Abstract
Cutaneous malignant melanoma is the most fatal skin cancer and although improved comprehension of its pathogenic pathways allowed to realize some effective molecular targeted therapies, novel targets and drugs are still needed. Aiming to add genetic information potentially useful for novel targets discovery, we performed an extensive genomic characterization by whole-exome sequencing and SNP array profiling of six cutaneous melanoma cell lines derived from metastatic patients. We obtained a total of 3,325 novel coding single nucleotide variants, including 2,172 non-synonymous variants. We catalogued the coding mutations according to Sanger COSMIC database and to a manually curated list including genes involved in melanoma pathways identified by mining recent literature. Besides confirming the presence of known melanoma driver mutations (BRAFV600E, NRASQ61R), we identified novel mutated genes involved in signalling pathways crucial for melanoma pathogenesis and already addressed by current targeted therapies (such as MAPK and glutamate pathways). We also identified mutations in four genes (MUC19, PAICS, RBMXL1, KIF23) never reported in melanoma, which might deserve further investigations. All data are available to the entire research community in our Melanoma Exome Database (at https://155.253.6.64/MExDB/). In summary, these cell lines are valuable biological tools to improve the genetic comprehension of this complex cancer disease and to study functional relevance of individual mutational events, and these findings could provide insights potentially useful for identification of novel therapeutic targets for cutaneous malignant melanoma.
Highlights
Cutaneous malignant melanoma is the most fatal form of skin cancer and its worldwide incidence has doubled in the past 20 years
By using GATK tool, we identified more than 128,000 single nucleotide variants (SNVs) per sample, of which over 90% were human known polymorphisms according to NCBI dbSNP132 database (Table 1)
Me01 resulted by far the most mutated among the six melanoma cell lines, while Me05 was the less mutated sample, even if this can partly be due to its lower sequencing yields
Summary
Cutaneous malignant melanoma is the most fatal form of skin cancer and its worldwide incidence has doubled in the past 20 years. Research studies conducted over the last decade on melanoma molecular pathogenesis improved the elucidation of its key signaling pathways, such as those mediated by Ras/Raf/MEK/ ERK (alias MAPK), PI3K/Akt/mTOR, Wnt/b-catenin/APC, MITF and glutamate cascade [2]. The understanding of their broad functional interplays and genetic alteration patterns helped to unravel the complexity and heterogeneity of melanoma and in the meantime provided targets for development of new mutationdriven therapeutic approaches (known as targeted therapy). The first combined clinical trial, using BRAF and MEK inhibitors on 162 BRAFV600 mutant melanoma patients, announced encouraging results for progression-free survival improvements [8]. A comprehensive knowledge of melanoma signalling pathways and mutation patterns could suggest potential targets for novel personalized treatments and combinatorial strategies, to improve clinical outcome of cutaneous malignant melanoma patients
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