Table 2.

Summary of the reported expression and function of the genes identified in the pathway analysis.

Gene	Datasets *			Direction	Reported Expression and Function
	K	S	B
Chemokines Bind Chemokine Receptors
CXCL8				↑CMM	Protein expression increased in CMM vs. nevi by IHC [28,29]
					Promotes melanoma progression and metastasis [33,34,35]
CXCL9 CXCL10				↑CMM	CXCL9 and CXCL10 increased gene expression in CMM vs. BN by qRT-PCR [30]
					CXCL9 and CXCL10 in gene signature that differentiates BN and CMM [55,56,57]
					CXCL9 increased gene expression in melanoma metastases vs. BN [58]
					CXCL9 and CXCL10 recruits CXCR3-expressing effector T cells and natural killer cells into melanoma [59]
					CXCL10 binds CXCR3 on tumor cells to promote metastases [36]
CCL27				↓CMM	Recruits T cells in melanoma mouse model [32]
Peptide Ligand-Binding Receptors
C3AR1				↑CMM	Increases melanoma tumor growth by inhibiting neutrophil and CD4+ T cell responses [31]
IL-4 and IL-13 Signaling Pathways
GATA3				↓CMM	Stabilizes HIF-1α to enhance cancer invasiveness under hypoxic conditions [60]
MMP3				↑CMM	Protein expressed in CMM lesions, but not normal skin, by IHC and IF [61]
					Promotes melanoma tumor growth and metastasis [37]
MMP13				↑CMM	Protein expression in some CMM cases, absent in BN, by IHC [62]
VIM				↓CMM	Protein uniformly expressed in BN and CMM melanocytes by IF [63]
Cytokine Signaling
GZMB				↑CMM	Increased GZMB-expressing cells in DN (severe atypia) and CMM vs. BN and DN (mild atypia) by IHC [42]
FCGR1B				↑CMM	Induced by interferon-γ [64,65]
GBP5				↑CMM	Induced by interferon-γ and type 1 interferons
					Stimulates assembly of NLRP3 inflammasome [39], which expands myeloid-derived suppressor cells in melanoma leading to immunosuppression and increased tumor growth [40]
KPNA2				↑CMM	Promotes proliferation, migration, and invasion in melanoma cells [38,41]
OAS2				↑CMM	Induced by type 1 interferons and important in anti-viral immune response
					Gene expression induced by UVB in human primary melanocytes (qRT-PCR) [66]
Metal Sequestration by Antimicrobial Peptides
S100A7 S100A8 S100A9				↑CMM	S100A7, S100A8, and S100A9 increased gene expression in CMM vs. BN by qRT-PCR [55,56,57]
					S100A7, S100A8, and S100A9 in gene signature that differentiates BN and CMM [55,56,57]
					S100A7, S100A8, and S100A9 linked to tumor growth and metastasis in multiple cancers [43]
					S100A9 promotes migration and metastasis of EMMPRIN-expressing melanoma cells [44]
Immune System
AIM2				↑CMM	Expression in dendritic cells promotes immunosuppressive tumor microenvironment and increased melanoma tumor growth [45]
ASB11				↓CMM	Downregulated by DNA damage, stabilizes pro-apoptotic protein BIK, which increases apoptosis [67]
C1QA				↑CMM	C1q protein (composed of C1QA, C1QB, and C1QC) expressed by mesenchymal cells and immune cells in melanoma by IHC [46] C1qa-/- mice have slower melanoma tumor growth, prolonged survival, decreased tumor angiogenesis, and decreased lung metastasis [46] C1q from non-bone marrow-derived cells promotes accelerated melanoma tumor growth [46] C1q promotes cell adhesion, migration, and proliferation of melanoma cells [46]
C1QB				↑CMM
DFNA5/ GSDME				↑CMM	Gene expression increased in CMM vs. normal skin by RNAseq [68]
					Included in pyroptosis-related gene signature for BN vs. CMM [68]
					Triggers pyroptosis and apoptosis [47]
					Deficiency in melanoma cells increases in vitro and in vivo tumor growth [47]
CHIT1				↑CMM	Produced by macrophages stimulated by interferon-γ and tumor necrosis factor-α [69]
					Increases transforming growth factor-β SMAD signaling [69], which plays role in melanoma metastasis [70] and angiogenesis in various cancers [71]
CTSB				↑CMM	Involved in metastasis [72,73], angiogenesis, and invasion of tumor cells, including melanoma [74,75,76]
FCGR3A				↑CMM	Expressed on subset of natural killer cells [77] Mediates antibody-dependent cell-mediated cytotoxicity [77]
GLA				↓CMM	Patients with GLA deficiency possibly have increased rate of melanoma [78]
KLRD1				↑CMM	Protein expressed on tumor infiltrating lymphocytes in CMM by IHC [79]
					Regulates natural killer cell cytotoxicity [79]
PYGL				↓CMM	Differentially expressed in BN with and without V600E BRAF mutation by microarray [80]
					Involved in glycogen metabolism, which regulates inflammatory responses and tumorigenesis [81,82,83]
RNF182				↑CMM	Suppresses Toll-like receptor-triggered immune response and decreases production of proinflammatory cytokines [84]
TREM2				↑CMM	Encodes for innate immune receptor on tumor infiltrating myeloid cells [85]
					TREM2 deletion decreases immunosuppressive regulatory myeloid cells within tumors, which decreases exhausted CD8+ T cell subsets and tumor growth [86]
Regulation of Insulin-like Growth Factor Transport and Uptake by Insulin-like Growth Factor Binding Proteins
IGFBP4				↑CMM	Protein expressed in CMM by IHC [87]
IGFBP5				↓CMM	Gene and protein expression increased in CMM vs. nevi by qRT-PCR and IHC [48]
					Gene expression increased in metastatic melanoma vs. BN by RNAseq [58]
					Overexpression inhibits in vitro proliferation, migration, invasion, epithelial to mesenchymal transition, and in vivo tumor growth and metastasis of melanoma cell lines [48]
PRSS23				↑CMM	Knockdown decreases cancer cell proliferation in breast and gastric cancer [49,50]
SCG2				↑CMM	Gene expression increased in VGM and metastatic melanoma vs. normal skin, BN, and melanoma in situ by microarray [27]
					Increases migration of melanoma cells [52]
					Plays role in chemoattraction and migration [51]
SPP1				↑CMM	Increased expression in CMM vs. BN across 5 studies (RNAseq, microarray, IHC) [58,88,89,90,91]
					Included in 5 protein assay that distinguishes BN vs. CMM by IHC [89]
					SPP1 treatment increases melanoma cell migration, invasion, and proliferation [54]
					SPP1 knockdown decreased in vitro and in vivo proliferation, migration, and invasion of melanoma cells [53]

* K, Krueger; S, Scatolini; B, Bastian; IF, immunofluorescence; IHC, immunohistochemistry; qRT-PCR, quantitative reverse transcription polymerase chain reaction; RNAseq, RNA sequencing.