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Background: Strategies to non-invasively detect cutaneous melanoma generally focus on differentiating melanoma from non-melanoma lesions. However, given the variabilities in practice and lack of guidelines, it is important for clinicians to understand how such strategies and technologies perform on borderline lesions of uncertain clinical behavior.  Objective: To evaluate LINC and PRAME gene expression and the presence of somatic mutations in BRAF, NRAS, and/or TERT in severely dysplastic nevi (SDN) and to assess, how combining gene expression and mutation analyses may impact test performance. Materials and Methods : One hundred three eligible skin lesions clinically suspicious for melanoma were non-invasively sampled via adhesive patches to enable genomic analyses. Afterward, these same lesions were immediately surgically biopsied to enable comparisons of genomic analyses with histopathologic diagnoses rendered by a panel of three dermatopathologists.  Twenty-three of these lesions analyzed were deemed borderline lesions of SDN histology by at least one dermatopathologist. RNA-based gene expression positivity by Pigmented Lesion Assay (PLA) analysis was defined by detectable levels of LINC and/or PRAME. DNA-based mutation positivity was defined as detection of somatic mutations in BRAF (non-V600E), NRAS, and/or the TERT promoter.  Results : Adding TERT mutation analyses to PLA gene expression increases the test’s sensitivity to rule out melanoma from 93% to 97% in this study.  In addition, 61% of PLA positive lesions that were not diagnosed as melanoma were found to have severe histologic atypia. PLA-positive lesions histopathologically diagnosed as melanomas harbored TERT mutations in 70% of cases while both SDN and non-melanoma lesions including nevi without severe histologic atypia harbored TERT mutations in 4% of cases.  BRAF non-V600E and NRAS mutations were only found in the melanoma group and adding these mutations did not further enhance the test’s sensitivity.  Conclusions and Relevance : PLA positivity increases with histologic atypia of pigmented skin lesions. Combining TERT mutation analyses with melanoma-associated gene expression provides additional genetic information to further non-invasively risk-stratify pigmented lesions.  These findings furthermore support that pigmented lesions exist on a spectrum of genomic atypia that may prove useful in identifying borderline lesions beyond their morphological appearance.

Risk stratification of severely dysplastic nevi by non-invasively obtained gene expression and mutation analyses