miRNA gene mutations commonly disrupt the proper functioning of miRNA genes

A growing number of mutations are being identified in the noncoding genome, including microRNA (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 >10,000 The Cancer Genome Atlas cancer samples and compared them with the corresponding miRNA sequencing data. Using different analytical approaches and rigorous statistical criteria, we revealed that a substantial fraction of mutations is deleterious for the proper functioning of miRNA genes affecting the level of mature miRNAs, isomiR profiles (precision of DROSHA/DICER1 cleavage), and/or 5p/3p miRNA strand balance. We also showed that most mutations, especially those identified as deleterious, destabilize the structure of miRNA precursors. The analysis showed that many miRNA gene mutations can damage miRNA genes and, if located in disease-related miRNA genes, may be pathogenic variants.