Prognostic and predictive blood biomarkers in gastric cancer and the potential application of circulating tumor cells

Table 2 Detection of cell-free tumor DNA in gastric cancer

Candidate biomarkers	Sample size	Sample type	Method/technology	Diagnostic value/outcome	Ref.
Total cell-free DNA level b-actin	GC = 53, HC = 21	Plasma	qPCR	AUC = 0.75, P < 0.0001	Sai et al[31], 2007
DNA methylation markers RPRM (Reprimo)	GC = 43, HC = 31	GC tissues and plasma	MSP	95.3% GC, 9.7% HC, P < 0.00001; Strong correlation between methyl status in tissues and plasma	Bernal et al[74], 2008
Gene amplification MYC gene copy number (MYC/GAPDH ratio)	GC = 57, HC = 39	Tissues and plasma	qPCR	AUC = 0.816; Strong positive correlation between MYC levels in GC tissues and plasma (r = 0.342; P = 0.009)	Park et al[75], 2009
RUNX3	GC (preoperative) = 65, GC (postoperative) = 43, HC = 50	Tissues and serum	qMSP	AUC = 0.8651, Sn = 95.5%, Sp = 62.5%; Decrease after surgical resection	Sakakura et al[76], 2009
KCNA4 + CYP26B1	GC = 46, GPL = 46, HC = 30	Serum	Discovery: Methylation microarray in tissues; Testing: MSP	AUC = 0.917, Sn = 91.3%, Sp = 92.1%	Zheng et al[77], 2011
SLC19A3	Discovery: GC = 45, HC = 60; Validation: GC = 20, HC = 20	Plasma	MSRED-qPCR	Increased in GC, P < 0.0001	Ng et al[78], 2011
Alu DNA sequences	GC = 54, HC = 59	Plasma	Alu81-qPCR	AUC = 0.784, Sn = 75%, Sp = 63%	Park et al[32], 2012
FAM5C + MYLK	GC = 58, GPL = 46, HC = 30	Serum	Discovery: MeDIP in cell lines; Testing: MSP	AUC = 0.838, Sn = 77.6%, Sp = 90% for GC vs HC; Sn = 30.4% for GPL vs HC; Decrease after surgical resection	Chen et al[79], 2012
XAF1	GC = 202, HC = 88	Tumor tissues and serum	qMSP	AUC = 0.909, P < 0.0001; 83.9% concordance between tissues and serum	Ling et al[33], 2013
Total cfDNA level	Early GC = 16; advanced GC = 14; HC = 34	Plasma	Measurement of cfDNA concentration	AUC = 0.991, Sn = 96.67%, Sp = 94.11% for GC vs HC	Kim et al[80], 2014
HER2 + MYC	GC = 81; gastritis = 63; HC = 32	Plasma and tissues	FISH and qPCR	AUC = 0.850, Sn = 69%, Sp = 92%	Park et al[34], 2014
HER2 gene copy number (HER2/RPPH1 ratio)	Discovery: GC = 52 (pre and post-operative treatment), HC = 40;Validation: GC = 25 plasma	Plasma and tissues	qPCR	AUC = 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 cases; Sn = 66.7%, Sp = 100%	Shoda et al[35], 2015
TP53	GC = 6	Plasma	Parallel sequencing	ctDNATP53 mutation in three out of six patients (50%)	Hamakawa et al[81], 2015
AKT1, AKT3, PIK3CA, PTEN, ARID1A, TP53 and BRAF	GC = 277	Plasma and tissues	MassARRAY system	32 out of 94 patients (34%) with a tissue mutation had a corresponding mutation in plasma	Fang et al[82], 2016
HER2	GC = 70	Plasma and tissues	dual-color ISH assay	ctDNA had a high concordance of HER2 amplification with tumor tissues(91.4%, Kappa index = 0.784, P < 0.001)	Gao et al[83], 2017
HER2	GC = 60; HC = 30	Plasma and tissues	digital droplet PCR	The preoperative plasma HER2 ratio correlated with the tumor HER2 status (P < 0.001); Sn = 73.3%, Sp = 93.3%	Shoda et al[36], 2017

AUC: Area under the curve; GC: Gastric cancer; GPL: Gastric precancerous lesions; HC: Healthy controls; MeDIP: Methylated DNA immunoprecipitation; MSP: Methylation-specific PCR; MSRED-qPCR: Methylation-sensitive restriction enzyme digestion and real-time quantitative PCR; Sn: Sensitivity; Sp: Specificity; FISH: Fluorescence in situ hybridization.