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Copyright ©The Author(s) 2015.
World J Gastroenterol. Nov 7, 2015; 21(41): 11636-11653
Published online Nov 7, 2015. doi: 10.3748/wjg.v21.i41.11636
Table 1 Proteomics-based biomarker models for detection of gastric cancer
BiomarkermodelApproach usedSample size and type(cancer/controls)Diagnostic value1Ref.
Five peaks - 3316, 6629, 3217, 3952, 6431 DaMB-WCX, MALDI-TOF-MST: GC = 32/HC = 32AUC = 0.86-0.99 for individual features (P < 0.001),Yang et al[148], 2012
V: GC = 30Sn = 79.3%, Sp = 86.5%
(GC I-II = 8)/HC = 30Sn = 71.7% for early stage GC
1546 Da (SERPINA1)MB-WCX, MALDI-TOF-MS; ELISA for validationT: GC = 70/HC = 72AUC (1546 Da) = 0.83 (P < 0.001), AUC (5335 Da) = 0.87 (P < 0.001) - calculated for training set; in validation set SERPINA1 concentration was significantly higher for GC patients than for all other controls (P < 0.001) and ENOSF1 concentration was significantly higher for GC patients than HC (P < 0.001)Yang et al[34], 2015
5335 Da (ENOSF1)V: GC = 36/HC = 36, BGD = 30, other cancers = 108
Fibrinogen α-chain, apolipoHPLC, LC-MS/MST: GC = 65/HC = 30, BGD = 23Sn = 90.9%, Sp = 90.6% (P = NA)Liu W et al[37], 2012
V: GC = 44/ HC = 30, BGD = 23
Six peaks at 2873, 3163, 4526, 5762, 6121 and 7778 m/z; For stage I three peaks at 2873, 6121 and 7778 m/zProtein Chip SELDI-TOF-MSGC = 169 (GCI = 27)/HC = 83Sn = 93.5%, Sp = 91.6%Li et al[26], 2012
Accuracy for stage I - 88.9%, (P = NA)
EGFR, proApoA1, ApoA1, TTR, RANTES, VN, DD, IL-6, A2M, CRP, PAI1xMAP (Luminex), ELISAT: GC = 120/BGD = 101, HC = 19AUC = 0.95, (P < 0.05)Ahn et al[35], 2012
V: GC = 95 (GC I-II = 75)/BGD = 43, HC = 8Sn = 88.8%, Sp = 89.7%
Sn (I-II ) = 92.3%
Sn (tumor size ≤ 2 cm) = 81.8%
Four peaks at 1867 (tubulin beta chain), 2701 (thymosin beta4 like protein3), 2094 (cytochrom b-c1 subunit), 1467 DaMB-WCX, MALDI-TOF-MST: GC = 40/HC = 39AUC (1867 Da) = 1,Fan et al[30], 2013
V: GC = 40/GA = 30, HC = 39AUC (1467 Da) = 0.83
AUC (2701 Da) = 0.71
AUC (2094 Da) = 0.70 (P < 0.05)
Sn = 95.0%, Sp = 97.1%
50 decision trees, 28 massesProtein Chip SELDI-TOF-MS,T: GC = 41/HC = 49Sn = 100%, Sp = 96.7%Ebert et al[24], 2004
V: GC = 28; GCI = 9/HC = 30For stage I Sn = 89.9%
(P = NA )
Three peaks at 3946, 3503 and 15958 DaSn = 92.8%, Sp = 86.7%
For stage I Sn = 89.9%
(P = NA )
Table 2 Autoantibody signatures with diagnostic value for gastric cancer
Biomarker signature descriptionTechnologyStudy designSample size (GC/controls)Diagnostic valueRef.
2 TAAs – p62, KocELISAGC vs HC135/82Sn = 19.3%, Sp = 97.6%, P < 0.01Zhang et al[62], 2001
3 TSAs - IQGAP3, KRT23 and REG3APARSE assayGC vs HC (age and sex matched)48/46Sn = 22.9%, Sp = 100%, P < 0.001Xu et al[149], 2012
3 TAAs – p16, p53, c-mycELISAGC vs HC74/82Sn = 21.6%, Sp = 97.6%; P < 0.001Looi et al[150], 2006
7 TAAs - p53, C-myc, p16, IMP1, Koc, p62 and SurvivinELISACardia GC vs HC88/140AUC = 0.73, Sn = 64%, Sp = 87%, P < 0.001Zhou et al[68], 2015
7 TAAs - C-myc, Cyclin B1, IMP1, Koc, P53, p62 and SurvivinELISA, fixed cut-offGC vs HC91/346Sn = 52.7%, Sp = 89.9%, P < 0.01Zhang et al[63], 2003
ELISA, individual cut-off (recursive partitioning)GC vs HC91/346Sn = 98.9%, Sp = 93.1%, P < 0.001Koziol et al[151], 2003
45 T7 phage-displayed TAA clones (including NY-ESO-1, DDX53, MAGE antigens etc.)T7 phage displayed TAA microarrayGC vs HC (age and sex matched)T:100/100AUC = 0.79, Sn = 59%, Sp = 90%, P < 0.001Zayakin et al[56], 2013
V:235/213
GC vs gastritis235/100AUC = 0.64, Sn = 58.7%, Sp = 55%, P < 0.001
GC vs gastric ulcer235/54AUC = 0.76, Sn = 58.7%, Sp = 81.5%, P < 0.001
Table 3 Cell-free DNA as biomarkers for detection of gastric cancer
Candidate biomarkersSample size and typeMethod/technologyDiagnostic value/outcomeRef.
Total cell-free DNA level
β-actin (total cf DNA level)GC = 53, HC = 21, plasmaqPCRAUC = 0.75, P < 0.0001Sai et al[90], 2007
DNA integrityqPCR (ratio of long vs short b-actin amplicons)No significant difference between GC and HC
Alu DNA sequencesGC = 54, HC = 59; plasmaAlu81-qPCRAUC = 0.784, Sn = 75%, Sp = 63%Park et al[91], 2012
Total cfDNA levelEarly GC = 16; advanced GC = 14; HC = 34; plasmaMeasurement of cfDNA concentrationAUC = 0.991, Sn = 96.67%, Sp = 94.11% for GC vs HCKim et al[92], 2014
Gene amplification
MYC gene copy number (MYC/GAPDH ratio)GC = 57, HC = 39; tissues and plasmaqPCRAUC = 0.816; strong positive correlation between MYC levels in GC tissues and plasma (r = 0.342; P = 0.009)Park et al[99], 2009
HER2 gene copy number (HER2/RPPH1 ratio)Discovery: GC = 52 (pre and post-operative treatment), HC = 40; plasma and tissuesqPCRAUC = 0.746, Sn = 53.9%, Sp = 96.7%; Positive correlation between GC tissues and plasma (r = 0.424; P = 0.00721); decrease in post-treatment plasma in HER2 + GC casesShoda et al[100], 2014
Validation: GC = 25 plasmaSn = 66.7%, Sp = 100%
DNA methylation markers
RPRM (Reprimo)GC = 43, HC = 31; GC tissues and plasmaMSP95.3% GC, 9.7% HC, P < 0.00001; Strong correlation between methyl status in tissues and plasmaBernal et al[107], 2008
RUNX3GC (preoperative) = 65, GC (postoperative) = 43, HC = 50, tissues and serumqMSPAUC = 0.8651, Sn = 95.5%, Sp = 62.5%; decrease after surgical resectionSakakura et al[152], 2009
KCNA4 + CYP26B1GC = 46, GPL = 46, HC = 30; serumDiscovery: Methylation microarray in tissues; Testing: MSPAUC = 0.917, Sn = 91.3%, Sp = 92.1%Zheng et al[109], 2011
SLC19A3Discovery: GC = 45, HC = 60; plasmaMSRED-qPCRIncreased in GC, P < 0.0001Ng et al[153], 2011
Validation: GC = 20, HC = 20AUC = 0.82, Sn = 85%, Sp = 85%
FAM5C + MYLKGC = 58, GPL = 46, HC = 30; serumDiscovery: MeDIP in cell lines; Testing: MSPAUC = 0.838, Sn = 77.6%, Sp = 90% for GC vs HC; Sn = 30.4% for GPL vs HC; decrease after surgical resectionChen et al[154], 2012
XAF1GC = 202, HC = 88, tumor tissues and serumqMSPAUC = 0.909, P < 0.0001; 83.9% concordance between GC tissues and serumLing et al[108], 2013
Table 4 Cell-free RNAs as biomarkers for detection of gastric cancer
Candidate biomarkersSample size and typeMethod/technologyDiagnostic value/outcomeRef.
Circulating cell-free miRNAs
miR-106a/let-7a ratioGC = 69, HC = 30; plasmaqRT-PCRAUC = 0.879, Sn = 85.5%, Sp = 80%Tsujiura et al[117], 2010
5-miRNA signature: miR-1, miR-20a, miR-27a, miR-34, miR-423-5pDiscovery: GC = 20, HC = 20; Validation: GC = 142, HC = 105; SerumDiscovery: Solexa sequencing; Testing: qRT-PCRAUC = 0.831 (validation set)Liu et al[155], 2011
miR-451Discovery: pre- and post-operative plasma, GC = 3; Validation: GC = 56, HC = 30Discovery: microarrayAUC = 0.96, Sn = 96%, Sp = 100%; decreased in 90% of post-operation plasma samplesKonishi et al[119], 2012
miR-486Testing: qRT-PCRAUC = 0.92, Sn = 86%, Sp = 97%; decreased in 93% of post-operation plasma samples
miR-378Discovery: GC = 7, CRC = 7, HC = 10;Discovery: microarrayAUC = 0.861, Sn = 87.5%, Sp = 70.73%;Liu et al[122], 2012
Validation: GC = 40, HC = 41; serumTesting: qRT-PCRNo significant differences across stages I-IV
miR-223Test set: GC = 10, HC = 10; Validation: GC = 60, HC = 60; plasmaqRT-PCRAUC = 0.9089Li et al[121], 2012
miR-21AUC = 0.7944
miR-218AUC = 0.7432
3 miRNA combinedAUC = 0.9531, Sn = 84.29%, Sp = 92.86%
No significant differences across stages I-IV
3-miRNA signature: miR-221, miR-744, and miR-376cDiscovery: GC = 14, HC = 14;Discovery: TaqMan array, validation: qRT-PCRSn = 82.4%, Sp = 58.8% (for GC vs HC)Song et al[124], 2012
Validation I: GC = 68, HC = 68Sn = 73.3% (for early GC)
Validation II: DYS = 46, HC = 46miR-221 elevated in DYS, no difference from HC for miR-376c and miR-744;
Pre-diagnosis serum samples, GC = 58Increase during GC development;
Sn = 79.3% (for GC 2-5 years before diagnosis)
miR-106bDiscovery: GC = 30, HC = 30qRT-PCRAUC = 0.773 (all in validation set)Cai et al[156], 2013
miR-20aValidation: GC = 60, HC = 60;AUC = 0.859
miR-221plasmaAUC = 0.796
miR-223GC = 50, HC = 47; serumqRT-PCRAUC = 0.85, Sn = 81%, Sp = 78%;Wang et al[157], 2014
Increased in advanced stages
miR-16AUC = 0.90, Sn = 79%, Sp = 78%
miR-100AUC = 0.71, Sn = 71%, Sp = 58%
Increased in advanced stages
miR-16Discovery: stage I non-cardia GC = 40, HC = HC; Validation: stage I non-cardia GC = 48, HC = 102Discovery: TaqMan array, validation: qRT-PCRAUC = 0.768 (all in validation set)Zhu et al[120], 2014
miR-25AUC = 0.694
miR-92aAUC = 0.732
miR-451AUC = 0.790
miR-486-5pAUC = 0.779
5 miRNA combinedAUC = 0.812, Sn = 72.9%, Sp = 89.2%; In vitro evidence that miR-16, miR-25 and miR92a but not miR-451 and miR486-5p are secreted from cancer cells
miR-222GC = 114, HC = 56; plasmaqRT-PCRAUC = 0.850, Sn = 66.1%, Sp = 88.3%Fu et al[158], 2014
miR-18aGC = 82, HC = 65, plasmaqRT-PCRAUC = 0.907, Sn = 80.5%, Sp = 84.6%; no association with stageSu et al[123], 2014
miR-18aGC = 104, HC = 65, plasma and GC tissuesqRT-PCRAUC = 0.8059, Sn = 84.6%, Sp = 69.2%Tsujiura et al[159], 2015
Overexpressed in GC; in vitro evidence that miR-18a is released by cancer cells; decreased in postoperative plasma
Circulating cell-free mRNAs and long non-coding RNAs
hTERT mRNAGC = 118, CAG = 40, HC = 58; plasmaqRT-PCRAUC = 0.891, Sn = 66%, Sp = 87%; strong positive correlation with advanced stage of GCKang et al[125], 2013
MACC1 mRNAGC = 76, HC = 54, plasmaqRT-PCRSn = 68%, Sp = 89%Burock et al[160], 2015
LINC00152Pre- and post-operative plasma GC = 79, GED = 31, HC = 81qRT-PCRAUC = 0.657, Sn = 48.1%, Sp = 85.2%Li et al[131], 2015