Comparison of mutation profiles in primary melanomas and corresponding nodal naevi using next‐generation sequencing

Abstract

Background. Nodal naevi (NN) represent aggregates of melanocytes within peripheral lymph nodes. NN are relatively often found in patients with malignant melanoma (MM), and may mimic metastatic disease. Aim. To study mutation profiles in MM and NN to find out whether NN descend from a primary MM. Methods. Next-generation sequencing was performed on formalin-fixed paraffinembedded tissue of 26 pairs of primary MM and corresponding NN detected by sentinel lymph node biopsy, and 29 MM-characteristic genes were investigated. Results. In this study, 90% of mutations were detected exclusively in either MM or NN, but not both, in the same patient; the percentage of identical NN and MM mutations in the same individual was only 10%. The most frequently discovered shared mutations were a C>G substitution in the CDKN2A gene and in-frame deletion in ARID1A. Oncogenic driver mutations were frequently observed in MM but only rarely in NN. About three-quarters of mutations in both MM and NN were characterized by C>T or G>A substitutions. The detected rate of ultraviolet (UV)related C>T base changes was comparably high in both primary MM (35%) and NN (32%). Conclusions. Based on our data, it seems that NN descend from previously UVexposed BRAF wildtype cutaneous melanocytes, rather than from primary MM or arrested progenitor cells.

Differential Induction of Reactive Oxygen Species and Expression of Antioxidant Enzymes in Human Melanocytes Correlate with Melanin Content: Implications on the Response to Solar UV and Melanoma Susceptibility

“…It has been established that acute exposure to solar UV is an underlying cause of melanomagenesis [ 1 ] and that the epidermal melanin content determines the response of melanocytes to solar UV and the risk for melanoma [ 11 , 43 , 44 ]. Cutaneous melanoma tumors contain somatic mutations in the genes that are associated with the DNA damage response, particularly in repair genes, in addition to an abundance of C > T transitions [ 45 , 46 ]. Given the increasing evidence for the role of oxidative stress in melanomagenesis and the role of melanin in determining the melanoma risk, we conducted this study to compare the antioxidant capacities of human melanocytes derived from different pigmentary phenotypes and their response to the oxidative effects of solar UV.…”

Melanocytic nevi in sentinel lymph nodes: association with cutaneous nevi and clinical relevance in patients with cutaneous melanomas

“…(McCarthy et al 1974 ) (6) Lymph nodes from melanoma surgery are more likely to contain NN than superficial lymph nodes excised for other cancers (Biddle et al 2003 ; Piana et al 2015 ) (7) electron microscopic studies of NN have revealed ultrastructural features identical to those of intradermal nevus cells (Erlandson and Rosen 1982 ). (8) Using next-generation sequencing, comparison of mutation profiles in primary melanomas and corresponding NN suggested that NN descend from cutaneous melanocytes, rather than from primary MM or arrested progenitor cells (Gambichler et al 2021 ).…”

“…It has been shown that also the density of cutaneous nevi of the arms is greater than that of nevi of the legs (Harrison et al 1999 ). Interestingly, the frequency of ultraviolet of ultraviolet light-associated mutations was relatively high not only in primary melanomas but also in NN (Gambichler et al 2021 ). Moreover, ultraviolet light seems to induce the expression of growth factors involved in the early migration process of malignant melanocytes (Wäster et al 2017 ).…”