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Frontiers in Biology

Front Biol    2012, Vol. 7 Issue (1) : 14-23
Finding biomarkers for non-small cell lung cancer diagnosis and prognosis
Tian XIAO1, Lei BAO2(), Hongbin JI1()
1. State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; 2. Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA
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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     
Corresponding Author(s): BAO Lei,; JI Hongbin,   
Issue Date: 01 February 2012
 Cite this article:   
Tian XIAO,Lei BAO,Hongbin JI. Finding biomarkers for non-small cell lung cancer diagnosis and prognosis[J]. Front Biol, 2012, 7(1): 14-23.
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SNPLocus/GeneHistologyPopulation# cases# controlsHazard ratioReference
rs27361005p15.33ADCEast Asian2098110481.27McKay et al., 2008
rs402710TERTADCEast Asian, nonsmoker174823211.54Hsiung et al., 2010
CLPTM1LBothEuropean615897321.14Miki et al., 2010
rs44888093q28ADCEast Asian2098110481.31Miki et al., 2010
rs105173015q25.1BothEuropean, smoker387848311.32Amos et al., 2008
rs8034191CHRNA5BothEuropean450273771.30Hung et al., 2008b
rs31175826p21.33BothEuropean953196741.30Wang et al., 2008
Tab.1  Genetic loci that modify the susceptibility of lung cancer identified by GWAS
ProteinTypeSample sizeStudy designMethodsDetailsReference
YKL-40Glycoprotein143 men and 46 womenStudy on prognosisELISAHigh serum YKL-40 levels have been associated with a poor prognosis.Th?m et al., 2010
TRACP5bPhosphatase141 newly diagnosed stage IIIA, IIIB or IV NSCLC patients and 41 normal subjectsBone metastasis or notIn-house immunoassayTRACP5b activity declined in patients who responded to treatment (P = 0.047), and elevated in patients who developed new BMet (P = 0.05)Yao et al., 2011
TGF ARG IGF1 IGF binding protein-3Growth factors61 patients with advanced NSCLC treated with EGFR-TKIs and 63 matched advanced NSCLC control patients without EGFR-TKIs treatmentDisease specific survival (DSS)ELISA Chemiluminescent assaysLow concentrations of TGFα and high concentrations of ARG were associated with a better DSS in EGFR TKIs patients compared with control patients. Patients with high concentrations of IGF binding protein-3 had significantly longer DSS, independent of treatment.Vollebergh et al., 2010
PEDFAngiogenesis inhibitor4 patients with NSCLC and 4 with pneumoniaTumor vs. normal2D-DIGE mass spectrometryPEDF was significantly overexpressed both in serum and pleural effusion from NSCLC patients.Rodríguez-Pi?eiro et al., 2010
TTRCarrier protein146 lung cancer, 13 pneumonia, 28 tuberculous pleurisy and 40 normal individualsTumor vs. normalSELDI ELISADownregulation of TTR was found in both ELISA and SELDI analysis.Liu et al., 2009
EMAP-IIProinflammatory cytokine30 healthy control subjects and 48 patients with untreated NSCLCTumor vs. normalELISAThe high EMAP-II (>100 pg/mL) group had a shorter survival compared with the low EMAP-II (<100 pg/mL) groupSen et al., 2008
CEA RBP AAT SCCA training set from 100 patients (50 with lung cancer and 50 age- and sex-matched controls). blinded validation set from 97 patients (49 lung cancer patients and 48 matched controls)Tumor vs. normal2D-DIGE MALDI-TOF MS90% of patients who fell into any one of three groupings in the CART analysis had lung cancer.Patz et al., 2007
Hp SAHp FHpPreproprotein10 NSCLC and 10 matched control patientsTumor vs. normal2D-DIGE ELISAStatistically significant differences between lung cancer patients and matched controls were found by ELISA for Hp (P<0.002), SAHp (P<0.001), and FHp (P<0.04)Hoagland et al., 2007
Serum cyclin B1 antibodyAntibody291 white subjectsTumor vs. normalELISARegression analysis identified gender as well as age in women smokers to be significant determinants of cyclin B1 antibody levels.Egloff et al., 2005
Tab.2  Serum protein biomarkers for NSCLC identified by 2D-DIGE and ELISA
TypemRNA/miRNASample sizeMethodsDetailsRef.
mRNAhnRNP-B1 Her2/neu18 patients with lung cancer before and during chemotherapyRT-PCRThe hnRNP-B1 mRNA was detectable in 14/18 sera, and Her2/neu-specific mRNA could be amplified from the serum of 7/18 patients.Rodríguez-Pi?eiro et al., 2010
5T45 advanced breast cancer patients, 14 NSCLC patients, and 25 normal controlHeminested RT-PCR5T4 mRNA was reproducibly detected in 8/19 (42%) cancer patient sera, but in only 3/25 (12%) normal control sera (P = 0.035).Liu et al., 2009
CEA103 consecutive patients with NSCLC who underwent a curative lobectomyRT-PCRPatients with CEA mRNA in the preoperative blood samples had a poor survival when compared with those without CEA mRNA.Sen et al., 2008
c-Met45 patients with NSCLC,31 patients with benign lung diseases and 20 normal controlReal-time PCR67.6% (23 of 34 patients) expressed higher amounts of circulating c-met by 1.4 to 8 times that of the normal control subjects. In addition, overexpression of circulating c-met was significantly correlated with nodal (N) stage (P = 0.011) and early recurrence (P<0.05).Patz et al., 2007
EGFR hTERT112 patients with lung tumor and 80 individuals without cancerReal-time PCRSerum hTERT mRNA was independently correlated with tumor size, number, presence of metastasis, recurrence, and smoking (all P<0.05). EGFR mRNA correlated with tumor number and clinical stage (both P<0.05).Hoagland et al., 2007
COX-2128 cancer patients and 103 healthy donorsRT-PCRSerum free COX-2 mRNA expression in peripheral blood were significantly lower in healthy donors than in patients (1.5 vs 2.0, z = - 6.02, P<0.001) and were not related to sex, age or smoking habits in either group.Egloff et al., 2005
miRNAmiR-25 miR-22375 healthy donors and 152 cancer patientsSolexa sequencing Real-time PCRSerum expression levels of miR-25 and miR-223 are significantly increased in LCS than in NS.Fleischhacker et al., 2001
miR-486 miR-30d miR-1 miR-499Discovery stage: 30 patients with longer survivaland 30 patients with shorter survival; Validation: 243 patients (randomly classified into two subgroups: n = 120 for the training set, and n = 123 for the testing set).Solexa sequencing Real-time PCREleven serum miRNAs were found to be altered more than 5-fold by Solexa sequencing between longer-survival and shorter-survival groups, and levels of four miRNAs (ie, miR-486, miR-30d, miR-1 and miR-499) were significantly associated with overall survival.Cheng et al., 2005
miR-1254 miR-574-5p31 controls and 22 patients with early-stage NSCLCReal-time PCRThe expression of hsa-miR-1254 and hsa-miR-574-5p was significantly increased in the early-stage NSCLC samples with respect to the controls.Miura et al., 2006
Tab.3  Serum mRNA/miRNAs biomarkers for NSCLC
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