| Background:Gastric cancer is the second most deadly malignancy in China.The prognosis of early gastric cancer is significantly better than that of advanced gastric cancer.However,it's unrealistic to apply the current screening methods centered on endoscopy to general screening,and the methods urgently need to be supplemented.However,the molecular mechanism of early stage of gastric carcinogenesis is still unclear.This study used whole exome sequencing to analyze early mucosa(atrophy,intestinal metaplasia,etc.)of the Correa cascade with different outcomes to explore the genomic change of the very early formation of gastric cancer,and to identify molecular markers that are meaningful for the identification of population at high risk of gastric cancer.Methods:In this study,there are patients followed up in Peking Union Medical College Hospital for a long time and collected gastric mucosal samples and blood samples.Patients with atrophic gastritis who didn't progress to gastric cancer after long-term follow-up were selected to constitute the stable group.Patients with early gastric cancer who undergone endoscopic mucosal dissection(ESD)and were followed up by magnifying endoscopy and took gastric mucosal and blood samples more than 6 months before ESD constituted the cancer group.In this way,a retrospective cohort was constructed.Two biopsy samples of the same site more than 3 years apart were taken from patients in the stable group.And the background mucosa before diagnosis of early gastric cancer and the para-cancerous mucosa at the diagnosis of gastric cancer were taken from patients in the cancer group.The genome features of the above samples,such as gene mutation,mutation burden,mutation signatures,microsatellite instability status,and copy number variation,were analyzed by whole exome sequencing.Results:A total of 15 patients in the cancer group and 15 patients in the stable group were included in this study,and 44 and 30 mucosal samples were taken respectively.The pathological diagnosis of mucosa in the two groups was mostly intestinal metaplasia.Whole exome sequencing analysis showed that the gene mutation with the highest frequency in the stable group was TTN(13.3%),while rare cancer-associated gene mutations;the background mucosa of the cancer group contained more cancer-associated gene mutations,such as FAT4,PDE4DIP,APC,MGAM and TNFRSF14.The average mutation burden of the stable group was 0.53±0.59/Mb,and its level was related to the history of Hp infection(p=0.048)and family history of gastric cancer(p=0.034).The average number of mutations in the DNA damage response(DDR)pathway of the cancer group samples was 0.57±1.61,which was significantly higher than that of the stable group(0.10±0.31,p=0.013).The number of DDR pathway mutations was significantly positively correlated to mutation burden(p<0.001,Pearson' s correlation coefficient=0.940).The copy number variation(CNV)analysis of the samples showed that most samples in the cancer group was rich in CNV,and CNV was found both in the mucosa bound to be cancerous and the mucosa bound to be para-cancerous.While in the stable group,all the sample had few CNV.The samples rich in CNV contained multiple oncogene amplification.Conclusion:Before the formation of gastric cancer,the gastric mucosa has already begun to accumulate gene mutations,including some cancer-associated genes.The accumulation of mutations is correlated to defects in DNA damage response pathways.Meanwhile,chromosomal structural variation,mainly copy number gains,also appears in gastric mucosa during about 18 months before the formation of gastric cancer,accompanied by the amplification of oncogenes.Such genomic changes might be diffuse in the gastric mucosa before gastric carcinogenesis. |
PDF Full Text Request