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Abstract 4833: Unraveling the role of microRNAs in multiple primary melanoma pathogenesis

Background Malignant cutaneous melanoma is a potentially lethal form of skin cancer whose worldwide incidence has been increasing constantly over the past decades. A fraction of all cutaneous melanoma patients (up to 8%) develop multiple melanomas during their lifetime, usually at a young age and within 3 years from the first tumor/diagnosis, a condition known as multiple primary melanoma (MPM). Patients affected by multiple primary melanoma could have a genetically determined susceptibility, though germline mutations in hereditary melanoma genes are rarely detected in these patients. Therefore, a better characterization of MPM pathogenesis and biological features is of the outmost importance. To characterize the biology of multiple-primary cutaneous melanoma, we performed a global microRNA (miRNA) profile by small-RNA sequencing of single and multiple primary melanomas, including familial melanoma and multiple tumors from the same patient. Material and methods RNA was extracted from formalin-fixed paraffin-embedded (FFPE) tissues of 3 benign nevi (BN), 9 single cutaneous melanomas (CM), 35 MPMs. We assessed the overall miRNA profile by small-RNA sequencing (Illumina). Sequencing data were analyzed using Genespring GX software (Agilent Technologies). The differentially expressed miRNAs were validated in all samples by qRT-PCR using miRCURY LNA assays (Qiagen). Melanoma isomiRs were identified as described in Loheret al. (PMID: 25229428). Pathway enrichment analysis of the differentially expressed miRNAs and their targets was performed using MetaCore software (Clarivate Analytics). Results MPM miRNA profiling revealed that MPMs with and without family history have a similar microRNA profile, which is different from CM and BN. Indeed, 22 miRNAs were differentially expressed in MPM compared to single cutaneous melanoma, including key miRNAs involved in epithelial-mesenchymal transition (EMT). Moreover, the comparison between the first and second tumor from the same patient revealed that the second tumor9s miRNA profile was different. Consequently, ten miRNAs were validated in a larger cohort of single and MPM samples (N=29). From our global miRNA analysis, we also identified some melanoma-specific miRNA isoforms (isomiRs) that showed a differential expression in our dataset and TCGA melanoma samples. We analyzed the pathways specifically regulated by the differentially expressed miRNAs and their network of target genes and the contribution of specific isomiRs to target regulation and MPM development. Conclusion Overall, our study demonstrated a more differentiated and less metastasis-prone status of MPM compared to single primary tumors and provided insights into miRNA/isomiR contribution to multiple melanoma molecular pathogenesis. Citation Format: Elisabetta Broseghini, Elisa Porcellini, Mattia Riefolo, Martina Lambertini, Giorgio Durante, Eric Londin, Annalisa Patrizi, Emi Dika, Manuela Ferracin. Unraveling the role of microRNAs in multiple primary melanoma pathogenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4833.