Analysis Of Significantly Mutated Gene In Gastric Cancer And Exploration Of Minimally Invasive Treatment For Early Gastric Cancer

Objective:Gastric cancer is a highly heterogeneous tumor in terms of clinicopathological phenotype and molecular level.We try to screen for mutated genes in gastric cancer through the whole exome and targeted sequencing based on high-throughput sequencing and explore the correlation of gene mutations with clinicopathological phenotypes and tumor prognosis,so as to provide initiative insights in the molecular mechanisms of tumorigenesis,progression,and metastasis in gastric cancer.Methods:Paired tumor and normal DNA samples of gastric cancer patients undergoing radical resection at the Cancer Hospital of the Chinese Academy of Medical Sciences from October 2018 to December 2020 were collected.Significantly mutated genes were identified and analyzed via whole-exome sequencing and targeted sequencing.The correlation between the significantly mutated genes and clinicopathological phenotypes including age of onset,gender,pathological type,degree of differentiation and lymph node metastasis was comparatively analyzed,and all patients were followed up to explore the association between mutated genes and tumor prognosis.Results:A total of 368 mutated genes were detected and 21 significantly mutated genes were identified.Among them,12 genes including TP53,CDH1,IRS2,KRAS and BRCA were found to have statistically significant differences in mutation rates between different clinicopathological phenotypes.Among them,TP53 is the most frequently mutated gene.It tends to mutate in male(72.4%vs 41.5%,p=0.001)and older patients(the age of onset was 58.51±10.45 years old for mutant vs 5391±12.57 years old for wild type,P=0.034).CDH1 gene mutations are more common in diffusely invasive gastric cancer(Borrmann classification)and diffuse type gastric cancer(Lauren classification)(both P<0.05).as well as in female(31.7%for female and 11.8%for male,P=0.009)and yonger patients(52.05±12.80 years old for mutant and 57.83±10.94 years old for wild type,P=0.033).The mutation rates of TP53,EPHA5 and SPTA1 in patients with signet ring cell carcinoma are lower than those without signet ring cell carcinoma(43.4%,0%,5.7%,respectively vs 76.6%,15.6%,21.9%,respectively,P<0.05).The BRCA2 gene mutation rate is higher in patients with lymph node metastasis(12/81,14.8%vs 0/42,0%,P=0.035).In 40 patients with intraoperative peritoneal flushing cytology,the mutation rates of KRAS and IIRS2 genes were higher in patients with positive cytology(33.3%(4/12)vs 3.6%(1/28)for KRAS gene,P=0.037;41.7%(5/12)vs 3.6(1/28)for IRS2 gene,P=0.009).Kaplan-Meier survival analysis showed that PTPRT gene mutation was correlated with the relapse-free survival rate(P=0.015)and EPHA5 and ARID1A gene mutations are related to the overall survival rate of the patients(P=0.000 and P=0.009).Conclusions:This study discovered the correlation of multiple significantly mutated genes with clinicopathological phenotypes and prognosis in gastric cancer.Mutation of CDH1 may be an important prognostic factor for diffuse gastric cancer.Mutation of BRCA2 may be more likely to cause lymph node metastasis in gastric cancer,which lead to a later staging.Mutations of KRAS and IRS2 may be correlated with positive peritoneal lavage fluids.If the association between them can be further verified,they may become potential markers for predicting peritoneal metastasis of gastric cancer.Mutations of EPHA5 and ARID1A may be associated with overall survival,and PTPRT mutation was associated with recurrence-free survival of gastric caner.However,it is necessary to further expand the sample size and extend the follow-up time to verify the reliability of the results.Background:With the improvement of equipment and techniques for endoscopic resection,the indications of endoscopic resection for early gastric cancer have expanded,and the number of cases treated by endoscopic resection has gradually increased.As a result of the limitations of preoperative evaluation,it was found that some patients did not meet the criteria for curative resection through the postoperative pathology.As for those patients,the guidelines suggested additional surgery.However,many patients had no residual tumor or lymph node metastasis after the additional surgery.This study intends to collect clinicopathological data of patients with early gastric cancer who underwent additional surgery after noncurative endoscopic resection to investigate the necessity and safety of salvage surgery.Methods:A total of 56 cases with early gastric cancer receiving salvage surgery after noncurative endoscopic resection were collected and the clinicopathological and follow-up information were analyzed to evaluate the necessity and safety of salvage surgery.The gender,age,and size of the lesion of the patients are the baseline data of the study.The clinicopathological characteristics mainly include the tumor differentiation,the depth of infiltration,Lauren’s classification,tumor remnants and lymph nodes metastasis.The evaluation of clinical outcome includes the operation method,operation time,intraoperative blood loss,number of lymph nodes dissected,surgical complications and recurrence of the tumor.Results:Among the 44 patients(78.6%)with submucosal invasion,38 of them(67.9%)were SM2(invasion submucosal invasion≥500 mm)according to the pathological results after endoscopic resection.There were 33 cases(58.9%)had positive margin.Among them,22 cases(39.3%)were positive for the basal margin,5 cases(8.9%)were positive for the lateral margin,and 6 cases(10.7%)were both positive.18 cases(18/56,32.1%)were undifferentiated cancer,24 cases(24/56,42.9%)had vascular tumor thrombus,and 11 cases had nerve invasion(11/56,19.6%).The rate of lymph node metastasis and positive residual tumor of salvage surgery were 10.7%(6/56)and 25%(14/56)according to the pathological results after gastrectomy.In the multivariate analysis,deeper submucosal invasion resulted as independent risk factor for residual tumor(OR=1.001,95%CI=1.000-1.002,P=0.036).Among the 12 cases with postoperative complications,three of them underwent unplanned reoperations because of anastomotic or intra-abdominal bleeding.There was no difference in the number of retrieved lymph nodes and rate of postoperative complications between laparoscopic and open surgery.Conclusion:For patients with the risk factors of lymph node metastasis after noncurative endoscopic resection,salvage surgery was necessary and laparoscopic approach was safe and feasible.Objective To investigate the therapeutic strategy in patients with early gastric cancer after noncurative endoscopic submucosal dissection(ESD).Method A total of 107 cases with early gastric cancer receiving noncurative endoscopic submucosal dissection were collected and the patients were classified into an additional gastrectomy group(n=41)and a simple follow-up group(n=66)according to the therapeutic method used after noncurative ESD.The clinicopathological information,short-and long-term clinical outcomes between the two groups were analyzed and compared.Results The mean age of the patients in the gastrectomy group and follow-up group was(59.2±8,7)years old and(64.7±8.8)years old,respectively.The depth of submucosal invasion was(1445.83±803.12)and(794.71±815.79)um,respectively.The difference between the two groups was statistically significant(P=0.020 for age and P=0.010 for depth of submucosal invasion).Compared with follow-up group,the undifferentiated histologic type,deep invasion of submucosa(SM2),diffuse type,lymphovascular invasion and neural invasion was more common in the gastrectomy group(P<0.05).The R0 resection rate of ESD in the gastrectomy group was significantly lower than the follow-up group(26.8%vs 65.2%,P=0.000).The positive residual tumor rate and LNM rate of additional gastrectomy group were 31.7%(13/41)and 9.76%(4/41)according to the pathological results after gastrectomy.The gastrectomy group had 2 cases of local recurrence(2/41,4.9%),while 5(5/66,7.6%)in the follow-up group(4.9%vs 7.6%,P=0.883).There was no significant difference in overall survival(OS)and disease-free survival(DFS)between the two study groups(P=0.066 and 0.938,respectively).Conclusion Assessment of LNM risk should be performed in patients with noncurative endoscopic resection.For patients with low risk of LNM who are intolerance of additional gastrectomy due to old age and comorbidities,close follow-up with endoscopy can be considered as an alternative.