Unraveling the role of microRNA/isomiR network in multiple primary melanoma pathogenesis

Emi Dika,Cristian Bassi,Manuela Ferracin,Annalisa Patrizi,Eric Londin,Phillipe Loher,Martina Lambertini,Elisa Porcellini,Mattia Riefolo,Massimo Negrini,Isidore Rigoutsos,Elisabetta Broseghini,Giorgio Durante,Cosimo Misciali,Roberta Roncarati

doi:10.1038/s41419-021-03764-y

Abstract

Malignant cutaneous melanoma (CM) is a potentially lethal form of skin cancer whose worldwide incidence has been constantly increasing over the past decades. During their lifetime, about 8% of CM patients will develop multiple primary melanomas (MPMs), usually at a young age and within 3 years from the first tumor/diagnosis. With the aim of improving our knowledge on MPM biology and pathogenesis, we explored the miRNome of 24 single and multiple primary melanomas, including multiple tumors from the same patient, using a small RNA-sequencing approach. From a supervised analysis, 22 miRNAs were differentially expressed in MPM compared to single CM, including key miRNAs involved in epithelial–mesenchymal transition. The first and second melanoma from the same patient presented a different miRNA profile. Ten miRNAs, including miR-25-3p, 149-5p, 92b-3p, 211-5p, 125a-5p, 125b-5p, 205-5p, 200b-3p, 21-5p, and 146a-5p, were further validated in 47 single and multiple melanoma samples. Pathway enrichment analysis of miRNA target genes revealed a more differentiated and less invasive status of MPMs compared to CMs. Bioinformatic analyses at the miRNA isoform (isomiR) level detected a panel of highly expressed isomiRs belonging to miRNA families implicated in human tumorigenesis, including miR-200, miR-30, and miR-10 family. Moreover, we identified hsa-miR-125a-5p|0|−2 isoform as tenfold over-represented in melanoma than the canonical form and differentially expressed in MPMs arising in the same patient. Target prediction analysis revealed that the miRNA shortening could change the pattern of target gene regulation, specifically in genes implicated in cell adhesion and neuronal differentiation. Overall, we provided a putative and comprehensive characterization of the miRNA/isomiR regulatory network of MPMs, highlighting mechanisms of tumor development and molecular features differentiating this subtype from single melanomas.

Highlights

Melanoma is a malignant tumor that develops from transformed melanocytes
multiple primary melanomas (MPMs) patients were tested for germline genetic alterations in CDKN2A, CDK4, and MITF gene[38], and only one patient was found to have a germline CDKN2A mutation
Families with history of melanoma could have a germline mutation that confers hereditary susceptibility and this is demonstrated in families where more than one member develop MPMs40,41

Summary

Introduction

Melanoma is a malignant tumor that develops from transformed melanocytes. The incidence of cutaneous melanoma (CM) has been rising constantly in the past several decades, reaching an age-standardized rate of 17.8, 16.1, and35.8 per 100,000 in Northern Europe, North America, and Australia-New Zealand, respectively (source IARC 2020).CM accounts for 3–5% of all skin cancers, determining up to 65% of the skin cancer-related deaths[1]. Melanoma is a malignant tumor that develops from transformed melanocytes. The incidence of cutaneous melanoma (CM) has been rising constantly in the past several decades, reaching an age-standardized rate of 17.8, 16.1, and. 35.8 per 100,000 in Northern Europe, North America, and Australia-New Zealand, respectively (source IARC 2020). CM accounts for 3–5% of all skin cancers, determining up to 65% of the skin cancer-related deaths[1]. The pathogenesis of CM is complex and poorly understood. Genetic, and phenotypic factors such as ultraviolet (UV) exposure, fair phototypes, multiple dysplastic nevi, and a positive family/ personal history of CM2. A family history of melanoma poses the highest risk for the development of this tumor[3,4]

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Conclusion