Table 1.

Novel biomarkers in the breakthrough of gastric cancer diagnosis

Biomarkers/proteomics techniques	Methods and Investigation	Ref.
MALDI-TOF-MS	Spectral peaks for the peptides with (m/z) values of 1741 and 4210 were the most significantly different between precancerous lesions, GC patients and healthy controls and the sensitivity and specificity of this diagnostic model was found to be clinically significant	Li et al[19]
SELDI	Compared to conventional biomarkers CEA, in a micro-particle enzyme immunoassay, 5 distinct protein peaks at 2046, 3179, 1817, 1725 and 1929 m/z were automatically chosen as components of the best biomarker pattern for diagnosis of GC, with a single protein peak at 4665 m/z, which could distinguish between stage I/II and stage III/IV gastric cancer with high specificity and sensitivity	Lu et al[20]
CTCs	Clinical researches have already proven than the CTC count can effectively predict prognosis, progression free survival (PFS) and overall survival (OS) for breast, prostate and colorectal cancers with good specificity and high repetition rate	Dawson et al[27]
piR-651 and piR-823	piR-651 and piR-823 are significantly lower in the peripheral blood of gastric cancer patients when compared to normal control	Cui et al[29]
miR-421	miR-421 level in CTC obtained from peripheral blood of GC patients was significantly higher than that of their control group and the transfection of miR-421 inhibitors could significantly inhibit tumor growth in vivo	Zhou et al[30]
miR-375 and miR-142-5p	miRNA expression profile in gastric cancer patients indicated that the combination of miR-375 and miR-142-5p could predict recurrence risk for gastric cancer patients	Zhang et al[31]
Survivin mRNA	Survivin mRNA is an independent prediction factor for disease free survival, whereby a high Survivin mRNA expression after radical tumor resection was an indicator of tumor recurrence	Cao et al[34]
B7-H3 mRNA	Quantitative RT-PCR confirmed that B7-H3 mRNA was expressed in all 4 GC cell lines and that the 5-yr survival rate of GC patients with high B7-H3 expression was significantly lower than the ones with low expression	Arigami et al[35]
miR-21, miR-106a and miR-17	miR-21, miR-106a and miR-17 expression patterns showed that the microRNA levels in the GC patients were significantly higher than the control group and the level of microRNA was related to the TNM staging, tumor size and histological classification[38]	Zheng et al[36]
MAGE mRNA	MAGE-1 and MAGE-3 mRNA is expressed in tumor cells and peripheral blood of GC patients while they are not expressed in the healthy controls; suggesting that MAGE could be a specific tumor marker in the detection of CTCs	Wang et al[39]
cfDNA	cfDNA significantly decreased after surgery and therefore, a decrease in the cfDNA level after surgery would imply positive outcome of the surgery and postoperative treatment while an increase in the cfDNA level would indicate poor outcome or signs of disease progression such as metastasis	Huang et al[44], Frattini et al[45], Sozzi et al[46]
cfDNA	As compared to GC patients and advanced GC patients, the level of cfDNA in normal subjects was lower; whereby the level of cfDNA in the 24-h-after-surgery group decreased significantly compared to the pre-operation group	Kim et al[47]
cfDNA	The mean level of plasma cfDNA in GC was 2.4-fold higher in the patient group compared with the control group, indicating that plasma cfDNA levels may be useful for predicting patients with gastric cancer	Park et al[48]
TP53 mutations	Targeted deep sequencing of plasma cell-free DNA by massively parallel sequencing was performed in patients with tumors harboring TP53 mutations and found detectable TP53 mutation levels in preoperative cfDNA to conclude that ctDNA could serve as a useful biomarker to monitor gastric cancer progression and residual disease	Hawakawa et al[49]
p14 promoter methylation	Analysis of GC specimen found that the rate of methylation of the p14 promoter in invasive GC was 45.5%	Leung et al[52]
p15 promoter methylation	Methylation of the p15 promoter was present in GC patients whereby there was a higher detection rate of abnormal methylation of MGMT, p15 and mismatch repair gene as compared to healthy controls	Leung et al[52]
MGMT, p15, and Hm-LH1 Methylation	The methylation specific polymerase chain reaction (MSP) method was used to detect the methylation status of MGMT, p15, and Hm-LH1 and found that there was a high detection rate of MGMT, p15 and Hm-LH1 methylation in the plasma of GC, with an even higher methylation detection rate in stages III, IV and distant metastasis GC while there was no abnormal corresponding methylation in the healthy controls	Kolesnikova et al[53] Tani et al[54]
p15 and p16 Methylation	methylation-specific PCR was used to investigate the methylation status of p15 and p16 in GC cell lines and tumor tissues and the findings implicated that the inactivation of the multiple tumor suppressor gene p15 and p16 genes was associated with the occurrence of GC	Leung et al[55,56]
p16 hyper-methylation	MSP was used to investigate the level of p16 in GC and they found out that the correlation of the immune-activity and hyper-methylation of p16 shows that methylation is an important mechanism for the deactivation of p16 in GC and that the inactivation of p16 expression was accompanied by the hyper-methylation of the promoter	Shim et al[57] Song et al[58]
Runt related transcription factor 3 (Runx3) gene methylation	The pre-operative and post-operative Runt related transcription factor 3 (Runx3) gene methylation level and the results showed that the Runx3 methylation index was related to the tumor grade, tissue type, lymphatic invasion and metastasis and its sensitivity was higher than CEA. On the other hand, the Runx3 methylation level in post-operative serum significantly	Sakakura et al[63]

MALDI-TOF-MS: Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry; SELDI: Surface-enhanced Laser Desorption Ionization; CTCs: Circulating tumor cells; cfDNA: Cell free DNA; ctDNA: Cell tumor DNA; MGMT: O6-methylguanine DNA methyltransferase; GC: Gastric cancer.