Abstract
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 569 lung adenocarcinoma (LUAD) and 597 lung squamous cell carcinoma (LUSC) samples generated in The Cancer Genome Atlas (TCGA) project. Altogether, we identified 1091 somatic sequence variants affecting 522 different miRNA genes and showed that half of all cancers had at least one such somatic variant/mutation. These sequence variants occurred in most crucial parts of miRNA precursors, including mature miRNA and seed sequences. Due to our findings, we hypothesize that seed mutations may affect 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 variants in miRNA genes and show that some of these genes are mutational hotspots, suggesting their potential role in cancer.
Highlights
Lung cancer is the most common cause of cancer-related morbidity and mortality worldwide [1]and is defined as a group of distinct diseases with high genetic and cellular heterogeneity [2]
We identified over 1000 somatic sequence variants in more than 500 different miRNA genes and showed that a substantial fraction of the mutated miRNA genes overlap in the two types of lung cancer
To identify somatic sequence variants in miRNA genes, we took advantage of somatic mutation calls performed on whole exome sequencing (WES) datasets of 569 lung adenocarcinoma (LUAD) and 497 lung squamous cell carcinoma (LUSC) paired tumor/normal samples generated within The Cancer Genome Atlas (TCGA) project
Summary
Lung cancer is the most common cause of cancer-related morbidity and mortality worldwide [1]and is defined as a group of distinct diseases with high genetic and cellular heterogeneity [2]. Non-small cell lung carcinoma (NSCLC) is the most common lung cancer subtype and can be further divided into lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), and large cell carcinoma (LCC). Genetic profiles of these cancers have been revealed by several whole genome and whole. Cancers 2019, 11, 793 exome next-generation sequencing (NGS) projects that led to the identification of thousands of somatic mutations within individual cancer genomes [3,4,5,6] Analysis of these mutations allowed the elucidation of several important protein-coding driver genes, including KRAS, EGFR, BRAF, MET, RIT1, ALK, and NF1 in LUAD and PIK3CA, FGFR1, and PTEN in LUSC [7,8,9]. Key drivers are not yet recognized for substantial fractions of LUAD and LUSC cases [7,8,9,10,11]
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