Yue-wen Gao， Chun-hua Zhang， Xing-mei Zuo，and Xi-zeng Hui*

Department of Surgery， Rizhao People's Hospital，Rizhao， Shandong 276828， China

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Genetic Basis of Gastric Cancer

Yue-wen Gao， Chun-hua Zhang， Xing-mei Zuo，and Xi-zeng Hui*

Department of Surgery， Rizhao People's Hospital，Rizhao， Shandong 276828， China

gastric cancer； genetic factors

Gastric cancer is the result of multiple risk factors， including environmental factors， genetic factors and the interaction between them. The environmental factors mainly include dietary， Helicobacter pylori infection and family history of gastric cancer. Genetic factors mainly refer to the susceptible genes that cause epigenetic alterations in oncogenes， tumor suppress genes， cell cycle regulators， DNA repair genes and signaling molecules. This paper summarizes the susceptible genes of gastric cancer and explores the genetic basis of it.

Chin Med Sci J 2016； 31（3）：192-195

G astric cancer is the result of complex interaction of environment and multiple genes. The evident risk factors of gastric cancer include dietary，the Helicobacter pylori infection， the family history and the genetic factors.1，2Though there is great progression in the diagnose and treatment of gastric cancer， the survival rate is still stagnant and poor， only about 20 percent of patients with gastric cancer can reach five-year survival. So a systematic view of the genetic basis of gastric cancer is necessary to help establish new strategies for prevention and treatment of gastric cancer. Genetic factors mainly refer to the susceptible genes of cancer that are involved in multiple genetic and epigenetic alterations of oncogenes， tumor suppressor genes， cell cycle regulators， DNA repair genes and signaling molecules.3

ONCOGENES

Oncogenes are genes whose normal activity promotes cell proliferation. Oncogenes function through the mechanism of gene mutation， gene insertion， chromosomal translocation，gene amplification and DNA hypomethylation. Oncogenes can be classified into five broad classes： secreted growth factors； cell surface receptors； components of intracellular signal transduction systems； DNA-binding nuclear proteins；components of the network of cyclins， cyclin-depen-dent kinases （CDKs） and kinases inhibitors that govern progress through the cell cycle.4

C-Met

C-Met， known as hepatocyte growth factor receptor， is encoded by a proto-oncogene， which is a membrane tyrosine kinase. C-Met gene locates at 7q31， and its product of transcription is a 6-kb mRNA， playing an important role in the intracellular signal transduction. Presently， researchersbelieve that C-Met can participate in the process of tumor invasion and metastasis. C-Met expression is positive in 82 percent of poorly differentiated gastric cancer and 50 percent of highly differentiated one. Its expression is evidently associated with the lymphatic metastasis of gastric cancer.5The amplifying of C-Met is related to the progression of gastric cancer. A study which detecting the expression of C-Met protein in 78 cases of gastric cancer tissue by immunohistochemical methods found that the C-Met expression was significantly related to the size，differentiation degree， infiltration depth， and lymph node metastasis. The C-Met was positively expressed in 77.9% of primary lesion of gastric cancer which has lymph node metastasis. The expression of C-Met in gastric cancer could promote the proliferation and metastasis of tumor cells.6Study of gastric mucosa precancerous lesions and C-Met gene expression in gastric cancer tissue revealed that C-Met gene has low expression in superficial gastritis， its expression gradually increased while the lesion developing from gut to hyperplasia， and then evolution of cancer； the advanced gastric cancer has the most significant expression.7So the oncogenesis of gastric cancer is associated with the expression of C-Met proto-oncogene. C-Met may have a synergic effect with osteopontin （OPN）and matrix metalloprotein-9 （MMP-9） in gastric cancer.8

C-erb-B2

C-erb-B2gene is located at 7q21 and its product of transcription is a trans-membrane glycoprotein which could function as a tyrosine kinase. C-erb-B2gene seldom mutates， and is overexpressed in human gastric cancer. Motojima et al9used a multiple factors analysis model to assess the recurrence of gastric cancer and discovered that C-erb-B2positive expression was an independent predictor of recurrent disease. Youemura et al10found that in C-erb-B2positive patients， the relative risk of death and recurrence was 3 to 5 times higher than that in C-erb-B2negative patients， and COX model analysis showed that C-erb-B2was an independent factor that affect the outcome of gastric cancer. Most researchers believe that the expression of C-erb-B2gene plays an important role in the malignant transformation of gastric cancer， lymph node metastasis，tumor proliferation infiltration， as well as some benign pathological changes of stomach.11It is suggested that the overexpression of C-erb-B2gene in gastric cancer has correlation with clinical pathologic staging， histological grade and lymph node metastasis.12

Bcl-2

Bcl-2 gene is the first gene that was found as apoptosis inhibiting gene. The encoded protein is located on the mitochondrial membrane， endoplasmic reticulum retinal and nuclear membrane. The main function of Bcl-2 is to prolong the life of the cell and increase the cell resistance to apoptosis stimulating factors.13It makes cells survive after DNA damage， gather mutation products together， and promote the generation and development of tumor. Studies have found that transgenic mice with overexpression of Bcl-2 was more prone to cancer.14

Chou et al15have found that SC-M gastric cancer cell lines transfected with Bcl-2 can accelerate retinoic acid induced growth suppression of SC-M cells， and Bcl-2 can make the transfected SC-M cells to stop growing 2 days earlier than those cells without transfection. These results indicated that the over expression of Bcl-2 may not only inhibit the apoptosis， but also can inhibit the growth of cells at the same time. Kim et al16found that decreasing the expression of Bcl-2 by RNA interference in MCG-803 gastric cancer cells induced cells apoptosis. Flow cytometry demonstrated the ratio of G0 stage arrest was 17 times higher than the untreated cells， suggesting that inhibiting Bcl-2 expression has a potential application value in treatment of gastric cancer.

TUMOR SUPPRESSOR GENES

P53

P53 gene encodes a 53 kD protein and functions as a regulator of DNA transcription. It bounds directly to DNA and recognizes DNA damage. P53 can induce cell cycle arrest in G1 stage， allow time for DNA to repair when DNA damage is “considered” repairable. When DNA is too excessively damaged to repair， P53 can promote apoptosis to prevent the cell which has an impaired DNA sequence from proliferating as a defective or malignant clone.13Fifty percent of human cancers are associated with p53 gene mutation. Zhu et al17found that no expression of P53 was detected in normal gastric mucosa epithelium， while the abnormal expression of P53 was found in the early stages of gastric mucosal cancer. When the gastric cancer lesions are aggravating， the expressional level of P53 rise throughout the whole cancer process.18Sirak et al19examined P53 expression in 357 patients cases of gastric cancer by immunohistochemical techniques， and found that prognosis of the patients who had positive expression of P53 were significantly worse than those with negative expression of P53， indicating that the over expression of mutant p53 attenuates the inhibition of cancer cells proliferation and promotes invasion and metastasis. It was reported that over expression of p53 and mutation of p53 in gastriccancer tissues were positively correlated with tumor metastasis， recurrence， as well as survival.20

Adenomatous polyposis coli （APC） a nd mutated in colorectal cancers （MCC）

APC and MCC genes both are located at 5q21. Grace et al21examined 120 patients of gastric cancer by immunohistochemical method， they found that 78% patients were absent of APC， indicating that inactivation of APC gene was closely related to the gastric cancer. Tamura et al22analyzed 24 cases of gastric cancer using flow cytometry sorting technology combined with PCR-RFLP， found that the absence rate of the APC gene in early gastric cancer was as high as 100%. Wang et al23reported that APC gene mutation rates of patients with gastric cancer were 32.4% in tumorous tissue and 18.2% in plasma respectively.

Deleted in colorectal carcinoma （DCC）

DCC gene is located at 18q and encodes a protein similar to cell adhesion molecules. Low expression of DCC leads to the decrease of cell adhesion and affects the interactions of normal cells， thus causing cell malignant cell malignant transformation. The level of DCC mRNA expression in gastric cancer tissue with lymph nodes metastasis was lower than that without lymph node metastasis， and it was also lower in differentiated gastric cancer tissue than that of high or moderate differentiated ones.24This indicated that DCC mRNA expression is associated with differentiation and staging of gastric cancer， and could be a marker to predict prognosis.

CELL CYCLE REGULATOR

Growth factors and cytokines regulate the proliferation，differentiation， apoptosis of cells mainly through CDKs and CDK inhibitors. Transforming growth factor-β （TGF-β）suppresses cell proliferation through cyclin-CDK.25，26

P16

P16 gene is located at 9p2.1 and encodes p16 protein，which suppress the interaction of CDK4 and Cyclin D1，inhibit downstream molecule activation and arrest cell cycle at G1 stage. No evidence has been reported on the association of p16 gene methylation with age， sex， tumor location， size and histological type in gastric cancer patients. However， p16 gene methylation was reported to be closely related to the lymph node metastasis and the infiltration depth of pathological changes.27Additionally， it was found that 5-fluorouracil can effectively reduce the recurrence of gastric cancer in patients with p16 gene positive methylation.28The mechanisms was considered that methylation of p16 gene reduce the protein expression in stomach tissue， and increase the number of cancer cells in S phase， so that enhance the absorption of 5-fluorouracil. Thus the inhibition of the gastric cancer cells proliferation by 5-fluorouracil is improved.

P15

P15 gene is located at 9p21 and encodes p15 protein. P15 protein can bind to CDK4 and CDK6， then inhibit the binding of CDK4-Cyclin D1 and CDK6-Cyclin D1， leading to the prohibition of cell proliferation. P15 gene silencing might be a key event intumorigenesis of gastric adenocarcinomas of the intestinal type.29

Rb

Rb gene encodes a 105 kD protein， named pRB， which is located in cell nucleus. It functions through regulating phosphorylation and dephosphorylation and interacting with Cyclins. Expression of Rb family proteins can potentially be used as a prognostic predictor of gastric cancer.30

CONCLUSION AND PROSPECTS

The mechanism of gastric cancer is complicated and influenced by various factors， including environmental risk factors and complex genetic basis. Long-time exposure to the risk factors makes the host vulnerable to stomach diseases which damage the stomach and interfere with its normal function， and finally lead to gene mutations. Accumulations of gene mutations lead to canceration and finally cause cancer. Great challenges still remain in complete understanding mechanism of early gastric cancer formation. Efficient strategy to prevent gastric cancer would be to leading a healthy life style and dietary habits. Identifying markers that has high sensitivity， specificity，and stability for diagnosis and predicting prognosis of gastric cancer is important for the management of the disease. Further studies on the inter-relationship of cancer gene， tumor-suppressor genes and diet， environment are needed. New therapeutic strategies， such as targeted therapy for gastric cancer， are of great significance and will be the focus of researches in future.

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for publication August 19， 2015.

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