Universally Differentially Expressed Genes In Gastric Cancer:Gain New Insights At The Individual Level

Identifying differentially expressed genes(DEGs)between cancer samples and normal controls is one of the most common ways to investigate carcinogenesis mechanisms.However,for a DEG detected with Student’s t test(T-test)or Significance Analysis of Microarrays(SAM)at the population-level through case-control comparison,we do not know whether it is DE in a particular cancer sample and its dysregulation frequency in a particular cancer type.A big challenge to clinical diagnosis and therapy of gastric cancer(GC)is its extreme heterogeneity,and thus it would be of special importance if we could find common biomarkers besides subtype-specific biomarkers for GC.Here,with gene expression profiles for 448 matched GC and normal tissue samples collected from The Cancer Genome Atlas(TCGA)and Gene Expression Omnibus(GEO)produced by 14 different laboratories,we firstly identified 7556 reproducible DEGs at the population level for GC by T-test.Then,from these DEGs,we identified 67 and 49 genes which were up-regulated and down-regulated,respectively,in at least 90% of the 448 GC samples compared with their own adjacent normal samples,defined as the universal DEGs for GC,including kinases,ion-channel genes,collagen-associated genes,receptors and others.At the same time,we calculated the frequencies of methylation aberrations within the universal DEGs’ promoter regions between 115 matched GC and normal samples.We found 21 universal down-regulated DEGs with significant higher frequencies of differential methylation(FDR<0.01)and 20 of which were hypermethylated with frequencies ranging from 64.35% to 88.70%.This result revealed that many of the DEGs universally down-regulated in GC were partly induced by the DNA hypermethylation in CpG sites within their promoters.For example,KCNE2,down-regulated in 94.57% of GC samples,were hypermethylated in 86.09% of the GC samples.Differential co-expression and pathway enrichment analyses revealed that the universal DEGs may induce GC through deregulating pathways for ECM-receptor interaction,gastric acid secretion,MAPK signaling pathway and other pathways associated with cell proliferation and cell invasion.In conclusion,the genes with universal mRNA expression aberrations in GC tissues are closely related with GC carcinogenesis,which provide potential biomarkers for GC diagnosis and treatment.