Identification Of Predisposition Genes And Prognostic Genes In Gastric Cancer

Gastric cancer(GC)is one of the most common malignancies worldwide.The incidence rate in Asia is significantly higher than that in western countries.GC is a multifactorial disease[3],among all the reasons,infections,smoking and diet habit factors are acknowledged[4],however,the genetic factor has been reported to play its role in tumorigenesis of GC[5].About 10%of GC cases occurred in families.CDH1 was the earliest predisposition gene and account for 30%～40%of hereditary diffused gastric cancer(HDGC)cases[6].Germline mutations in ATM,PALB2 and BRCA1 were also reported to play a causative role in GC lately[7,8].A recent study report the discordance of mutations between Asian and Caucasian populations with GC[9],which indicate the necessity to conduct research in different populations.Moreover,germline mutations in non-HDGC is still largely unknown,and almost all the studies in genetics of GC are regardless of specific populations.Additionally,the prognosis of GC is poor.Five-year survival rate is reported to be less than 10%[2].The mechanism of metastasis and prognosis of gastric cancer remains mysterious.Therefore,identification of genes related to the prognosis of gastric cancer will be helpful for clinical treatment.This study consists of two parts.In the first part,germline mutations was analyzed using large scale genomic data from a published research[10]and The Cancer Genome Atlas(TCGA)[11].The mutation frequency of cancer predisposition genes were calculated and validated in another 78 GC patients from Chinese cohort by targeted sequencing.As a result,we found that MSH6,MUTYH and MLH1,which are critical in DNA repair pathway,have a higher rate of deleterious mutation in Asian GC population.In the second part,genes associated with prognosis or differentiated type in gastric cancer were identified from frequently mutated genes or highly-expressed genes using large scale genomic data from The Cancer Genome Atlas(TCGA).The frequency of deleterious somatic mutations for each gene was calculated to select the frequently mutated genes.DESeq2 was used to analyze the gene expression data.Then survival analysis was performed on highly-expressed genes in the tumor tissue and significance was evaluated by log-rank test.As a result,the frequency for deleterious mutations in PIK3CA and APC was significantly discordant between different grades of gastric cancer.2040 genes were up-regulated in tumor tissue,while 2357 genes were down-regulated.Among the up-regulated genes,7 genes were associated with poor prognosis of gastric cancer and one was associated with better prognosis.In this study,by analyzing TCGA gastric cancer dataset and sequencing data from GC patients of Chinese cohort,we have identified genes with a higher deleterious germline mutation rate in GC patients of Chinese cohort and genes associated with differentiation types or prognosis in TCGA GC cohort.Our work will provide clues for future research on potential prognostic markers in clinical treatment.