Abstract
The most common histological subtypes of cutaneous melanoma include superficial spreading and nodular melanoma. However, the spectrum of somatic mutations developed in those lesions and all potential druggable targets have not yet been fully elucidated. We present the results of a sequence capture NGS analysis of 114 primary nodular and superficial spreading melanomas identifying driver mutations using biostatistical, immunohistochemical and/or functional approach. The spectrum and frequency of pathogenic or likely pathogenic variants were identified across 54 evaluated genes, including 59 novel mutations, and the newly identified TP53 loss-of-function mutations p.(L194P) and p.(R280K). Frequently mutated genes most commonly affected the MAPK pathway, followed by chromatin remodeling, and cell cycle regulation. Frequent aberrations were also detected in the genes coding for proteins involved in DNA repair and the regulation and modification of cellular tight junctions. Furthermore, relatively frequent mutations were described in KDR and MET, which represent potential clinically important targets. Those results suggest that with the development of new therapeutic possibilities, not only BRAF testing, but complex molecular testing of cutaneous melanoma may become an integral part of the decision process concerning the treatment of patients with melanoma.
Highlights
Group Male Female ≤66 >66 pT1 (≤1 mm) pT2 (>1–2 mm) pT3 (>2–4 mm) pT4 (>4 mm) Head Trunk Upper extremities Lower extremities SSM NM No Yes No Yes No Yes Absent Non-brisk Brisk No Yes No Yes No Yes melanoma genes lacked a detailed description of how the evaluation of pathogenicity of the detected mutations was performed
next generation sequencing (NGS) analyses of primary CMs from 114 patients (Table 1) revealed on average 288 variants detected per sample, including all the detected synonymous and non-synonymous variants with variant allele frequency (VAF) >10%
In samples with mutually-exclusive BRAF and NRAS mutations, we identified an additional mutation in 34/62 (54.8%) BRAF mutations (BRAFmut) and in 26/35 (74.3%) NRASmut cases, respectively
Summary
Group Male Female ≤66 >66 pT1 (≤1 mm) pT2 (>1–2 mm) pT3 (>2–4 mm) pT4 (>4 mm) Head Trunk Upper extremities Lower extremities SSM NM No Yes No Yes No Yes Absent Non-brisk Brisk No Yes No Yes No Yes melanoma genes lacked a detailed description of how the evaluation of pathogenicity of the detected mutations was performed (especially when it comes to novel, non-curated variants, and single nucleotide variants with a conflicting interpretation). Data on the prevalence of pathogenic and likely pathogenic (class 4 and 5) mutations and their contribution to melanomagenesis has not yet been analyzed systematically. In this study, targeted generation sequencing (NGS) analysis was performed using a custom-designed panel (spanning 219 kbp) in a sample set of 114 primary CMs from Czech patients, all with complete clinico-pathological data. The goal of the study was (i) to perform NGS analysis and a comprehensive biostatistical evaluation of the pathogenicity of the detected variants, (ii) to describe the spectrum and frequency of somatic class 4/5 mutations in primary CMs, (iii) to validate the biostatistical algorithm for pathogenicity prediction, and (iv) to analyze the relationship between frequently mutated genes and clinico-pathological variables or disease outcome, including disease-free survival (DFS), local recurrence-free survival (LFS), and metastasis-free survival (MFS).
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