Abstract: Gastric cancer is the malignant tumor derived from gastric epithelium, and frequently occurs among people over 50 years old. Males have a higher incidence rate than females. With the change of dietary habit, increased working pressure and helicobacter pylori infection, gastric cancer in younger men is increasing. Gastric cancer can occur in any part of the stomach (especially for gastric antrum). Early symptoms are hidden and similar to diseases like gastritis, gastric ulcer etc. Thus, early gastric cancer testing is difficult. Gastric cancer is the fourth most common cancer and the second most deadly cancer. The incidence rate among different genders, countries and races are also varied. East Asia, Eastern Europe, and South America have the highest rate.
Keywords: Gastric Cancer Testing, Biomarker, Detection Method
1. Molecular Markers for Gastric Cancer
1.1. CEA
CEA is the most widely used marker for digestive tract cancer in clinical practice. CEA is known as the independent risk factor for forecasting recurrence of liver metastasis[3]. In the advanced stage of gastric cancer, the CEA level increases. Thus, CEA is not a effective screening method. It's reported that CEA level in ascites can exactly forecast post-surgery peritoneal recurrence after gastrectomy for gastric cancer. Measurement of CEA level by both immunohistochemistry and common cytological examination can improve the sensitivity. Detection of CEA mRNA with RT-PCR can assist in testing micrometastases in abdominal cavity.
1.2. CA19-9
CA19-9 is the glycolipid antigen and usually used as the marker for digestive tract cancers. It's especially expressed in colorectal cancer, pancreatic cancer and gastric cancer. Gastric cancer patients with positive CA19-9 have specific clinicopathological characteristics, e.g. gastric antrum, differentiated tissue, obvious lymphatic and venous invasion, higher metastatic rate of lymph node, advanced stage. The sensitivity and specificity of CA19-9 for recurrence is 56% and 74% respectively. Using together with other tumor markers(e.g. CEA) can obviously improve the sensitivity to 87%.
2. Other Common Biomarkers
Tumor markers(e.g. CA72-4, AFP, CA125) have been widely applied in the gastric cancer testing. CA72-4 usually has higher sensitivity and accuracy than CEA. But applications and researches of CA72-4 in predictive screening and early detection are less. Gastric cancer with positive AFP usually shows higher clinical stages. Liver metastasis easily happens. Compared with AFP negative group, AFP secretory gastric cancer in positive group shows more invasive proliferation and enhanced angiogenesis. CA125 level is thought to be relevant to peritoneal dissemination of gastric cancer. During the radical operation, positive CA125 of patients may be used as the predictor of peritoneal dissemination.
2.1. HER2
HER2 is the first clinical molecular marker for gastric cancer, and coded from the ERBB2 gene on chromosome 17. Prognosis and predictive value of HER2 still remain unknown. But some researches show the incidence rate of HER2 amplification in gastric cancer is 6% - 23%. (mainly seen in intestinal cancer.) Trastuzumab is the first HER2 targeted drug and has been identified as the standard treatment for HER2-positive gastric cancer. Clinical data for supporting the curative effect are available. But drug resistance of HER2 targeted therapy is still the hot research topic. Dysregulation of PI3K/Akt/mTOR pathway is one of the key mechanisms of drug resistance.
3. New Biomarkers
3.1. FGFR2
FGFR family includes FGFR1 till FGFR4, and can bind with FGFs to initiate various cellular processes, e.g. proliferation, differentiation and angiogenesis. Gene amplification of FGFR can result in the overexpression of receptor or increased activity of kinase. Overexpression frequency of FGFR2 is 31.1%, higher than EGFR, HER2 and MET. Researches show amplification of FGFR2 is related to higher clinical stages, lymph node metastasis and poor prognostic survival of gastric cancer.
3.2. E-cadherin
E-cadherin is the transmembrane molecule coded by CDH1 gene, and involved in calcium ion-mediated adhesion between cells. It's very important to adhesion and differentiation of gastric epithelial cells, and also the key factor for preventing malignant transformation. The gene mutation of CDH1 or other inactivated mechanisms is closely relevant to the invasiveness and metastasis of gastric cancer. Hereditary diffuse gastric cancer(HDGC) is caused by germline mutation of CDH1. Carriers of mutations show the 83% risk of gastric cancer. Epigenetic alterations of CDH1 can be used as the prognostic marker. Promoter methylation of CDH1 may be the potential biomarker for gastric cancer.
3.3. MET
MET is both the transmembrane tyrosine kinase receptor and HGF receptor. After activation, it promotes cancer cell growth, angiogenesis, migration and metastasis. Amplification or overexpression of MET is closely relevant to development, therapeutic effect and prognosis of gastric cancer. Immunohistochemical analysis shows expression of MET is related to lymphatic invasion and poor prognostic survival. It's possible to be the prognostic predictor of gastric cancer patients. Besides, MET signaling pathway is related to chemotherapy resistance of gastric cancer. MET may be the predictive marker of chemotherapy. Patients with low level HGF have better reaction to Trastuzumab. Ki-67 antigen is an unstable non-histone nucleoprotein which is highly expressed in axillary nodes except breast tissue. It's obviously related to patients’ shorter life span. Based on the results, patients with higher proliferative activity in lymph node metastasis may require more active treatments and closer clinical surveillance. This biomarker may be the prognostic factor for treatment decision.
3.4. VEGF
VEGF is a key growth factor and involved in tumor associated angiogenesis. It promotes the neovascularization by binding with VEGFR to activate downstream signaling pathway. VEGF and its receptor usually up-regulate in gastric cancer. The inhibited activity can decrease proliferation and invasion metastasis in cancer. Anti VEGF/VEGFR antibodies like ramucirumab have shown the antitumor effect, and are used with chemotherapy for the first(second)-line treatment. High expression of VEGF-D may become the predictive marker for the curative effect of ramucirumab, showing the potential in gastric cancer treatment.
3.5. TP53
TP53 gene is the key tumor suppressor gene, regulating cell growth, apoptosis and DNA damage reaction. In gastric cancer, mutation sites of p53 are wide. Incidence rate is 3.2%-65%. The p53 mutation rate in EBV-associated gastric cancer is low. The 72 codon of TP53 SNP Arg72Pro is related to shorter life span, and can predict chemotherapeutic effect. The disease progression of advanced gastric cancer patients treated with paclitaxel and cisplatin is affected.
3.6. PD-1/PD-L1
PD-1 is the key immune checkpoint. Binding with ligand PD-L1 can inhibit T cell activity and induce tumor immune tolerance. Expression rate of PD-L1 in gastric cancer is 15%-70%, related to poor prognosis. Anti PD-1 antibodies like pembrolizumab and nivolumab improve ability of immune system. Clinical researches show pembrolizumab is effective to treated advanced gastric cancer. Remission rate for patients with positive PD-L1 and MSI-High is especially higher. These markers can be used for predicting therapeutic effect. The research promotes applications of immune checkpoint inhibitors in gastric cancer.
3.7. PIK3CA
Microsatellite is the repetitive sequence of 1-6 nucleotide. MSI is caused by insertion or deletion of these units, resulting in genomic instability and increased tumor risk. In gastric cancer, 15%-30% tumor shows MSI, caused by epigenetic silencing of MLH1 gene. MSI-High (over 30% unstable microsatellite) is related to better prognosis. The invasion and metastasis ability is lower. Korean research shows over 63% MSI-High gastric cancer is involved in specific gene mutation. PIK3CA mutation frequently appears in MSI-positive gastric cancer. PIK3CA inhibitor may be effective. MSI frequency can be used as predictive and prognostic markers for gastric cancer patients.
4. Gastric Cancer Testing
Biomarkers are molecules related to development of cancers. Measuring their level can help to find patients’ abnormal molecular changes. This article summarizes applications of blood based biomarkers in the early gastric cancer testing. High sensitive biomarkers may replace endoscopy, and promote non-invasive, sensitive, specific and cost-effective detection method.
5. Recommended Products
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Target |
Antibody |
Recombinant Protein |
ELISA Kit |
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CEA |
CEA antibody |
CEA recombinant protein |
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CA19-9 |
CA19-9 recombinant protein |
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CA72-4 |
CA72-4 antibody |
CA72-4 recombinant protein |
CA72-4 ELISA Kit |
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AFP |
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CA125 |
CA125 antibody |
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HER2 |
HER2 antibody |
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FGFR |
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E-cadherin |
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HGF |
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VEGF |
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TP53 |
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PD-1 |
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PD-L1 |
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PIK3CA |
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CDH1 |
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CHFR |
CHFR ELISA Kit |
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DAPK |
DAPK recombinant protein |
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GSTP1 |
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RUNX3 |
RUNX3 antibody |
RUNX3 ELISA Kit |
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TFPI2 |
TFPI2 antibody |
REFERENCES
[1]Karimi P, Islami F, Anandasabapathy S, Freedman ND, Kamangar F. Gastric cancer: descriptive epidemiology, risk factors, screening, and prevention. Cancer Epidemiol Biomarkers Prev. 2014 May;23(5):700-13.
[2]Matsuoka T, Yashiro M. Novel biomarkers for early detection of gastric cancer. World J Gastroenterol. 2023 May 7;29(17):2515-2533.
[3]Matsuoka T, Yashiro M. Biomarkers of gastric cancer: Current topics and future perspective. World J Gastroenterol. 2018 Jul 14;24(26):2818-2832.