Abstract
Chronic sun‐damaged (CSD) melanoma represents 10%–20% of cutaneous melanomas and is characterized by infrequent BRAF V600E mutations and high mutational load. However, the order of genetic events or the extent of intra‐tumor heterogeneity (ITH) in CSDhigh melanoma is still unknown. Ultra‐deep targeted sequencing of 40 cancer‐associated genes was performed in 72 in situ or invasive CMM, including 23 CSDhigh cases. In addition, we performed whole exome and RNA sequencing on multiple regions of primary tumor and multiple in‐transit metastases from one CSDhigh melanoma patient. We found no significant difference in mutation frequency in melanoma‐related genes or in mutational load between in situ and invasive CSDhigh lesions, while this difference was observed in CSDlow lesions. In addition, increased frequency of BRAF V600K, NF1, and TP53 mutations (p < .01, Fisher's exact test) was found in CSDhigh melanomas. Sequencing of multiple specimens from one CSDhigh patient revealed strikingly limited ITH with >95% shared mutations. Our results provide evidence that CSDhigh and CSDlow melanomas are distinct molecular entities that progress via different genetic routes.
Highlights
Melanoma can broadly be categorized according to its origin, that is, whether it is localized on skin that shows high chronic sun damage (CSD) or not
We found no significant difference in mutation frequency in melanoma-related genes or in mutational load between in situ and invasive CSDhigh lesions, while this difference was observed in CSDlow lesions
We further demonstrated that intra-tumor heterogeneity is limited throughout progression in a patient case with CSDhigh melanoma
Summary
Melanoma can broadly be categorized according to its origin, that is, whether it is localized on skin that shows high chronic sun damage (CSD) or not. Lentigo maligna (LM), the in situ phase of LMM, can be overlooked, both by patients and during medical examinations, due to its slow growth and strong resemblance to benign hyperpigmented skin lesions. Knowledge of the mutational landscape of CSDhigh melanomas is limited They rarely harbor BRAF V600E mutation, but have recurrent NFKBIE promoter mutations and KIT aberrations, and increased mutational load (Boussemart et al, 2018; Curtin, Busam, Pinkel, & Bastian, 2006; Curtin et al, 2005; Eroglu et al, 2018; Shain, Garrido, et al, 2015). In order to resolve ITH in CSDhigh melanoma, we performed genomic analysis of multiple biopsies from one CSDhigh melanoma patient These data unveiled striking similarity of all specimens on the different genomic levels, with a few notable differences
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