Dissecting the Mutational Landscape of Cutaneous Melanoma: An Omic Analysis Based on Patients from Greece

Abstract

Melanoma is a lethal type of skin cancer, unless it is diagnosed early. Formalin-fixed, paraffin-embedded (FFPE) tissue is a valuable source for molecular assays after diagnostic examination, but isolated nucleic acids often suffer from degradation. Here, for the first time, we examine primary melanomas from Greek patients, using whole exome sequencing, so as to derive their mutational profile. Application of a bioinformatic framework revealed a total of 10,030 somatic mutations. Regarding the genes containing putative protein-altering mutations, 73 were common in at least three patients. Sixty-five of these 73 top common genes have been previously identified in melanoma cases. Biological processes related to melanoma were affected by varied genes in each patient, suggesting differences in the components of a pathway possibly contributing to pathogenesis. We performed a multi-level analysis highlighting a short list of candidate genes with a probable causative role in melanoma.

Keywords: FFPE; SNPs; bioinformatics; cutaneous melanoma; somatic mutations; whole exome sequencing.

Figure 1

Mutation spectrum for each patient. C > T transitions account for 85.6% of the mutations (median rate).

Figure 2

(a) Common genes between the 73-genes list, the 1571 Network of Cancer Genes (NCG) genes and the >5% mutated genes in melanoma from COSMIC; (b) Characterisation of genes carrying non-synonymous mutations based on COSMIC data. M-melanoma-associated genes (>20% mutated in COSMIC) and C-cancer-census genes (>5% in melanoma samples). * Denotes genes highlighted by MutSigCV (version 1.41).

Figure 3

(a) Statistically significant biological processes with the corresponding number of genes found as mutated in at least one patient; (b) 30 top-prioritised mutated genes, D-probably damaging and P-possibly damaging mutation, as predicted by PolyPhen2.