miRNA gene mutations commonly disrupt the proper functioning of miRNA genes

A growing number of mutations are being identified in the noncoding genome, including miRNA genes. However, little is known about the consequences of these mutations and how harmful they are to the functioning of miRNA genes. To evaluate the effects of miRNA gene mutations, we took advantage of a large collection of somatic mutations identified in miRNA genes in > 10K TCGA cancer samples and compared them with the corresponding miRNA-seq data. Using different analytical approaches and highly rigorous statistical criteria, we identified many mutations (n = 87) that affect the level of mature miRNAs (predominantly decreasing), isomiR profiles (precision of DROSHA/DICER1 cleavage), and/or 5p/3p miRNA strand balance. Taken together, the analysis revealed that most miRNA gene mutations, not only those in the seed, may be deleterious for the proper functioning of miRNA genes. We also showed that most miRNA gene mutations destabilize the structure of miRNA precursors and that mutations identified as deleterious are associated with a stronger destabilizing effect. Moreover, although most cancer somatic mutations are randomly occurring neutral variants, some mutations that alter the function of well-known cancer-related miRNA genes, such as MIR21 , MIR142 , or MIR205 , might be functional variants in cancer.