Unexpected UVR and non-UVR mutation burden in some acral and cutaneous melanomas

Abstract

Ultraviolet radiation (UVR) mutagenesis causes nearly all cutaneous melanomas, however, since UVR signatures are largely absent in acral melanoma, as well as melanoma in sun-protected sites, the cause of these melanomas is unknown. Wholegenome sequencing data generated as part of the Australian Melanoma Genome Project was supplemented with a detailed histopathological assessment with the melanomas then classified as UVR or non-UVR related, based on their mutation signatures. The clinicopathological characteristics of melanomas with mutation signatures for their subtype were compared. Three (of 35 = 8.6%) acral melanomas, all clinically and pathologically verified as arising from acral or subungual locations, had predominant UVR mutation burden, whereas four (of 140 = 2.9%) cutaneous melanomas showed predominant non-UVR mutations. Among the acral melanomas, the few that were UVR dominant occurred in younger patients, had a higher mutation load and a proportion of mutation burden due to UVR, which was similar to that in melanomas from intermittently UVR-exposed skin. Acral melanomas with a UVR signature occurred most frequently in subungual sites and included tumors harboring BRAF or NF1 mutations. Cutaneous melanomas dominated by non-UVR signatures had lower mutation burdens counts and their primary tumors were thicker and had more mitoses than in other cutaneous melanomas. No histopathological features predicted UVR dominance in acral melanomas or non-UVR dominance in cutaneous melanomas. Our finding of acral/subungual melanomas with predominant UVR mutagenesis suggests that the nail plate and acral skin do not provide complete protection from UVR. Our data also confirm that cutaneous melanomas not caused by UVR are infrequent. Identifying where mutation burden is discordant with primary tumor anatomical site is likely to be clinically significant when determining treatment options for metastatic acral and cutaneous melanoma patients.

Patterns of genomic evolution in advanced melanoma

“…1c ). One acral melanoma had a UV-associated mutational signature, as has also been observed by others 18 , 19 . Overall though, patients with sun-exposed primary tumors had a higher mutational load than patients with primary lesions at sites with little or no such exposure ( p < 0.001, Mann–Whitney U -test [MW]; Supplementary Figure 1a ).…”

Genetic Alterations in Primary Acral Melanoma and Acral Melanocytic Nevus in Korea: Common Mutated Genes Show Distinct Cytomorphological Features

“…NF1 mutations are detected in 14e17% of all melanomas and are associated with the highest mutation burden and strongest UV signature (Cancer Genome Atlas, 2015; Cirenajwis et al, 2017;Hayward et al, 2017). Rawson et al (2017) reported that acral melanomas with high UV signatures occur on subungual sites and harbor BRAF or NF1 mutations. In our study, of 11 patients with NF1 mutations, only one had a left thumbnail subungual melanoma.…”

Physical activity, cardiorespiratory fitness and risk of cutaneous malignant melanoma: Systematic review and meta-analysis

“…Immunosuppressive therapy or immunosuppressive UV radiation-related cell damage also increase the risk of melanoma [ 7 ]. In addition, adiposity, chronic inflammation, and oxidative stress have all been positively related to melanoma incidence [ 6 , 8 , 9 , 56 ].…”

“…UV radiation-related DNA damage is the most relevant modifiable melanoma risk factor, and oxidative stress, chronic inflammation, and impaired immune function all represent contributing factors [ 6 – 9 ]. In contrast, surprisingly little is known about the independent effects of physical activity and cardiorespiratory fitness on melanoma prevention, although physical exercise has a positive impact on numerous biological pathways, such as increased DNA repair capacity, decreased levels of oxidative stress, reduced inflammation, and enhanced immune function [ 10 – 13 ].…”