Molecular Pathways in Melanomagenesis: What We Learned from Next-Generation Sequencing Approaches

Abstract

Purpose of ReviewConventional clinico-pathological features in melanoma patients should be integrated with new molecular diagnostic, predictive, and prognostic factors coming from the expanding genomic profiles. Cutaneous melanoma (CM), even differing in biological behavior according to sun-exposure levels on the skin areas where it arises, is molecularly heterogeneous. The next-generation sequencing (NGS) approaches are providing data on mutation landscapes in driver genes that may account for distinct pathogenetic mechanisms and pathways. The purpose was to group and classify all somatic driver mutations observed in the main NGS-based studies.Recent FindingsWhole exome and whole genome sequencing approaches have provided data on spectrum and distribution of genetic and genomic alterations as well as allowed to discover new cancer genes underlying CM pathogenesis.SummaryAfter evaluating the mutational status in a cohort of 686 CM cases from the most representative NGS studies, three molecular CM subtypes were proposed: BRAFmut, RASmut, and non-BRAFmut/non-RASmut.

Identification and clinical evaluation of senescence-associated markers to distinguish melanocytic nevi from melanomas

“…The NGS approaches in melanocytic neoplasms have expanded the current knowledge from the clinical and histological features to the molecular alterations, offering insights into their biological implications (Palmieri et al, 2018). The results from whole exome and whole genome sequencing studies in melanomas are available (Berger et al, 2012;Hodis et al, 2012;Krauthammer et al, 2012;TCGA, 2015;Hayward et al, 2017).…”

“…UV signature: It is estimated that 75% of genomic sequence variations are CàT substitutions and <5% CCàTT, as a result of the mutagenic UV-radiation. This makes melanoma the cancer with the highest mutational burden (Palmieri et al, 2018). More than 90% of the BRAF mut and NRAS mut melanomas harbor a UV signature (TCGA, 2015) and UV-radiation is thought to predominate during the stages of melanoma development and nevus initiation, since even BRAF and RAS could be attributed to UVA/UVB damage .…”

“…It is activated by RAS protein and in turn activates MEK1-2 kinases, which activate ERK1-2. BRAF mutations, which were first characterized in 2002, are reported in 50-66% of melanomas (Davies et al, 2002;Palmieri et al, 2018) and at lower frequency in various cancers. They are all within the kinase domain, with V600E (previously reported as V599E) mutation being the most frequent (90%).…”

“…Yet, it is insufficient for melanoma development. BRAF V600E mutations in melanoma are more frequently identified in younger patients and sites with intermittent sun exposure (Palmieri et al, 2018); these non-CSD melanomas can be associated with nevi. In contrast, high-CSD melanomas have other BRAF mutations, activating NRAS or KIT mutations or loss of function in NF1, they occur in older patients and are not associated with nevi (WHO, 2018).…”

“…In contrast, high-CSD melanomas have other BRAF mutations, activating NRAS or KIT mutations or loss of function in NF1, they occur in older patients and are not associated with nevi (WHO, 2018). BRAF mut melanomas have more commonly PTEN and CDKN2A alterations in comparison to RAS mut and BRAF non-mut /RAS non-mut (Palmieri et al, 2018). It controversially seems that BRAF mutation has no prognostic significance on progression free survival, but it has on the overall survival after melanoma progression (Long et al, 2011).…”