Genetic variation in microRNA networks: the implications for cancer research

Abstract

Single nucleotide polymorphisms (SNPs) in microRNA (miRNA) genes (miR-SNPs) can be predicted to affect function by modulating the transcription of the primary transcript, pri-miRNA and pre-miRNA processing and maturation, or miRNA–mRNA interactions. Functional support for each of these mechanisms has been found for several individual miR-SNPs. SNPs in mature miRNAs and miRNA binding sites function analogously to modulate the miRNA–mRNA interaction and create or destroy miRNA binding sites. Several elements have to converge for an miRNA binding site SNP to be considered functional: the SNP must have a proven association with cancer, both the miRNA and its predicted target must be expressed in the tissue, and the allelic changes must result in differential binding of the miRNA and affect expression of the target gene. Computational prediction of miRNA binding sites and up-to-date coverage of SNPs is an essential part of these studies. Programs such as Patrocles and PolymiRTS intercalate and cross-reference these data with dbSNP information, and as such are invaluable in aiding the search for polymorphic miRNA binding sites. Case–control studies have provided evidence for an association of miR-SNPs and SNPs in miRNA-binding sites and cancer risk. These studies differ in the degree of functional support for the predicted interaction and mechanistic insight, as well as validation status. Although still lacking biological validation, SNPs in the miRNA processing machinery are likely to affect the miRNAome as a whole, perhaps leading to overall suppression of miRNA output. Despite several reported associations, none of the studies of SNPs in miRNA processing machinery has been independently validated, nor has the biological mechanisms of how they affect miRNA maturation and cancer been delineated. IsomiRs are miRNA structural variants that may arise from variable cleavage sites for DROSHA and DICER1 in the hairpin. A few isomiRs have been implicated in cancer, but associations with cancer risk have not been established. Both the regulatory and coding regions of genes can harbour miRNA binding sites, but research in this area remains scant. Sensitive alleles identified in epidemiological studies, but with obscure functional roles, should perhaps be tested under miRNA prediction algorithms that are not limited to the 3′ untranslated region of genes, particularly if evidence indicates that altered expression of that gene can be associated with the phenotypes.