Challenges of deciphering gastric cancer heterogeneity

Table 1 Selection of commonly altered microRNAs in the peripheral blood of gastric cancer patients

miRNA	Alteration	Sensitivity (%)	Specificity (%)	Ref.
miR1-8a	Up-regulated	80.5	84.6	[125]
miR-21	Up-regulated	-1	-1	[134,202-205]
miR-187	Up-regulated	82.5	60.98	[133]
miR-199a-3p	Up-regulated	80.0	74.0	[206,207]
miR-200c	Up-regulated	65.4	100.0	[122]
miR-371-5p	Up-regulated	75.0	63.4	[133]
miR-378	Up-regulated	87.5	70.7	[133]
miR-451	Up-regulated	96.0	100.0	[208]
miR-486	Up-regulated	86.0	97.0	[208]
miR-223 and miR-21, miR-218	miR-223 and miR-21 were up-regulated, miR-218 was down-regulated	84.3	92.9	[203]
miR-1, miR-20a, miR-27a, miR-34 and miR-423-5p	Up-regulated	80.0	81.0	[209]
miR-221, miR-744, and miR-376c	Up-regulated	82.4	58.8	[210]
miR-375, miR-142-5p	Up-regulated	> 85.0	> 85.0	[211]
miR-19b-3p, miR-16-5p	Up-regulated	49.0	91.0	[212]
		81.3	58.6

¹Different studies reported different sensitivity and specificity values.

Table 2 Selection of genes commonly detected in the peripheral blood of gastric cancer patients who displayed altered methylation patters

Gene	Function12	Specimen	Ref.
APC	Acts as an antagonist of the Wnt signalling pathway	Serum	[171]
BCL6B	Acts as a sequence-specific transcriptional repressor in association with BCL6	Plasma	[162]
CDH1	Cadherins are calcium-dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner in connecting cells	Serum	[158]
DAPK1	Death-associated protein kinase 1 is a positive mediator of gamma-interferon induced programmed cell death	Serum	[161]
GSTP1	Mediates the voltage-dependent potassium ion permeability of excitable membranes	Serum	[161]
KCNA4	Plays an important role in detoxification by catalysing the conjugation of many hydrophobic and electrophilic compounds with reduced glutathione	Serum	[175]
MLH1	Involved in DNA mismatch repair	Serum	[171]
p15 (CDKN2B)	Functions as a cell growth regulator that inhibits cell cycle G1 progression	Serum	[158,161]
p16 (CDKN2A)	Plays an important role in cell cycle regulation by decelerating cell progression from G1 phase to S phase	Serum	[159,160,164,165]
RARB	Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes, such as embryonic morphogenesis, cell growth and differentiation	Serum	[158]
RASSF1A	Required for death receptor-dependent apoptosis	Serum	[174]
RUNX3	It functions as a tumour suppressor, and the gene is frequently deleted or transcriptionally silenced in cancer	Serum	[173,176]
SOX17	Involved in the regulation of embryonic development and in the determination of cell fate	Serum	[213]
TIMP3	Inhibitor of matrix metalloproteinases	Tissues, peritoneal washes, serum	[163,171]
TFPI2	May play a role in the regulation of plasmin-mediated matrix remodelling	Serum	[170]

¹http://www.genecards.org;

²Methylation-specific PCR.

Table 3 Common protein biomarkers used in clinical settings for gastric cancer management

Biomarker	Name of protein	Clinical application	Related cancer types
CEA	Carcinoembryonic antigen	Used as a diagnostic aid in different cancers, primarily colorectal cancer. Additionally used as an aid for monitoring response to treatment and detecting recurrence of disease	Colorectal, pancreatic, breast, lung, thyroid, ovarian, endometrial, liver, and bladder cancers. Elevated in benign conditions, such as smoking, peptic ulcer disease, inflammatory bowel disease, pancreatitis, hypothyroidism, cirrhosis, biliary obstruction, and bronchitis
CA19-9	Cancer antigen 19-9	Used as an aid for assessing the effectiveness of treatment and for detecting the recurrence of disease	Colorectal, oesophageal, liver, and pancreatic cancers. Elevated levels common in benign conditions, such as pancreatitis, biliary disease, cirrhosis, and cystic fibrosis (acute phase)
CA72-4	Cancer antigen 72-4	Used as an aid for monitoring response to treatment and for detecting the recurrence of disease	Ovarian, breast, colon, endometrial, gallbladder, and pancreatic cancer. Elevated levels in rheumatoid arthritis and ovarian cysts
AFP	Alpha fetoprotein	Used as an aid to assess response to cancer treatment	Nonseminomatous germ cell tumours, hepatocellular carcinoma, colon, pancreatic, and biliary cancers. Elevated in benign conditions, such as viral hepatitis, cirrhosis, and pregnancy
b-HCG	Free beta-subunit of human choriogonadotropin	Used as an aid to assess response to cancer treatment	Testicular, ovarian, trophoblastic tumours (choriocarcinomas and invasive hydatidiform moles), pancreatic, lung, bladder, and, rarely, lymphoma and breast cancers. Elevated in benign conditions, such as hypogonadal states, marijuana use; rarely, it is elevated during pregnancy and in postmenopausal women
PG I/II	Pepsinogen I/II ratio	Used as aid for detecting atrophic gastritis	-
HER2/neu	Receptor tyrosine-protein kinase erbB-2, ERBB2	Used as an aid in the selection of appropriate treatment and monitoring treatment responses	Breast (primary or metastatic), lung, bladder and pancreatic cancers, Wilm’s tumour