LAUSR

Tumor ulceration in cutaneous melanoma represents one of the top prognostic indicators for clinical outcome, associated with reduced progression free and overall survival. Despite this influence, the underlying biology driving tumor ulceration remains largely unexplored. One of the potential mediators of ulceration are microRNAs (miRNAs). These short, non-coding RNAs are frequently dysregulated in cancer and can impact tumor biology via mediation of gene expression. Distinct miRNA expression patterns have been identified in melanoma that can function as predictive biomarkers of disease progression and metastasis. However, the presence of a unique miRNA profile in ulcerated melanoma has not yet been assessed. miRNA and mRNA expression was assessed in 35 ulcerated and non-ulcerated cutaneous melanomas using the NanoString Human miRNA and Tumor Signaling 360 mRNA assays and validated in an independent cohort. Linear models and moderated t-tests were used to detect differential expression between ulcerated and non-ulcerated tumors. Pathway enrichment and functional annotations were determined using public databases. Pearson correlations were employed to predict miRNA-mRNA binding pairs. Differentially expressed mRNAs were identified as miRNA targets using Ingenuity Pathway Analysis. Comparison between groups revealed significant upregulation of 13 miRNAs in ulcerated relative to non-ulcerated tumors (p <0.03). 4 of these miRNAs were also significantly upregulated in the validation cohort (miR-363-3p, miR-196b-5p, miR-135b-5p and miR-223-3p, p <0.02). Conversely, 11 miRNAs were significantly downregulated in ulcerated relative to non-ulcerated tumors (p <0.05), of which, miR-376c-5p was also significantly downregulated in the validation cohort (p=0.009). 21 mRNAs were differentially expressed in ulcerated relative to non-ulcerated tumors, with 3 being significant in the validation cohort as well (FPR, IL-11, and ADM, p <0.05). 9 of these 21 mRNAs were then identified as predicted targets of multiple differentially expressed miRNAs in ulcerated tumors. 2 of the differentially expressed mRNAs had an inverse correlation in expression with regulatory miRNAs in our tumor samples (SOCS3 and miR-218-5p, and IL7R and miR-376c-5p). Each of the mRNAs significantly upregulated in both the original and validation cohorts have been previously associated with angiogenesis, migration or pro-metastatic cell survival in the context of cancer and pathway analysis identified significant enrichment for “granulocyte adhesion and diapedesis” (p=0.02) in ulcerated tumors. This study demonstrates that a unique subset of miRNAs and mRNAs are differentially expressed in ulcerated melanoma when compared to non-ulcerated. These findings also provide novel insight regarding how increased angiogenesis and metastasis may contribute to melanoma tumor ulceration. Citation Format: Emily Schwarz, Mallory J. DiVincenzo, Casey Ren, Zoe Barricklow, Maribelle Moufawad, Lianbo Yu, Paolo Fadda, Colin Angell, Sara Zelinskas, Steven Sun, John H. Howard, Catherine Chung, Craig Slingluff, Alejandro A. Gru, Kari Kendra, William E. Carson. Expression patterns of microRNAs and associated target genes in ulcerated primary cutaneous melanoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3764.