Clinical, environmental and histological distribution ofBRAF,NRASandTERTpromoter mutations among patients with cutaneous melanoma: a retrospective study of 563 patients*

Abstract

Summary Background The distinct somatic mutations that define clinical and histopathological heterogeneity in cutaneous melanoma could be dependent on host susceptibility to exogenous factors like ultraviolet radiation. Objectives Firstly, to characterize patients with cutaneous melanoma clinically and pathologically based on the mutational status of BRAF, NRAS and TERT promoter. Secondly, to elucidate the modified features due to the presence of TERT promoter mutations over the background of either BRAF or NRAS mutations. Methods We performed a retrospective study on 563 patients with melanoma by investigating somatic mutations in BRAF, NRAS and TERT promoter. Results We observed co‐occurrence of TERT promoter mutations with BRAF and NRAS mutations in 26.3% and 6.9% of melanomas, respectively. Multivariate analysis showed an independent association between BRAF mutations and a decreased presence of cutaneous lentigines at the melanoma site, and an increased association with the presence of any MC1R polymorphism. We also observed an independent association between TERT promoter mutations and increased tumour mitotic rate. Co‐occurrence of BRAF and TERT promoter mutations was independently associated with occurrence of primary tumours at usually sun‐exposed sites, lack of histological chronic sun damage in surrounding unaffected skin at the melanoma site, and increased tumour mitotic rate. Co‐occurrence of NRAS and TERT promoter mutations was independently associated with increased tumour mitotic rate. The presence of TERT promoter together with BRAF or NRAS mutations was associated with statistically significantly worse survival. Conclusions The presence of TERT promoter mutations discriminates BRAF‐ and NRAS‐mutated tumours and indicates a higher involvement of ultraviolet‐induced damage and tumours with worse melanoma‐specific survival than those without any mutation. These observations refine classification of patients with melanoma based on mutational status.

The prognostic value of circulating tumor DNA in patients with melanoma: A systematic review and meta-analysis

“…The rapid development of kits for detecting multiple genes and implying multiple mutations has also brought profound changes to the diagnosis, treatment and prognosis of melanoma. BRAF mutations account for the vast majority of melanomas, followed by NRAS, TERT promoter and other specific gene mutations [ 13 , 15 , 33 , 34 ]. There are also references in the literature that gene mutations in melanoma patients are related to drug resistance, such as BRAFV600E and NRASQ61K mutations [11] .…”

Co‐occurrence of TERT promotor mutations with BRAF or NRAS alterations correlates with worse prognosis in melanoma

“…New predisposition genes have been described in melanoma, and key somatic events, such as BRAF mutation, directly translated into target therapy 1 . However, the correlation between the mitogen‐activated protein kinase (MAPK) pathway and TERT promotor gene mutations and clinicopathological features remains elusive in melanoma 2 …”

“…It is known that melanomas arising on the trunk tend to occur in younger individuals and are associated with melanocytic naevi and BRAF mutations 2–4 . Studies have shown that melanomas arising on areas with chronic sun damage tend to develop in older individuals carrying other mutation profiles, including NRAS mutations 1,3 .…”

“…In this issue of the BJD , Manrique‐Silva et al compare clinicopathological variables with mutation profiles in a cohort of Spanish patients with melanoma 2 . Concurrent TERT promotor mutations were observed in 61·4% (148 of 241) of BRAF and 60% (39 of 65) of NRAS mutant tumours 2 .…”

“…In this issue of the BJD , Manrique‐Silva et al compare clinicopathological variables with mutation profiles in a cohort of Spanish patients with melanoma 2 . Concurrent TERT promotor mutations were observed in 61·4% (148 of 241) of BRAF and 60% (39 of 65) of NRAS mutant tumours 2 . The TERT promotor mutations occurred together with BRAF and NRAS mutations, indicating a link between TERT expression and MAPK pathway activation 2 .…”