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Supplementary Table 1: Differentially Methylated Genes and Functions of the Genes Before/After Treatment with A) Doxorubicin and B) FUMI and in C) Responders Vs

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Supplementary Table 1: Differentially Methylated Genes and Functions of the Genes Before/After Treatment with A) Doxorubicin and B) FUMI and in C) Responders Vs Supplementary Table 1: Differentially methylated genes and functions of the genes before/after treatment with a) doxorubicin and b) FUMI and in c) responders vs. non- responders for doxorubicin and d) FUMI Differentially methylated genes before/after treatment a. Doxo GENE FUNCTION CCL5, CCL8, CCL15, CCL21, CCR1, CD33, IL5, immunoregulatory and inflammatory processes IL8, IL24, IL26, TNFSF11 CCNA1, CCND2, CDKN2A cell cycle regulators ESR1, FGF2, FGF14, FGF18 growth factors WT1, RASSF5, RASSF6 tumor suppressor b. FUMI GENE FUNCTION CCL7, CCL15, CD28, CD33, CD40, CD69, TNFSF18 immunoregulatory and inflammatory processes CCND2, CDKN2A cell cycle regulators IGF2BP1, IGFBP3 growth factors HOXB4, HOXB6, HOXC8 regulation of cell transcription WT1, RASSF6 tumor suppressor Differentially methylated genes in responders vs. non-responders c. Doxo GENE FUNCTION CBR1, CCL4, CCL8, CCR1, CCR7, CD1A, CD1B, immunoregulatory and inflammatory processes CD1D, CD1E, CD33, CD40, IL5, IL8, IL20, IL22, TLR4 CCNA1, CCND2, CDKN2A cell cycle regulators ESR2, ERBB3, FGF11, FGF12, FGF14, FGF17 growth factors WNT4, WNT16, WNT10A implicated in oncogenesis TNFSF12, TNFSF15 apoptosis FOXL1, FOXL2, FOSL1,HOXA2, HOXA7, HOXA11, HOXA13, HOXB4, HOXB6, HOXB8, HOXB9, HOXC8, regulation of cell transcription HOXD8, HOXD9, HOXD11 GSTP1, MGMT DNA repair APC, WT1 tumor suppressor d. FUMI GENE FUNCTION CCL1, CCL3, CCL5,CCL14, CD1B, CD33, CD40, CD69, immunoregulatory and inflammatory IL20, IL32 processes CCNA1, CCND2, CDKN2A cell cycle regulators IGF2BP1, IGFBP3, IGFBP7, EGFR, ESR2,RARB2 growth factors HOXA1, HOXA2, HOXA7, HOXA9, HOXB4, HOXB6, regulation of cell transcription HOXC8, HOXD9 BRCA1, GSTP1 DNA repair WT1, RASSF6 tumor suppressor ABCB1 development of resistance to anticancer drugs Red marked genes- genes with higher methylation levels after treatment Green marked genes- genes with higher methylation levels before treatment Supplementary Table 2: Ingenuity Pathway analysis of: a) genes differentially methylated before and after treatment with doxorubicin and b) genes differentially methylated before and after treatment with FUMI; c) genes differentially methylated between responders and non-responders for doxorubicin and d) genes differentially methylated between responders and non-responders for FUMI 2a. Top Canonical Pathways overrepresented P-value FDR Ratio Molecules associated with the pathway in differentially methylated genes before/after treatment (doxorubicin) 9.88E-06 0.003 13/126 ABCG1,APOA5,APOB,APOD,CYP7A1,FGA, LXR/RXR activation IL37,IL1RL1,KNG1,RBP4,SAA1,TNFRSF1B,TTR Communication between 1,97E-04 0.03 9/93 CCL5,CCL15, CD86, CD8A,CXCL10, IL5,IL8 Innate and Adaptive IL37,TNFSF13B Immune Cells Role of Cytokines in 2.86E-04 0.03 7/52 IFNA4,IL5,IL8,IL21,IL24,IL26,IL37 Mediating Communication Between Immune Cells Molecules 2b. Top Canonical Pathways overrepresented P-value FDR Ratio Molecules associated with the pathway in differentially methylated genes before/after treatment (fumi) Retinoate Biosynthesis 2.19E-03 0.2 4/30 ADH7,ALDH1A3,RDH5,RDH8 Gαi Signaling 2.24E-03 0.2 8/128 ADCY4,FPR1,GABBR2,GNB5,GNG4,HTR1B, P2RY14,PRKAR1B LXR/RXR Activation 2.36E-03 0.2 8/126 CCL7,FGA,GC,IL18RAP,PLTP,S100A8,TF, TNFRSF1B Cardiac β-adrenergic 3.86E-03 0.2 8/139 ADCY4,AKAP2,GNB5,GNG4,PKIA,PPP1R7, Signaling PRKAR1B,RYR2 2c. Top Canonical Pathways overrepresented P-value FDR Ratio Molecules associated with the pathway in differentially methylated genes responders vs. non - responders (doxorubicin) Communication between 6.36E-05 0.027 17/93 CCL4,CCR7,CD40,CD86,CD8A,CXCL10, Innate and Adaptive HLA-C,HLA-E,IFNA21,IFNA13,IL5,IL8,IL10, Immune Cells TLR1,TLR4,TLR7,TNFSF13B Atherosclerosis Signaling 1.27E-04 0.027 21/131 ALOX15,APCC1,APOD,CD40,COL1-1A2,8A1, A1,A2,CXCL12,IL8,ITGA4,LPL,MMP1,ORM2, PDGFC,PLA2G-7,16,1B,RBP4,SELE,TNFSF12 2d. Top Canonical Pathways overrepresented P-value FDR Ratio Molecules associated with the pathway in differentially methylated genes responders vs. non responders (fumi) cAMP-mediated Signaling 2.15E-06 0.0009 34/217 ADCY5,8,9,ADORA1,ADRB3,AKAP12,CHRM5, CNGA2,DRD1,4,5,FPR1,GABBR2,GRM4,8, HTR-4,7,1B,1D,1E,LHCGR,OPR-D1,K1,P2RY- 13,14,PDE4-B,C,PKIA,PPP3R2,PTGER2, RAP1GAP,RGS7,S1PR3,VIPR2 G-Protein Coupled Receptor 3.11 E-05 0.006 35/260 ADCY5,8,9,ADORA1,ADRB3,CHRM5,DRD- Signaling 1,4,5,FPR1,GABBR2,GNA15,GRM-1,4,8, HTR-4,81B,1D,1E,2A, LHCGR,OPR-D1,K1, P2RY-13,14,PDE-4B,4C,PRKCG,PTGER2, RAP1GAP,RGS7,S1PR3, VIPR2 Dopamine-DARPP32 3.26E-04 0.03 23/161 ADCY-5,8,9,ATP2A-1,3,DRD-1,4,5,GRIN2A Feedback in cAMP GUCY1A3,KCNJ-2,6,9,10,NOS1,PLCD1, Signaling PPP1-CA,R14C,3A,PPP3R2,PRK-CG,CQ,G2 Supplementary Table 3: A) List of the 46 genes differentially methylated before and after treatment with both drugs -genome wide screening Probe Gene Descriptions CytoMap location cg15814508 P2RY14 purinergic receptor P2Y, G-protein coupled, 14 3q24-q25.1 cg09748960 BTNL2 butyrophilin-like protein 2 6p21.3 cg11122968 CD33 CD33 molecule 19q13.3 cg08654334 DIRC1 disrupted in renal carcinoma protein 1 2q33 cg12351433 LHCGR lutropin-choriogonadotropic hormone receptor 2p21 cg22081096 ABCA6 ATP-binding cassette sub-family A member 6 17q24.3 cg05000446 C9orf131 uncharacterized protein C9orf131 9p13.3 cg16505204 THRSP thyroid hormone-inducible hepatic protein 11q14.1 cg14458834 HOXB4 homeobox protein Hox-B4 17q21.32 cg16175792 HSD3B1 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type I 1p13.1 cg08920071 CD101 immunoglobulin superfamily, member 2 1p13 cg08704606 MRC1 macrophage mannose receptor 1-like protein 1 10p12.33 cg12925542 WDR49 WD repeat-containing protein 49 3q26.1 cg02622316 ZSCAN12 zinc finger protein 96 6p21 cg08130265 LINC00597 long intergenic non-protein coding RNA 597 15q23-q24 cg19176447 AKAP2 protein kinase A anchoring protein 2 9q31.3 cg12840719 CDKN2A cyclin-dependent kinase inhibitor 2A 9p21 cg21087137 GLIPR1L1 GLI pathogenesis-related 1 like 1 12q21.2 cg26189983 TNFRSF1B tumor necrosis factor receptor superfamily member 1B 1p36.22 cg24893837 ARSB arylsulfatase B 5q14.1 cg16670497 GSTM2 glutathione S-aralkyltransferase M2 1p13.3 cg23110514 LCE3E Late envelope protein 17 1q21.3 cg03889226 OLIG3 oligodendrocyte transcription factor 3 6q23.3 cg22334665 SLC22A16 solute carrier family 22 member 16 6q22.1 cg12717594 RECK reversion-inducing-cysteine-rich protein with kazal motifs 9p13.3 cg05421688 FAM163A neuroblastoma-derived secretory protein 1q25.2 cg02657438 STON2 stoned B homolog 2 14q31.1 cg19063972 SOX21 transcription factor SOX-21 13q31-q32 cg15778232 PHB2 Repressor of estrogen receptor activity 12p13 cg15343119 GALR1 galanin receptor type 1 18q23 cg09636671 LMOD1 leiomodin-1 1q32 cg15016628 BRS3 bombesin receptor subtype-3 Xq26.3 cg04574507 CD1B CD1b molecule 1q22-q23 cg14988503 CDKL2 cyclin-dependent kinase-like 2 4q21.1 cg12827188 FGA fibrinogen, A alpha polypeptide 4q28 cg08157292 PPP1R7 Protein phosphatase 1 regulatory subunit 22 2q37.3 cg17480438 KIAA1244 brefeldin A-inhibited guanine nucleotide-exchange protein 3 6q23.3 cg15377518 ZEB2 Zinc finger homeobox protein 1b 2q22.3 cg16742703 KLK3 kallikrein-3 19q13.41 cg15494458 BPI recombinant BPI holoprotein, rBPI 20q11.23 cg07136161 CYLC2 cylicin-2 9q31.1 cg07084163 UGT3A2 UDP-glucuronosyltransferase 3A2 5p13.2 cg00779924 GATA3-AS1 GATA3 antisense RNA 1 10p14 cg21792432 POT1 protection of telomeres 1 7q31.33 cg03996822 RASSF6 ras association domain-containing protein 6 4q13.3 cg09848074 KLRG2 killer cell lectin-like receptor subfamily G member 2 7q34 B) Function of the genes differentially methylated before and after treatment with both drugs Differentially methylated genes before/after treatment with both drugs GENE FUNCTION P2RY14, BTNL2, CD33,CD101, CD1B, Immunoregulatory and inflammatory processes MRC1, CDKN2A, CDKL2 cell cycle regulators GALR1 / RASSF6 /TNFRSF1B growth factors/ tumor suppressor /apoptosis ABCA6 macrophage lipid homeostasis CYLC2, BRS3 sperm cell division, maturation, or function BPI / GATA3-AS1, LINC00597 antibacterial activity / RNA gene HOXB4, ZSCAN12, SOX21 / PHB2 regulation of cell transcription /transcriptional repression DIRC1, C9orf131, WDR49, GLIPR1L1, unknown LCE3E, FAM163A , KIAA1244, KLRG2 LHCGR receptor for lutropin-choriogonadotropic hormone THRSP/ KLK3 regulation of lipogenesis/ serine-type peptidase activity AKAP2, GSTM2, RECK / OLIG3, ZEB2, enzyme binding / DNA binding/ protein binding HSD3B1, POT1/STON2, LMOD1, FGA ARSB / PPP1R7 arylsulfatase activity/ enzyme regulator activity SLC22A16 transmembrane transport of small molecules UGT3A2 glucuronosyltransferase activity Supplementary Table 4: List of the 333 differentially methylated genes associated to treatment response with both drugs Probe Gene Descriptions CytoMap location cg23178308 PDXK pyridoxine kinase 21q22.3 cg07981910 DAB2IP disabled homolog 2-interacting protein 9q33.1-q33.3 cg00695416 CBR1 carbonyl reductase (NADPH) 1 21q22.13 cg14696870 FCER1A high affinity immunoglobulin epsilon receptor alpha-subunit 1q23 cg19246110 ZNF671 zinc finger protein 671 19q13.43 cg18349835 VIPR2 vasoactive intestinal polypeptide receptor 2 7q36.3 cg11638200 PRKCQ protein kinase C, theta 10p15 cg03716999 RNF207 RING finger protein 207 1p36.31 cg04920951 GSTP1 glutathione S-transferase P 11q13 cg20261167 SPP1 Bone sialoprotein 1 4q22.1 cg05105069 TCEAL7 TCEA-like protein 7 Xq22.1 cg25802424 IRS2 insulin receptor substrate 2 13q34 cg06825142 DRD4 dopamine D4 receptor 11p15.5 cg05702774 SUCNR1 succinate receptor 1 3q25.1 cg21475402 BCAN chondroitin sulfate proteoglycan 7 1q31 cg14998713 ETS1 v-ets erythroblastosis
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