Interaction Analysis Between Germline Susceptibility Loci And Somatic Alterations On Gastric Cancer

Objective:Gastric cancer is one of the most common cancers in the world.The majority of gastric cancer cases is sporadic and results from complex interplay between genetic and environmental factors.Environmental risk factors for gastric cancer include high-salt diet,smoking,and infectious agents,which involve the bacterium Helicobacter pylori and Epstein Barr Virus.Besides,the genetic variations have been determined to contribute to the pathogenesis of gastric cancer.A germline mutation(or germinal mutation)is any detectable variation within germ cells(cells that,when fully developed,become sperm and ovum).Large scale of genome-wide association studies have been conducted in recent years,and it have found many susceptibility loci which are related to cancers.There are also several cancer susceptibility loci identified in gastric cancer,including 1q22(MUC1),3q13.32(ZBTB20),5p13.1(PRKAA1),5q14.3(lnc-POLR3G-4),6p21.1(UNC5CL)8q24(PSCA)and 10q23(PLCE1).Somatic mutations keep happening during life time,and there is one kind of somatic mutations which confer selective growth advantage to tumor and is called the driver mutations.A growing number of whole-exome or whole-genome sequencing studies have been conducted to define the landscape of somatic mutations in gastric cancer,and it did identify many driver genes.Meanwhile,the copy number alterations and characteristic mutational signatures were also found to play important roles in the development of gastric cancer.Recent studies have revealed the associations between germline mutations and somatic alterations in tumor development.However,the distinct associations between the genetic susceptibility variants and somatic alterations in gastric cancer are still unknown.So it is necessary to conduct a special analysis which focuses on the interaction between germline susceptibility loci and somatic mutation in gastric cancer.Methods:Our study generally included the enrichment analysis and case-only association analysis to detect the interactions.The cases were consisted of 443 gastric cancer samples from TCGA STAD project.TCGA STAD project conducted the whole-exon sequencing of fresh frozen gastric adenocarcinoma primary tumor tissue and blood or non-malignant gastric mucosa,and the gene mutation information or copy number alteration information of each patient are available online.Risk SNPs related to gastric cancer were extracted from the reported GWAS studies or exome array analyses,and then we defined the cancer susceptibility genes and built the cancer susceptibility regions.We also collected cancer driver genes from previous studies and publicly available database.We performed enrichment analyses to examine whether driver genes are enriched in germline susceptibility regions,and whether cancer susceptibility genes are enriched in driver genes.Then we made a pathway enrichment analysis to explore whether driver genes and susceptibility genes are enriched in the same pathways.Finally,serial association analyses were conducted to investigate how the risk SNP genotypes affect the somatic alterations during gastric cancer development with the logistic regression model and multiple linear regression model.Results:Enrichment analysis showed that gastric cancer susceptibility genes were more likely to be enriched in driver genes than in all the genes(P = 5.78x10-3).The susceptibility genes and driver genes were commonly enriched in 8 biological pathways,including reactome pathway of signaling by PDGF and PPARA activates gene expression.Gastric cancer susceptibility locus of rs2285947 at 7p15.3 was associated with truncation mutation within signaling by PDGF pathway(OR= 0.26,95%CI = 0.12-0.55,P = 3.93x 10-4).The rs1679709 at 6p22.1 was connected with COSMIC Signature 15(P = 0.026).Moreover,rs1679709 was also associated with copy number values of RFC4 which is related to Signature 15.Conclusion:In conclusion,these results provided evidence for the relationship between germline variants and somatic alterations,which facilitate understanding the interactive mechanism of germline variations with somatic alterations in gastric cancer development,and will contribute to the precise medical treatment of gastric cancer in the future.