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Table 1. Somatic variance calling tools
Analysis tactic Variant callers
[31]
Heuristic approaches qSNP , RADIA [32] , Shimmer [33] , SOAPsnv [34] , VarDict [35] , VarScan2 [36]
Joint genotype analysis CaVEMan [37] , FaSD-somatic [38] , JointSNVMix2 [39] , SAMtools [40] , Seurat* [41] , SNVSniffer [42] ,
SomaticSniper [43] , Virmid [44]
Allele frequency deepSNV [45] , EBCall [46] , LoFreq [47] , LoLoPicker [48] , MuTect [49] , Strelka [50]
[51]
Haplotype analysis FreeBayes , HapMuC [52] , LocHap [53] , MuTect2 [49] , Platypus [54]
Machine learning BAYSIC [55] , MutationSeq [56] , SNooPer [57] , SomaticSeq [58]
Single-sample analysis GATKcan [59] , ISOWN [60] , OutLyzer [61] , Pisces [62] , SiNVICT [63] , SomVarIUS [64]
[71]
Structural or copy number variation calling APOLOH [65] , BIC-Seq [66] , BreakDancer [67] , Break-Pointer [68] , CNVkit [69] , CoNIFER [70] , Delly ,
HYDRA [72] , GASV [73] , GASVPro [74] , Meerkat [65] , PeSV-Fisher [75] , VariationHunter-CommonLaw [76]
RNA-seq variant calling eSNVdetect [77] , SNPiR [78] , VarDict [35] , VarScan2 [36]

Table 2. Driver mutation calling tools
Analysis tactic Driver callers
Functional impact CanPredict [81] , Condel [82] , FATHMM [83] , GERP++ [84] , GOSS [85] , MutationAssessor [86,87] , MutationTaster [88] ,
Oncodrive-fm [89] , PMUT [90] , PolyPhen-2 [91] , PROVEAN [92] , SIFT [93] , SNPs3D [94] , TransFIC [95]
Mutation frequency DrGaP [96] , MuSiC [97] , MutSig/MutSigCV [25] , Youn and Simon [98]
Machine learning CHASM [99,100] , DMI [101]
Structural or copy number focus ADMIRE [102] , CMDS [103] , GISTIC2 [104] , JISTIC [105]
Positional/structural clustering iPAC [106] , NMC [107]
Pathway/network analysis BioInfoMiner [108] , Dendrix [109] , GSEA [110] , HotNet [109] , MEMo [111] , Multi-Dendrix [112] , NetBox [113] , PathScan [114] ,
Patient-oriented gene sets [115] , RME [116]

most frequently mutated genes of this pathway. Other pathways found significantly altered in CM include
the phosphoinositide 3-kinase (PI3K) pathway, tumour protein 53 (TP53) signaling, cell cycle regulation and
the telomere length maintenance pathway. In the next section, the most significant genes involved in such
key processes, harboring driver mutations, are summarized.

BRAF
The BRAF gene encodes a serine/threonine protein kinase, belonging to the RAF family. This protein acts
as a downstream effector of RAS-signalling in the MAPK cascade, affecting cell proliferation and survival.
Mutations in this gene have been identified in various cancers. According to the COSMIC database 44% of
melanomas arising from skin tissue have mutations in BRAF. In non-acral CM, the BRAF mutation of the
kinase-activation domain at amino acid position 600, is the most common somatic mutation. Interestingly,
BRAF V600E mutation results from a T →A transversion and not a C>T substitution, which is characteristic
of UV light induced mutagenesis. Nevertheless, epidemiological and genomic evidence implies that UV
radiation contributes to the formation of BRAF V600E. Soon after the characterization of BRAF V600E
mutation in melanomas, it became apparent that its distribution greatly differs among different melanoma
subtypes [117] . In particular, BRAF V600E mutations are more common in younger CM patients, whose
melanomas arise on intermittently sun-exposed skin, on anatomical sites such as the trunk and proximal
extremities. In contrast, melanomas arising on chronically sun-damaged skin, usually on anatomical sites
like head, neck and the distal extremities of older individuals, have infrequent BRAF mutations, with
BRAF V600K being more frequent than BRAF V600E [118] . Acral melanomas bear BRAF mutations much
less frequently. Targeting the BRAF-V600E mutant protein with specific inhibitors exposed new therapeutic
aspects for the management of such an aggressive disease. The oncogenic activation of BRAF mutations is
considered a necessary but not sufficient condition to transform melanocytes to melanoma cells, a suggestion
which is also supported by the frequent occurrence of such mutations in benign nevi [119] .

RAS
RAS proteins are small GTPases functioning as GDP-GTP-regulated binary switches that control many
fundamental cellular processes. RAS proteins connect a great variety of upstream signals from activated