, Beer D G, Wistuba I I, Watson M A, Garraway L A, Ladanyi M, Travis W D, Pao W, Rubin M A, Gabriel S B, Gibbs R A, Varmus H E, Wilson R K, Lander E S, Meyerson M (2007). Characterizing the cancer genome in lung adenocarcinoma. Nature, 450(7171): 893-898

[85] Wrage M, Ruosaari S, Eijk P P, Kaifi J T, Hollmén J, Yekebas E F, Izbicki J R, Brakenhoff R H, Streichert T, Riethdorf S, Glatzel M, Ylstra B, Pantel K, Wikman H (2009). Genomic profiles associated with early micrometastasis in lung cancer: relevance of 4q deletion. Clin Cancer Res, 15(5): 1566-1574

[86] Wu X, Ye Y, Rosell R, Amos C I, Stewart D J, Hildebrandt M A, Roth J A, Minna J D, Gu J, Lin J, Buch S C, Nukui T, Ramirez Serrano J L, Taron M, Cassidy A, Lu C, Chang J Y, Lippman S M, Hong W K, Spitz M R, Romkes M, Yang P (2011). Genome-wide association study of survival in non-small cell lung cancer patients receiving platinum-based chemotherapy. J Natl Cancer Inst, 103(10): 817-825

[87] Yamashita J, Matsuo A, Kurusu Y, Saishoji T, Hayashi N, Ogawa M (2002). Preoperative evidence of circulating tumor cells by means of reverse transcriptase-polymerase chain reaction for carcinoembryonic antigen messenger RNA is an independent predictor of survival in non-small cell lung cancer: a prospective study. J Thorac Cardiovasc Surg, 124(2): 299-305

[88] Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, Yi M, Stephens R M, Okamoto A, Yokota J, Tanaka T, Calin G A, Liu C G, Croce C M, Harris C C (2006). Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell, 9(3): 189-198

[89] Yao N S, Wu Y Y, Janckila A J, Ku C H, Hsieh A T, Ho C L, Lee S H, Chao T Y (2011). Serum tartrate-resistant acid phosphatase 5b (TRACP5b) activity as a biomarker for bone metastasis in non-small cell lung cancer patients. Clin Chim Acta, 412(1-2): 181-185

[90] Yoon K A, Park J H, Han J, Park S, Lee G K, Han J Y, Zo J I, Kim J, Lee J E, Takahashi A, Kubo M, Nakamura Y, Lee J S (2010). A genome-wide association study reveals susceptibility variants for non-small cell lung cancer in the Korean population. Hum Mol Genet, 19(24): 4948-4954

[91] Yu S L, Chen H Y, Chang G C, Chen C Y, Chen H W, Singh S, Cheng C L, Yu C J, Lee Y C, Chen H S, Su T J, Chiang C C, Li H N, Hong Q S, Su H Y, Chen C C, Chen W J, Liu C C, Chan W K, Chen W J, Li K C, Chen J J, Yang P C (2008). MicroRNA signature predicts survival and relapse in lung cancer. Cancer Cell, 13(1): 48-57

[92] Zeng X, Hood B L, Sun M, Conrads T P, Day R S, Weissfeld J L, Siegfried J M, Bigbee W L (2010). Lung cancer serum biomarker discovery using glycoprotein capture and liquid chromatography mass spectrometry. J Proteome Res, 9(12): 6440-6449

[93] Zeng X, Hood BL, Zhao T, Conrads TP, Sun M, Gopalakrishnan V, Grover H, Day RS, Weissfeld JL, Wilson DO, Siegfried JM, Bigbee WL(2011). Lung cancer serum biomarker discovery using label-free liquid chromatography-tandem mass spectrometry. J Thorac Oncol, 6(4): 725-734

Acknowledgements

This work was supported by the National Basic Research Program of China (No. 2010CB912102), the National Natural Science Foundation of China (Grant Nos.30871284 and 30971461), the Chinese Academy of Sciences (No. 2010KIP504), and the Science and Technology Commission of Shanghai Municipality (No. 09JC1416300). H. J. is a scholar of the Hundred Talents Program of the Chinese Academy of Sciences.

RIGHTS & PERMISSIONS

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg