Epigenetics of human cutaneous melanoma: setting the stage for new therapeutic strategies

Sigalotti, Luca; Covre, Alessia; Fratta, Elisabetta; Parisi, Giulia; Colizzi, Francesca; Rizzo, Aurora; Danielli, Riccardo; Nicolay, Hugues JM; Coral, Sandra; Maio, Michele

doi:10.1186/1479-5876-8-56

Journal of Translational Medicine

Table 1 Genes with an altered DNA methylation status in human CM

From: Epigenetics of human cutaneous melanoma: setting the stage for new therapeutic strategies

PATHWAY	GENE	METHYLATION STATUS IN CM^a	PERCENT	FREQUENCY	SOURCE	MODULATED BY 5-AZA-CdR	REF.
APOPTOSIS	DAPK ^b	methylated	19	16/86	tumor	ND^c	[39]
	HSPB6	methylated	100	8/8	cell line	YES	[32]
	HSPB8	methylated	69	11/16	tumor	YES	[128]
	RASSF1A	methylated	NA	NA	cell line	YES	[41]
		methylated	46	6/13	cell line	YES	[129]
		methylated	69	11/16	cell line	ND	[44]
		methylated	63	26/41	serum	NA	[130]
		methylated	28	13/47	serum	NA	[124]
		methylated	19	6/31	serum	NA	[39]
		methylated	25	10/40	tumor	ND	[101]
		methylated	36	9/24	tumor	NA	[129]
		methylated	55	24/44	tumor	YES	[40]
		methylated	57	49/86	tumor	YES	[39]
	TMS1	methylated	8	3/40	tumor	ND	[101]
		methylated	50	5/10	tumor	YES	[131]
	TNFRSF10C	methylated	57	23/40	tumor	YES	[101]
	TNFRSF10D	methylated	80	32/40	tumor	YES	[101]
	TP53INP1	methylated	19	3/16	tumor	YES	[22]
	TRAILR1	methylated	80	8/10	cell line	YES	[98]
		methylated	13	5/40	tumor	ND	[101]
	XAF1	methylated	NA	NA	cell line	YES	[99]
ANCHORAGE-INDEPENDENT GROWTH	TPM1	methylated	8	3/40	tumor	ND	[101]
CELL CYCLE	CDKN1B	methylated	0	0/13	cell line	ND	[129]
		methylated	0	0/40	tumor	ND	[101]
		methylated	9	4/45	tumor	ND	[132]
	CDKN1C	methylated	35	7/20	tumor	YES	[21]
	CDKN2A	methylated	76	31/41	serum	NA	[130]
		methylated	10	3/30	tumor	YES	[36]
		methylated	13	5/40	tumor	ND	[101]
		methylated	19	11/59	tumor	ND	[133]
		methylated	57	34/60	tumor	ND	[37]
	TSPY	methylated	100	5/5 male patients	tumor and cell line	YES	[134]
CELL FATE DETERMINATION	MIB2	methylated	19	6/31	tumor	ND	[135]
	APC	methylated	15	6/40	tumor	ND	[101]
		methylated	17	9/54	tumor	YES	[136]
	WIF1	methylated	NA	NA	cell line	YES	[137]
CHROMATIN REMODELING	NPM2	methylated	50	12/24	tumor	YES	[32]
DEGRADATION OF MISFOLDED PROTEINS	DERL3	methylated	23	3/13	cell line	NO	[138]
DIFFERENTIATION	ENC1	methylated	6	1/16	tumor	YES	[22]
	GDF15	methylated	75	15/20	tumor	YES	[21]
	HOXB13	methylated	20	4/20	tumor	YES	[21]
DNA REPAIR	MGMT	methylated	0	0/13	cell line	ND	[129]
		methylated	50	8/16	cell line	ND	[44]
		methylated	63	26/41	serum	NA	[130]
		methylated	19	6/31	serum	NA	[39]
		methylated	13	5/40	tumor	ND	[101]
		methylated	31	26/84	tumor	ND	[139]
		methylated	34	29/86	tumor	YES	[39]
DRUG METABOLISM	CYP1B1	methylated	100	20/20	tumor	YES	[21]
	DNAJC15	methylated	50	10/20	tumor	YES	[21]
EXTRACELLULAR MATRIX	COL1A2	methylated	63	45/24	tumor	YES	[32]
		methylated	80	16/20	tumor	YES	[21]
	MFAP2	methylated	30	6/20	tumor	YES	[21]
IMMUNE RECOGNITION	BAGE	demethylated	83	10/12	cell line	YES	[140]
	HLA class I	methylated	NA	NA	cell line	YES	[97]
	HMW-MAA	methylated	NA	NA	tumor and cell line	YES	[93]
	MAGE-A1	demethylated	NA	NA	cell line	YES	[45]
	MAGE-A2, -A3, -A4	demethylated	NA	NA	tumor	YES	[47]
INFLAMMATION	PTGS2	methylated	20	4/20	tumor	YES	[21]
INVASION/METASTASIS	CCR7	no CpG island	NA	NA	cell line	YES	[141]
	CDH1	methylated	88	14/16	cell line	ND	[44]
	CDH8	methylated	10	2/20	tumor	YES	[21]
	CDH13	methylated	44	7/16	cell line	ND	[44]
	CXCR4	methylated	NA	NA	cell line	YES	[141]
	DPPIV	methylated	80	8/10	cell line	YES	[142]
	EPB41L3	methylated	5	1/20	tumor	YES	[21]
	SERPINB5	methylated	100	7/7	cell line	ND	[143]
		methylated	13	5/40	tumor	YES	[144]
	LOX	methylated	45	18/40	tumor	YES	[101]
	SYK	methylated	3	1/40	tumor	ND	[101]
		methylated	30	6/20	tumor	YES	[21]
	TFPI-2	methylated	13	5/40	tumor	ND	[101]
		methylated	29	5/17	tumor	YES	[145]
	THBD	methylated	20	8/40	tumor	YES	[101]
		methylated	60	12/20	tumor and cell line	YES	[146]
	TIMP3	methylated	13	5/40	tumor	ND	[101]
PROLIFERATION	MT1G	methylated	21	5/24	tumor	YES	[32]
	WFDC1	methylated	20	4/20	tumor	YES	[21]
		methylated	25	10/40	tumor	ND	[101]
SIGNALING	DDIT4L	methylated	29	7/24	tumor	YES	[32]
	ERα	methylated	17	2/12	cell line	ND	[129]
		methylated	50	8/16	cell line	ND	[44]
		methylated	24	26/109	serum	NA	[123]
		methylated	51	55/107	tumor	ND	[123]
	PGRβ	methylated	56	9/16	cell line	ND	[44]
	PRDX2	methylated	8	3/36	tumor	YES	[138]
	PTEN	methylated	23	3/13	cell line	ND	[129]
		methylated	62	23/37	serum	YES	[147]
		methylated	0	0/40	tumor	NA	[101]
	3-OST-2	methylated	15	2/13	cell line	ND	[129]
		methylated	56	14/25	tumor	NA	[129]
	RARRES1	methylated	13	2/16	tumor	YES	[22]
	RARβ2	methylated	44	7/16	cell line	ND	[44]
		methylated	46	6/13	cell line	YES	[129]
		methylated	13	4/31	serum	NA	[39]
		methylated	22	5/23	tumor	NA	[129]
		methylated	20	5/25	tumor	YES	[129]
		methylated	60	24/40	tumor	ND	[101]
		methylated	70	74/106	tumor	YES	[39]
	RIL	methylated	88	14/16	cell line	ND	[44]
	SOCS1	methylated	75	30/40	tumor	ND	[101]
		methylated	76	31/41	serum	NA	[130]
	SOCS2	methylated	44	18/41	serum	NA	[130]
		methylated	75	30/40	tumor	ND	[101]
	SOCS3	methylated	60	3/5	tumor	YES	[148]
	UNC5C	methylated	23	3/13	cell line	NO	[138]
VESCICLE TRANSPORT	Rab33A	methylated	100	16/16	tumor and cell line	YES	[149]
TRANSCRIPTION	HAND1	methylated	15	2/13	cell line	ND	[129]
	HAND1	methylated	63	10/16	cell line	ND	[44]
	OLIG2	methylated	63	10/16	cell line	ND	[44]
	NKX2-3	methylated	63	10/16	cell line	ND	[44]
	PAX2	methylated	38	6/16	cell line	ND	[44]
	PAX7	methylated	31	5/16	cell line	ND	[44]
	RUNX3	methylated	23	3/13	cell line	ND	[129]
		methylated	29	5/17	cell line	ND	[150]
		methylated	4-17	2/52-5/30	tissues	NA	[150]
TBD	BST2	methylated	50	10/20	tumor	YES	[21]
	FAM78A	methylated	8	1/13	cell line	NO	[138]
	HS3ST2	methylated	56	14/25	tumor	ND	[129]
	LRRC2	methylated	5	1/20	tumor	YES	[21]
	LXN	methylated	95	19/20	tumor	YES	[21]
	PCSK1	methylated	60	12/20	tumor	YES	[21]
	PPP1R3C	methylated	25	4/16	tumor	YES	[22]
	PTPRG	methylated	8	1/13	cell line	NO	[138]
	QPCT	methylated	100	20/20	tumor	YES	[21]
	SLC27A3	methylated	46	6/13	cell line	NO	[138]

^a, methylation status of the gene found in CM as compared to that found in normal tissue;
^b, gene symbol: APAF-1, Apoptotic Protease Activating Factor 1; APC, adenomatous polyposis coli; BAGE, B melanoma antigen; BST2, bone marrow stromal cell antigen 2; CCR7, chemokine (C-C motif) receptor 7; CDH1, cadherin 1;CDH8, cadherin 8; CDH13, cadherin 13; CDKN1B, cyclin-dependent kinase inhibitor 1B; CDKN1C, cyclin-dependent kinase inhibitor 1C; CDKN2A, cyclin-dependent kinase inhibitor 2A; COL1A2, alpha 2 type I collagen; CXCR4, chemokine (C-X-C motif) receptor 4; CYP1B1, cytochrome P450, family 1, subfamily B, polypeptide 1; DAPK, death-associated protein kinase; DDIT4L, DNA-damage-inducible transcript 4-like; DERL3, Der1-like domain family, member 3; DNAJC15, DnaJ homolog, subfamily C, member 15; DPPIV, dipeptidyl peptidase IV; ENC1, ectodermal-neural cortex-1; EPB41L3, erythrocyte membrane protein band 4.1-like 3; ERα, Estrogen Receptor alpha; FAM78A, Family with sequence similarity 78, member A; GDF15, growth differentiation factor 15; HAND1, heart and neural crest derivatives expressed 1; HLA class I, human leukocyte class I antigen; HMW-MAA, high molecular weight melanoma associated antigen; HOXB13, homeobox B13; HS3ST2, heparan sulfate (glucosamine) 3-O-sulfotransferase 2; HSPB6, heat shock protein, alpha-crystallin-related, B6; HSPB8 heat shock 22 kDa protein 8; LRRC2, leucine rich repeat containing 2; LOX, lysyl oxidase; LXN, latexin; MAGE, melanoma-associated antigen, MFAP2, microfibrillar-associated protein 2; MGMT, O-6-methylguanine-DNA methyltransferase; MIB2, mindbomb homolog 2; MT1G, metallothionein 1G; NKX2-3, NK2 transcription factor related, locus 3; NPM2, nucleophosmin/nucleoplasmin 2; OLIG2, oligodendrocyte lineage transcription factor 2; PAX2, paired box 2; PAX7, paired box 7; PCSK1, proprotein convertase subtilisin/kexin type 1; PGRβ, progesterone receptor β; PPP1R3C, protein phosphatase 1, regulatory (inhibitor) subunit 3C; PRDX2, Peroxiredoxin; PTEN, Phosphatase and tensin homologue; PTGS2, prostaglandin-endoperoxide synthase 2; PTPRG, Protein tyrosine phosphatase, receptor type, G; QPCT, glutaminyl-peptide cyclotransferase; RARB, Retinoid Acid Receptor β2; RASSF1A, RAS associacion domain family 1; RIL, Reversion-induced LIM; RUNX3, runt-related transcription factor 3; SERPINB5, serpin peptidase inhibitor, clade B, member 5; SLC27A3, Solute carrier family 27; SOCS, suppressor of cytokine signaling; SYK, spleen tyrosine kinase; TFPI-2, Tissue factor pathway inhibitor-1; THBD, thrombomodulin; TIMP3, tissue inhibitor of metalloproteinase 3; TMS1, Target Of Methylation Silencing 1; TNFRSF10C, tumor necrosis factor receptor superfamily, member 10C; TNFRSF10D, tumor necrosis factor receptor superfamily, member 10D; TP53INP1, tumor protein p53 inducible nuclear protein 1; TPM1, tropomyosin 1 (alpha); TRAILR1, TNF-related apoptosis inducing ligand receptor 1; TSPY, testis specific protein, Y-linked; UNC5C, Unc-5 homologue C; WFDC1, WAP four-disulfide core domain 1; WIF1, Wnt inhibitory factor 1; XAF1, XIAP associated factor 1.
^c, NA, not applicable; ND, not done; TBD, to be determined.

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ISSN: 1479-5876

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