A pan-cancer integrative atlas of expressionand somatic mutations in microRNA biogenesis pathway

Introduction: MicroRNAs (miRNA) are key players in posttranscriptionalgene expression regulation and are known to bederegulated in various cancers. The cellular miRNA pool is producedthrough the activity of a set of proteins that form the miRNAbiogenesis machinery. In This study, we comprehensivelyinvestigated almost all the miRNA biogenesis pathway genes(i.e., DROSHA, DGCR۸, XPO۱, XPO۵, DICER۱, TARBP۲,AGO۱-۴, DDX۵, DDX۱۷, DDX۲۰, PRKRA, GEMIN۴, TNRC۶A)in terms of expression status and genomic mutations inseveral cancer types.Materials and Methods: We analyzed over ۶۷۰۰ samplesacross ۱۳ types of cancer tissue (i.e. Bladder, Breast, Brain,Colon, Esophageal, Kidney, Liver, Lung, Prostate, Stomach,Thyroid, Uterine) using the cancer genome atlas (TCGA)whole-exome datasets. mRNA Raw counts (HTSeq - Counts)were normalized and using the DEseq۲ package in R, then wecompared normal vs. tumor samples expression profiles. Moreover,the cBioPortal database was used for somatic mutationinvestigation for both the TCGA and PCAWG cohorts. Somatic mutation Frequency (Percentage of samples with a somatic mutation)and the lollipop plots were extracted from the cBioPortaldatabase and dissimilarity between genes in terms of alterationfrequency was quantified.Results: Our differential expression analysis revealed thatDICER۱ was either downregulated or remained unchangedacross cancers, which was in contrast to the expression patternsof other main components of the miRNA biogenesis pathway.Interestingly, this different behavior was also observed for themutation analyses where we found that DICER۱ harbored thehighest frequency of deletion and point mutations compared toother canonical genes. Moreover, our analysis indicated that theexpression of the miRNA shuttling proteins XPO۱ and XPO۵was significantly enhanced in almost all the cancer types analyzed,which suggests that the shuttling of miRNAs between thenucleus and the cytosol is considerably deregulated in variouscancers. Finally, we uncovered that the Argonaute family memberAGO۲ exhibited a completely different pattern of expressionand mutation compared to other AGOs.Conclusion: Our comprehensive study reveals that key alterationsoccur in the expression and genomic sequences of miRNAbiogenesis components across different types of cancer andhighlights the specific behavior of canonical genes in terms ofexpression and occurred mutations