| OBJECTIVES : Summarize the clinicopathological characteristics of gastric cancer which impact on prognosis by reviewing the experience of diagnosis and treatment on 3121 cases of resectable gastric cancer in our hospital.Analyze the treatment efficiency of the gastric cancer patients before and after subspecialty adjustment.To analyze the regular patten of lympha node metastasis of defferent tumor location.To identify the genomic change of gastric cancer with liver metastasis,and verify the function of the genes which screened by exon sequencing of primary and metastatic sites of gastric cancer with liver metastasis.METHODS:(1)The clinicopathological characteristics and follow-up data of 3121 gastric cancer patients between Dec.2005 and Dec.2014 admitted in Renji Hospital Shanghai Jiaotong University School of Medicine were collected and retrospectively analyzed.The lymph nodes metastasis data of 1142 patients with D2 gastrectomy among the cohort has also been collected.The impact factors on prognosis were analyzed.(2)Paraffin-embedded tissues of 23 gastric cancer cases including primary tumor,liver metastasis and non-cancerous stomach tissue were used to proceed the exon sequencing.Find the significantly mutated gene and pathway by bioinformatics analysis.(3)To verify the function of TGF-β related genes ACVR2 A,SMAD,INHBA in primary sites and tumor microenvironment related gene ASPN,MST1 screened by exon sequencing through transwell experiment.RESULT:(1)In our cohort,2919(93.5%)cases were treated by radical resection,202(6.5%)cases with palliative resection;849 cases(27.2%)were treated with total gastrectomy,2272(72.8%)cases with subtotal gastrectomy;2835 cases(90.8%)were treated with open surgery,286 cases(9.2%)with laparoscopic surgery;134 cases of patients were treated with combined devisceration.There were 596 cases(19.1%)of upper gastric cancer,662 cases(21.2%)of middle gastric cancer,1473 cases(47.2%)of lower gastric cancer,362 cases(11.6%)of total gastric cancer and 28 cases(0.9%)of remnant gastric cancer in our cohort.Mean tumor size was 4.9±3.1 cm,median 4.5cm;1507 cases(48.3%)of diffuse type and 1614 cases(51.7%)of intestinal type with Lauren classification;149 cases(4.8%)of well,716 cases(22.9%)of moderate and 2256 cases(72.3%)of poor with differentiation;567 cases(18.2%)of early gastric cancer,2554 cases(81.8%)of advanced gastric cancer;119 cases(4.7%)of type Ⅰ,351 cases(13.7%)of type Ⅱ,1726 cases(67.6%)of type Ⅲ and 358 cases(14.0%)of type Ⅳ with Borrmann classification in AGC;494 cases(15.9%)of IA,235 cases(7.5%)of IB,338 cases(10.8%)of IIA,431 cases(13.8%)of IIB,391 cases(12.5%)of IIIA,567 cases(18.2%)of IIIB,484 cases(15.5%)of IIIC and 181 cases(5.8%)of IV according to post-operative TNM stage.The average number of lymph node metastasis in cohort was 5.0 ± 7.0 pieces,the median number of lymph node metastasis was 2;the average number of inspected lymph nodes was 23.4±8.5 pieces,the median number of inspected lymph nodes was 22.2719 cases(87.1%)of the patients which the inspected number of lymph node ≥15 pieces.The 1,3,5-year overall survival rates were 86.9%,63.0% and 53.7% respectively of whole group.The 1,3,5-year survival rates of the cases with radical resection were 88.9%,66.7% and 57.4% respectively.The five-year survival rates of patients with different stages of were 92.4% of IA,87.6% of IB,75.7% of IIA,63.2% of IIB,50.1% of IIIA,33.7% of IIIB,20.2% of IIIC and 8.8% stage IV.Univariate analysis showed that age(P<0.001),tumor location(P<0.001),tumor size(P<0.001),Lauren classification(P<0.001),Bormann type(P<0.001),radical surgery(P<0.001),T stage(P<0.001),N stage(P<0.001),M stage(P<0.001),number of lymph nodes inspected(P<0.001),differentiation(P<0.001),nerve invasion(P<0.001)and vessel invasion(P<0.001)were statistically significantly correlated with overall survival of gastric cancer patients.Cox regression analysis showed that tumor size,surgical radical,T stage,N stage,M stage and vascular invasion were independent predictors of long-term survival.After subspecialized reform,incidence of postoperative hemorrhage,anastomotic leak,intra-abdominal infections and overall perioperative complications were decreased compared with which before subspecialized reform,incidence of anastomotic obstruction rise slightly,but not statistically significant;incidence of postoperative pancreatic leakage increased significantly after subspecialized reform.The data of overall survival,blood loss in operation,lymph node resection and postoperative discharge time was significantly improved after subspecialized reform.In 1142 cases of D2 gastrectomy,there was significantly difference from incidence of No.1,No.2,No.3,No.4sb,No.4d,No.5,No.6 and No.12 a lymph node metastasis between groups of upper gastric cancer,middle gastric cancer and lower gastric cancer.In 181 cases of stage IV,there was significant differences of prognosis according to tumor residue.Whether liver metastasis was resectable or not shows significantly different influence on the prognosis of patients with 57 cases with liver metastases.(2)The most characteristic change is the C>T conversion including ACG>ATG,CCG>CTG,GCG>GTG and TCG>TTG in primary tumor and liver metastases of 23 samples of gastric cancer with liver metastasis by exon sequencing.Primary gastric cancer identified 19,227 somatic mutations including 16986 SNVs and 2241 indels.11456 somatic mutations located in the protein coding region,including 7577 non-synonymous mutations,3330 synonymous mutations,and 549 in UTR.Liver metastases identified 9885 somatic mutations including 8998 SNVs and 887 indels.5856 somatic mutations located in the protein coding region,including 4010 non-synonymous mutations,1556 synonymous mutations and 290 in UTR.TP53 is the most significant driver gene of gastric cancer with liver metastasis.Other driver genes(P<0.01)in primary tumor includes ACVR2 A,CNTN6,SMAD4,CCDC62,SULT1B1,NELL2,ACY3,OR51M1,VIP,NIPA2,HCFC2,C17orf80,SRFBP1,CLDN5,CTNNB1,INHBA.The driver gene(P<0.01)in liver metastases includes TP53,CTCFL,ASPN,PLD5,MST1,CEBPE,KLK5,GRAP2,ARHGAP42,FAM9 A,OSTC,CDC27,DEFB129,KLRG1,CNOT3,GABRA6,TTLL13,KLRK1,ZCCHC17,TIGD3,DPEP2,CCDC70,TAS2R16,DOLPP1,PCGF5,CRTC2,DAPP1,PARK2,CCDC28 A,ING2,VAMP7,ZDHHC12 and DYNC1I2.TP53 mutations rate in GC with liver metastasis was significantly higher than GC without distant metastasis in TCGA database(70%VS38%).Biological function and signaling pathways enrichment by KEGG and PANTHER show there are difference in the pathway such as heterotrimeric G-protein signaling pathway-Gi alpha and Gs alpha mediated pathway,cytoskeletal regulation by Rho GTPase,p53 pathway by glucose deprivation,Interleukin signaling pathway,TGF-beta signaling pathway,Notch signaling pathway and so on between gastric cancer with liver metastasis and without distant metastasis.Shared mutation is 5%-52.3% in primary tumor with average of 27.7% and 4.7%-60.0% in liver metastases with average of 33.0%.(3)Transwell experiments showed that interfering TGF-β signaling pathway related genes ACVR2 A,SMAD4 and INHBA will significantly affect the migration of gastric cancer cells,as well as the tumor microenvironment associated protein-coding genes ASPN and MST1.CONCLUSION:(1)Age,tumor location,tumor size,Lauren classification,Bormann type,radical surgery,T stage,N stage,M stage,number of lymph nodes inspected,differentiation,nerve invasion and vessel invasion were statistically significantly correlated with overall survival of gastric cancer patients.Tumor size,surgical radical,T stage,N stage,M stage and vascular invasion were independent predictors of long-term survival.After subspecialized reform of department of gastrointestinal surgery in our hospital,the efficacy of gastric cancer has been improved.Metastasis of different groups of lymph node of D2 radical gastectomy patients is significant related with tumor location.Whether there is residual tumor after gastric surgery in patients of stage IV,and curative resection of liver metastases can have a significant impact on the prognosis.(2)Liver metastases have similar and also special gene mutation compare to primary tumor.TP53 and TGF-β signaling pathway mutant rate was significantly higher in patients of gastric cancer with liver metastasis.Mutant genes in the primary tumor of liver metastases were significantly enriched to biological pathways such as cell motion,tumor microenvironment and chromatin remodeling.(3)Alternative of TGF-β signaling pathway related gene ACVR2 A,SMAD4,INHBA and tumor microenvironment related gene ASPN,MST1 can influence the migration capacity of gastric cancer cell. |
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