Dataset Information

Somatic Mutations in miRNA Genes in Lung Cancer-Potential Functional Consequences of Non-Coding Sequence Variants.

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.

SUBMITTER: Galka-Marciniak P

PROVIDER: S-EPMC6627760 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Somatic Mutations in miRNA Genes in Lung Cancer-Potential Functional Consequences of Non-Coding Sequence Variants.

Galka-Marciniak Paulina P Urbanek-Trzeciak Martyna Olga MO Nawrocka Paulina Maria PM Dutkiewicz Agata A Giefing Maciej M Lewandowska Marzena Anna MA Kozlowski Piotr P

Cancers 20190608 6

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 m ...[more]

PMID: 31181801

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Project description:BackgroundRecently, a number of large-scale cancer genome sequencing projects have generated a large volume of somatic mutations; however, identifying the functional consequences and roles of somatic mutations in tumorigenesis remains a major challenge. Researchers have identified that protein pocket regions play critical roles in the interaction of proteins with small molecules, enzymes, and nucleic acid. As such, investigating the features of somatic mutations in protein pocket regions provides a promising approach to identifying new genotype-phenotype relationships in cancer.MethodsIn this study, we developed a protein pocket-based computational approach to uncover the functional consequences of somatic mutations in cancer. We mapped 1.2 million somatic mutations across 36 cancer types from the COSMIC database and The Cancer Genome Atlas (TCGA) onto the protein pocket regions of over 5,000 protein three-dimensional structures. We further integrated cancer cell line mutation profiles and drug pharmacological data from the Cancer Cell Line Encyclopedia (CCLE) onto protein pocket regions in order to identify putative biomarkers for anticancer drug responses.ResultsWe found that genes harboring protein pocket somatic mutations were significantly enriched in cancer driver genes. Furthermore, genes harboring pocket somatic mutations tended to be highly co-expressed in a co-expressed protein interaction network. Using a statistical framework, we identified four putative cancer genes (RWDD1, NCF1, PLEK, and VAV3), whose expression profiles were associated with overall poor survival rates in melanoma, lung, or colorectal cancer patients. Finally, genes harboring protein pocket mutations were more likely to be drug-sensitive or drug-resistant. In a case study, we illustrated that the BAX gene was associated with the sensitivity of three anticancer drugs (midostaurin, vinorelbine, and tipifarnib).ConclusionsThis study provides novel insights into the functional consequences of somatic mutations during tumorigenesis and for anticancer drug responses. The computational approach used might be beneficial to the study of somatic mutations in the era of cancer precision medicine.

Dataset Information

Somatic Mutations in miRNA Genes in Lung Cancer-Potential Functional Consequences of Non-Coding Sequence Variants.

Publications

Somatic Mutations in miRNA Genes in Lung Cancer-Potential Functional Consequences of Non-Coding Sequence Variants.

Similar Datasets

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