Skip to content
BY-NC-ND 3.0 license Open Access Published by De Gruyter Open Access July 8, 2014

The role of genetic and other biomarkers in NSCLC prognosis

Diana Schveigert, Saulius Cicenas, Jaroslav Bublevic, Renatas Askinis, Virginijus Sapoka and Janina Didziapetriene
From the journal Open Medicine


The development of non-small-cell lung cancer (NSCLC) is a multistep process, which is triggered and maintained by various factors. Many steps of non-small-cell lung carcinogenesis, risk factors and biomarkers have been identified; however no consistent model has been established of personalized medicine for these patients. Distinct various gene expression, products of mutated genes and other markers such as circulating nucleic acids or tumor cells has been proven to be potential biomarkers of non-small cell lung cancer as well as potential targets for new treatment strategies. This article will highlight promising biomarkers in non-small cell lung cancer prognosis.

[1] Steels E, Paesmans M, Berghmans T, Branle F, Lemaitre F, Mascaux C, Meert AP, Vallot F, Lafitte JJ, Sculier JP. Role of p53 as a prognostic factor for survival in lung cancer: a systematic review of the literature with a meta-analysis. Eur Respir J. 2001, 18(4):705–719 in Google Scholar PubMed

[2] Gasco A, Molina-Vila MA, Bertran-Alamillo J, Mayo C, Costa C, Capitan AG, Massuti B, Camps C, et al. Association of p53 mutations with progression-free survival (PFS) and overall survival (OS) in EGFR-mutated non-small cell lung cancer (NSCLC) patients (p) treated with erlotinib. J Clin Oncol (Meeting Abstracts) 2012, 30(15):e18143 10.1200/jco.2012.30.15_suppl.e18143Search in Google Scholar

[3] Liu L, Wu C, Wanf Y, Zhong R, Duan S, Wei S, Lin S, Zhang X, Tan W, Yu D, Nie S, Miao X, Lin D. Combined effect of genetic polymorphisms in P53, P73, and MDM2 on non-small cell lung cancer survival. J Thorac Oncol. 2011, 6(11):1793–1800 in Google Scholar PubMed

[4] Heist RS, Zhou W, Chirieac LR, Cogan-Drew T, Liu G, Su L, Neuberg D, Lynch TJ, Wain JC, Christiani DC. MDM2 polymorphism, survival, and histology in early-stage non-small-cell lung cancer. J Clin Oncol. 2007, 25(16):2243–2247 in Google Scholar PubMed

[5] Pine SR, Mechanic LE, Bowman ED, Welsh JA. MDM2 SNP309 and SNP354 Are Not Associated with Lung Cancer Risk. Cancer Epidemiol Biomarkers Prev. 2006, 15(8):1559–1561 in Google Scholar PubMed

[6] Zhuo W, Zhang L, Zhu B, Ling J, Chen Z. Association of MDM2 SNP309 variation with lung cancer risk: evidence from 7196 cases and 8456 controls. PLoS One. 2012, 7(7):e41546 in Google Scholar PubMed PubMed Central

[7] Zheng M, Yang J, Xu X, Sebolt JT, Wang S, Sun Y. Efficacy of MDM2 inhibitor MI-219 against lung cancer cells alone or in combination with MDM2 knockdown, a XIAP inhibitor or etoposide. Anticancer Res. 2010, 30(9):3321–3331 Search in Google Scholar

[8] Li J, Poi MJ, Tsai MD. Regulatory mechanisms of tumor suppressor P16(INK4A) and their relevance to cancer. Biochemistry. 2011, 50(25):5566–5582 in Google Scholar PubMed PubMed Central

[9] Ota N, Kawakami K, Okuda T, Takehara A, Hiranuma C, Oyama K, Ota Y, Oda M, Watanabe G. Prognostic significance of p16(INK4a) hypermethylation in non-small cell lung cancer is evident by quantitative DNA methylation analysis. Anticancer Res. 2006, 26(5B):3729–3732 Search in Google Scholar

[10] Yoshino M, Suzuki M, Tian L, Moriya Y, Hoshino H, Okamoto T, Yoshida S, Shibuya K, Yoshino I. Promoter hypermethylation of the p16 and Wif-1 genes as an independent prognostic marker in stage IA non-small cell lung cancers. Int J Oncol. 2009, 35(5):1201–1209 10.3892/ijo_00000437Search in Google Scholar PubMed

[11] Gazdar AF. Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene. 2009; 28 Suppl 1:S24–S31 in Google Scholar PubMed PubMed Central

[12] da Cunha Santos G, Shepherd FA, Tsao MS. EGFR mutations and lung cancer. Annu Rev Pathol. 2011, 6:49–69 in Google Scholar PubMed

[13] Bittner N, Ostoros G, Geczi L. New treatment options for lung adenocarcinoma — in view of molecular background. Pathol Oncol Res. 2013, 10.1007/ s12253-013-9719-9719 Search in Google Scholar

[14] Cappuzzo F, Ciuleanu T, Stelmakh L, Cicenas S, Szczesna A, Juhasz E, Esteban E, Molinier O, Brugger W, Melezinek I, Klingelschmitt G, Klughammer B, Giaccone G, SATURN investigators. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol. 2010, 11(6):521–529 in Google Scholar

[15] Maemondo M, Minegishi Y, Inoue A, Kobayashi K, Harada M, Okinaga S, Morikawa N, Oizumi S, Tanaka T, Isobe H, Kudoh S, Haqiwara K, Nukiwa T, Gemma A. First-line gefitinib in patients aged 75 or older with advanced non-small cell lung cancer harboring epidermal growth factor receptor mutations: NEJ 003 study. J Thorac Oncol. 2012, 7(9):1417–1422 in Google Scholar

[16] Fukuoka M, Wu YL, Thonqprasert S, Sunpaweravong P, Leong SS, Sriuranpong V, Chao TY, Nakaqawa K, Chu DT, Saijo N, Duffield EL, Rukazenkov Y, Speake G, Jiang H, Armour AA, To KF, Yang JC, Mok TS. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol. 2011, 29(21):2866–2874 in Google Scholar

[17] Mendez M, Custodio A, Provencio M. New molecular targeted therapies for advanced non-smallcell lung cancer. J Thorac Dis. 2011, 3(1):30–56 Search in Google Scholar

[18] Kosaka T, Yamaki E, Mogi A, Kuwano H. Mechanisms of resistance to EGFR TKIs and development of a new generation of drugs in nonsmall-cell lung cancer. J Biomed Biotechnol. 2011, 2011:165214 in Google Scholar

[19] Sasaki T, Rodig SJ, Chirieac LR, Jänne PA. The biology and treatment of EMLK4-ALK non-small cell lung cancer. Eur J Cancer. 2010, 46(10):1773–1780 in Google Scholar

[20] Shaw AT, Solomon B. Targeting anaplastic lymphoma kinase in lung cancer. Clin Cancer Res. 2011, 17(8):2081–2086 in Google Scholar

[21] Wu SG, Kyo YW, Chang YL, Shih JY, Chen YH, Tsai MF, Yu CJ, Yang CH, Yang PC. EML4-ALK translocation predicts better outcome in lung adenocarcinoma patients with wild-type EGFR. J Thorac Oncol. 2012; 7(1):98–104 in Google Scholar

[22] Camidge DR, Bang YJ, Kwak EL, Iafrate AJ, Varella-Garcia M, Fox SB, Riely GJ, Solomon B, Ou SH, Kim DW, Salgia R, Fidias P, Engelman JA, Gandhi L, Janne PA, Costa DB, Shapiro GI, Lorusso P, Ruffner K, Stephenson P, Tang Y, Wilner K, Clark JW, Shaw AT. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol. 2012, 13(10):1011–1019 in Google Scholar

[23] Zhang GB, Chen J, Wang LR, Li J, Li MW, Xu N, Wang Y, Shentu JZ. RRM1 and ERCC1 expression in peripheral blood versus tumor tissue in gemcitabine/ carboplatin-treated advanced non-small cell lung cancer. Cancer Chemother Pharmacol. 2012, 69(5):1277–1287 in Google Scholar PubMed

[24] Olaussen KA, Dunant A, Fouret P, Brambilla E, Andre F, Haddad V, Taranchon E, Filipits M, Pirker R, Popper HH, Stahel R, Sabatier L, Pignon JP, Tursz T, Le Chevalier T, Soria JC, IALT Bio Investigators. DNA repair by ERCC1 in non-smallcell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med. 2006, 355(10):983–991 in Google Scholar PubMed

[25] Allingham-Hawkins D, Lea A, Levine S. ERCC1 expression analysis to guide therapy in non-small cell lung cancer. PLoS Curr. 2010, 2:RRN1202 10.1371/currents.RRN1202Search in Google Scholar PubMed PubMed Central

[26] Zheng Z, Chen T, Li X, Haura E, Sharma A, Bepler G. DNA synthesis and repair genes RRM1 and ERCC1 in lung cancer. N Engl J Med. 2007, 356(8):800–808 in Google Scholar PubMed

[27] Simon GR, Schell MJ, Begum M, Kim J, Chiappori A, Haura E, Antonia S, Bepler G. Preliminary indication of survival benefit from ERCC1 and RRM1-tailored chemotherapy in patients with advanced nonsmall cell lung cancer: evidence from an individual patient analysis. Cancer. 2012, 118(9):2525–2531 in Google Scholar PubMed PubMed Central

[28] Karachaliou N, Mayo C, Costa C, Magri I, Gimenez-Capitan A, Molina-Vila MA, Rosell R. KRAS mutations in lung cancer. Clin Lung Cancer. 2013, 14(3):205–214 in Google Scholar PubMed

[29] Guan JL, Zhoang WZ, An SJ, Yang JJ, Su J, Chen ZH, Yan HH, Chen ZY, Huang ZM, Zhang XC, Nie Q, Wu YL. KRAS mutation in patients with lung cancer: a predictor for poor prognosis but not for EGFR-TKIs or chemotherapy. Ann Surg Oncol. 2013, 20(4):1381–1388 in Google Scholar PubMed

[30] Aviel-Ronen S, Blackhall FH, Shepherd FA, Tsao M-S. K-ras mutations in non-small-cell lung carcinoma: a review. Clin Lung Cancer. 2006, 8(1):30–38 in Google Scholar PubMed

[31] Eberhard DA, Johnson BE, Amler LC, Goddard AD, Heldens SL, Herbst RS, Ince WL, Janne PA, Januario T, Johnson DH, Klein P, Miller VA, Ostland MA, Ramies DA, Sebisanovic D, Stinson JA, Zhang YR, Seshagiri S, Hillan KJ. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol. 2005, 23(25):5900–5909 in Google Scholar PubMed

[32] Brugger W, Triller N, Blasinska-Morawiec M, Curescu S, Sakalauskas R, Manikhas GM, Mazieres J, Whittom R, Ward C, Mayne K, Trunzer K, Cappuzzo F. Prospective molecular marker analysis of EGFR and KRAS from a randomized, placebo-controlled study of erlotinib maintenance therapy in advanced non-small-cell lung cancer. J Clin Oncol. 2011, 29(31):4113–4120 in Google Scholar PubMed

[33] Carbone DP, Ciernik IF, Kelley MJ, Smith MC, Nadaf S, Kavanaugh D, Maher VE, Stipanov M, Contois D, Johnson BE, Pendleton CD, Seifert B, Carter C, Read EJ, Greenblatt J, Top LE, Kelsey MI, Minna JD, Berzofsky JA. Immunization with mutant p53-and K-ras-derived peptides in cancer patients: immune response and clinical outcome. J Clin Oncol. 2005, 23(22):5099–5107 in Google Scholar PubMed

[34] Acquaviva J, Smith DL, Sang J, Friedland JC, He S, Sequeira M, Zhang C, Wada Y, Proia DA. Targeting KRAS-mutant non-small cell lung cancer with the Hsp90 inhibitor ganetespib. Mol Cancer Ther. 2012, 11(12):2633–2643 in Google Scholar PubMed

[35] Dingemans AM, Mellema WW, Groen HJ, van Wijk A, Burgers SA, Kunst PW, Thunnissen E, Heideman DA, Smit EF. A phase II study of sorafenib in patients with platinum-pretreated, advanced (stage IIIb or IV) non-small cell lung cancer with a KRAS mutation. Clin Cancer Res. 2013, 19(3):743–751 in Google Scholar

[36] Jänne PA, Shaw AT, Pereira JR, Jeannin G, Vansteenkiste J, Barrios C, Franke FA, Grinsted L, Zazulina V, Smith P, Smith I, Crino L. Selumetinib plus docetaxel for KRAS-mutant advanced nonsmall-cell lung cancer: a randomized, multicenter, placebo-controlled, phase 2 study. Lancet Oncol. 2013, 14(1):38–47 in Google Scholar

[37] Enfield KS, Pikor LA, Martinez VD, Lam WL. Mechanistic roles of noncoding RNAs in lung cancer biology and their clinical implications. Genet Res Int. 2012, 2012:737416 10.1155/2012/737416Search in Google Scholar PubMed PubMed Central

[38] Wang R, Wang ZX, Yang JS, Pan X, De W, Chen LB. MicroRNA-451 functions as a tumor suppressor in human non-small cell lung cancer by targeting ras-related protein 14 (RAB14). Oncogene. 2011, 30(23):2644–2658 in Google Scholar PubMed

[39] Liu X, Lu KH, Wang KM, Sun M, Zhang EB, Yang JS, Yin DD, Liu ZL, Zhou J, Liu ZJ, De W, Wang ZX. MicroRNA-196a promotes non-small cell lung cancer cell proliferation and invasion through targeting HOXA5. BMC Cancer. 2012, 12:348 in Google Scholar PubMed PubMed Central

[40] Yuxia M, Zhennan T, Wei Z. Circulating miR-125b is a novel biomarker for screening non-small-cell lung cancer and predicts poor prognosis. J Cancer Res Clin Oncol. 2012, 138(12):2045–2050 in Google Scholar PubMed

[41] Jusufovic E, Rijavec M, Keser D, Korosec P, Sodja E, Iljazovic E, Radojevic Z, Kosnik M. let-7b and miR-126 are down-regulated in tumor tissue and correlate with microvessel density and survival outcomes in non-small-cell lung cancer. PLoS One. 2012, 7(9):e45577 in Google Scholar PubMed PubMed Central

[42] Navarro A, Diaz T, Gallardo E, Vinolas N, Marrades RM, Gel B, Campayo M, Quera A, Bandres E, Garcia-Foncillas J, Ramirez J, Monzo M. Prognostic implications of miR-16 expression levels in resected non-small-cell lung cancer. J Surg Oncol. 2011, 103(5):411–415 in Google Scholar PubMed

[43] Yu SL, Chen HY, Chang GC, Chen CY, Chen HW, Singh S, Cheng CL, Yu CJ, Lee YC, Chen HS, Su TJ, Chiang CC, Li HN, Hong QS, Su HY, et al. MicroRNA signature predicts survival and relapse in lung cancer. Cancer Cell. 2008, 13(1):48–57 in Google Scholar PubMed

[44] Gao W, Xu J, Shu Y. miRNA expression and its clinical implications for the prevention and diagnosis of non-small-cell lung cancer. Expert Rev Respir Med. 2011, 5(5):699–709 in Google Scholar PubMed

[45] Wan G, Mathur R, Hu X, Zhang X, Lu X. miRNA response to DNA damage. Trends Biochem Sci. 2011, 36(9):478–484 in Google Scholar PubMed PubMed Central

[46] Galluzzi L, Morselli E, Vitale I, Kepp O, Senovilla L, Criollo A, Servant N, Paccard C, Hupe P, Robert T, Ripoche H, Lazar V, Harel-Bellan A, Dessen P, Barillot E, Kroemer G. miR-181a and miR-630 regulate cisplatin-induced cancer cell death. Cancer Res. 2010, 70(5):1793–1803 in Google Scholar PubMed

[47] Wei J, Gao W, Zhu CJ, Liu YQ, Mei Z, Cheng T, Shu YQ. Identification of plasma microRNA-21 as a biomarker for early detection and chemosensitivity of non-small cell lung cancer. Chin J Cancer. 2011, 30(6):407–414 in Google Scholar PubMed PubMed Central

[48] van der Drift MA, Hol BE, Klaassen CH, Prinsen CF, van Aarssen YA, Donders R, van der Stappen JW, Dekhuijzen PN, van der Heijden HF, Thunnissen FB. Circulating DNA is a non-invasive prognostic factor for survival in non-small cell lung cancer. Lung Cancer. 2010, 68(2):283–287 in Google Scholar PubMed

[49] Catarino R, Coelho A, Araujo A, Gomes M, Nogueira A, Lopes C, Medeiros R. Circulating DNA: diagnostic tool and predictive marker for overall survival of NSCLC patients. PLoS One. 2012, 7(6):e38559 in Google Scholar PubMed PubMed Central

[50] Kumar S, Guleria R, Singh V, Bharti AC, Mohan A, Das BC. Efficacy of circulating plasma DNA as a diagnostic tool for advanced non-small cell lung cancer and its predictive utility for survival and response to chemotherapy. Lung Cancer. 2010, 70(2):211–217 in Google Scholar PubMed

[51] Ludovini V, Pistola L, Gregorc V, Floriani I, Rulli E, Piattoni S, Di Carlo L, Semeraro A, Darwish S, Tofanetti FR, Stocchi L, Mihaylova Z, Bellezza G, Del Sordo R, Daddi G, Crino L, Tonato M. Plasma DNA, microsatellite alterations, and p53 tumor mutations are associated with disease-free survival in radically resected non-small cell lung cancer patients. J Thorac Oncol. 2008, 3(4):365–373 in Google Scholar PubMed

[52] Gautschi O, Bigosch C, Huegli B, Jermann M, Marx A, Chasse E, Ratschiller D, Weder W, Joerger M, Betticher DC, Stahel RA, Ziegler A. Circulating deoxyribonucleic acid as prognostic marker in nonsmall-cell lung cancer patients undergoing chemotherapy. J Clin Oncol. 2004, 22(20):4157–4164 in Google Scholar PubMed

[53] O’Flaherty JD, Gray S, Richard D, Fennell D, O’Leary JJ, Blackhall FH, O’Byrne KJ. Circulating tumour cells, their role in metastasis and their clinical utility in lung cancer. Lung Cancer. 2012, 76(1):19–25 in Google Scholar PubMed

[54] Tanaka F, Yoneda K, Hasegawa S. Circulating tumor cells (CTCs) in lung cancer: current status and future perspectives. Lung Cancer: Targets and Therapy. 2010, 1:77–84 10.2147/LCTT.S6828Search in Google Scholar PubMed PubMed Central

[55] Krebs MG, Sloane R, Priest L, Lancashire L, Hou JM, Greystoke A, Ward TH, Ferraldeschi R, Hughes A, Clack G, Ranson M, Dive C, Blackhall FH. Evaluation and prognostic significance of circulating tumor cells in patients with non-small-cell lung cancer. J Clin Oncol. 2011, 29(12):1556–1563 in Google Scholar PubMed

[56] Nieva J, Wendel M, Luttgen MS, Marrinucci D, Bazhenova L, Kolatkar A, Santala R, Whittenberger B, Burke J, Torrey M, Bethel K, Kuhn P. Highdefinition imaging of circulating tumor cells and associated cellular events in non-small cell lung cancer patients: a longitudinal analysis. Phys Biol. 2012, 9(1):016004 in Google Scholar PubMed PubMed Central

[57] Das M, Riess JW, Frankel P, Schwartz E, Bennis R, Hsieh HB, Liu X, Ly JC, Zhou L, Nieva JJ, Wakelee HA, Bruce RH. ERCC1 expression in circulating tumor cells (CTCs) using a novel detection platform correlates with progression-free survival (PFS) in patients with metastatic non-small-cell lung cancaer (NSCLC) receiving platinum chemotherapy. Lung Cancer. 2012, 77(2):421–426 in Google Scholar PubMed

Published Online: 2014-7-8
Published in Print: 2014-6-1

© 2014 Versita Warsaw

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Scroll Up Arrow