Abstract
Cutaneous melanoma (CM) is the most lethal tumor among skin cancers, and its incidence is constantly increasing. A deeper understanding of the molecular processes guiding melanoma pathogenesis could improve diagnosis, treatment and prognosis. MicroRNAs play a key role in melanoma biology. Recently, next generation sequencing (NGS) experiments, designed to assess small-RNA expression, revealed the existence of microRNA variants with different length and sequence. These microRNA isoforms are known as isomiRs and provide an additional layer to the complex non-coding RNA world. Here, we collected data from NGS experiments to provide a comprehensive characterization of miRNA and isomiR dysregulation in benign nevi (BN) and early-stage melanomas. We observed that melanoma and BN express different and specific isomiRs and have a different isomiR abundance distribution. Moreover, isomiRs from the same microRNA can have opposite expression trends between groups. Using The Cancer Genome Atlas (TCGA) dataset of skin cancers, we analyzed isomiR expression in primary melanoma and melanoma metastasis and tested their association with NF1, BRAF and NRAS mutations. IsomiRs differentially expressed were identified and catalogued with reference to the canonical form. The reported non-random dysregulation of specific isomiRs contributes to the understanding of the complex melanoma pathogenesis and serves as the basis for further functional studies.
Highlights
Malignant cutaneous melanoma (CM) results from transformation of pigments-producing cells known as melanocytes
Tumor characterization at the small RNA level, when focusing only on canonical miRNAs, has the risk to overlook and lose important information that could improve our understanding of cancer pathogenesis
We provided a comprehensive characterization of isomiR dysregulation in benign nevi, melanoma at different stages and sources, and melanoma metastasis
Summary
Malignant cutaneous melanoma (CM) results from transformation of pigments-producing cells known as melanocytes. Melanoma risk is increased in people harboring specific germline genetic alterations [3], which include mutations in Cyclin Dependent Kinase Inhibitor 2A (CDKN2A) gene [4,5], Cyclin Dependent Kinase 4 (CDK4), Telomerase Reverse Transcriptase (TERT), Microphthalmiaassociated transcription (MITF), BRCA1-associated protein-1 (BAP1), and Protection of telomeres 1 (POT1) [6]. Sporadic cutaneous melanoma is characterized by one of the highest tumor mutation rates, mainly due to UV exposure [7]. The most frequently mutated genes in sporadic melanoma are B-Raf Proto-Oncogene ( known as v-Raf murine sarcoma viral oncogene homolog B, BRAF), neuroblastoma RAS viral oncogene homolog (N-RAS), Neurofibromin 1 (NF1), proto-oncogene receptor tyrosine kinase (KIT) and Phosphatase and Tensin homolog (PTEN) [8]. Based on the pattern of mutated genes, a genomic classification of melanoma has been established and melanomas have been classified into four subtypes: mutant BRAF, mutant RAS, mutant NF1, and Triple-WT (wild-type) [9]
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