title: Identification of microRNAs associated with invasive and aggressive phenotype in cutaneous melanoma by next-generation sequencing.
abstract: A comprehensive repertoire of human microRNAs (miRNAs) that could be involved in early melanoma invasion into the dermis remains unknown. To this end, we sequenced small RNAs (18-30 nucleotides) isolated from an annotated series of invasive melanomas (average invasive depth, 2.0 mm), common melanocytic nevi, and matched normal skin (n=28). Our previously established bioinformatics pipeline identified 765 distinct mature known miRNAs and defined a set of top 40 list that clearly segregated melanomas into thin (0.75 mm) and thick (2.7 mm) groups. Among the top, miR-21-5p, let-7b-5p, let-7a-5p, miR-424-5p, miR-423-5p, miR-21-3p, miR-199b-5p, miR-182-5p, and miR-205-5p were differentially expressed between thin and thick melanomas. In a validation cohort (n=167), measured expression of miR-21-5p and miR-424-5p, not previously reported in melanoma, were significantly increased in invasive compared with in situ melanomas (P<0.0001). Increased miR-21-5p levels were significantly associated with invasive depth (P=0.038), tumor mitotic index (P=0.038), lymphovascular invasion (P=0.0036), and AJCC stage (P=0.038). In contrast, let-7b levels were significantly decreased in invasive and in situ melanomas compared with common and dysplastic nevi (P<0.0001). Decreased let-7b levels were significantly associated with invasive depth (P=0.011), Clark's level (P=0.013), ulceration (P=0.0043), and AJCC stage (P=0.011). These results define a distinct set of miRNAs associated with invasive and aggressive melanoma phenotype.
authors.affiliation: Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, CT, USA.
authors.forename: Sankhiros
authors.initials: S
authors.lastname: Babapoor
authors.affiliation: CICATS Biostatics Center, University of Connecticut Health Center, Farmington, CT, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Wu
authors.affiliation: Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, CT, USA.
authors.forename: James
authors.initials: J
authors.lastname: Kozubek
authors.affiliation: Department of Dermatology, University of Connecticut Health Center, Farmington, CT, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Auidi
authors.affiliation: Department of Dermatology, University of Connecticut Health Center, Farmington, CT, USA.
authors.forename: Jane M
authors.initials: JM
authors.lastname: Grant-Kels
authors.affiliation: Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, CT, USA.|Department of Dermatology, University of Connecticut Health Center, Farmington, CT, USA.
authors.forename: Soheil S
authors.initials: SS
authors.lastname: Dadras
mesh_terms: D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008545:Melanoma / Q000145:classification* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D035683:MicroRNAs / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D012867:Skin / Q000378:metabolism / Q000473:pathology; D012878:Skin Neoplasms / Q000145:classification* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D035683:MicroRNAs