Somatic mutations in miRNA genes in lung cancer – potential functional consequences of non-coding sequence variants

A growing body of evidence indicates that miRNAs may either drive or suppress oncogenesis. However, little is known about somatic mutations in miRNA genes. To determine the frequency and potential consequences of miRNA gene mutations, we analyzed whole exome sequencing datasets of ∼500 lung adenocarcinoma (LUAD) and ∼500 lung squamous cell carcinoma (LUSC) samples generated in the TCGA. Altogether, we identified >1000 mutations affecting ∼500 different miRNA genes and showed that half of all cancers had at least one such mutation. Mutations occurred in most crucial parts of miRNA precursors, including mature miRNA and seed sequences. We showed that seed mutations strongly affected miRNA:target interactions, drastically changing the pool of predicted targets. Mutations may also affect miRNA biogenesis by changing the structure of miRNA precursors, DROSHA and DICER cleavage sites, and regulatory sequence/structure motifs. We identified 10 significantly overmutated hotspot miRNA genes, including the miR-379 gene in LUAD enriched in mutations in the mature miRNA and regulatory sequences. The occurrence of mutations in the hotspot miRNA genes was also shown experimentally. We present a comprehensive analysis of somatic mutations in miRNA genes and show that some of these genes are mutational hotspots, suggesting their potential role in cancer.