Supplementary Table 1: Differentially methylated 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 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 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 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 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- Coupled 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 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 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 protein Hox-B4 17q21.32 cg16175792 HSD3B1 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4- type I 1p13.1 cg08920071 CD101 immunoglobulin superfamily, member 2 1p13 cg08704606 MRC1 macrophage 1-like protein 1 10p12.33 cg12925542 WDR49 WD repeat-containing protein 49 3q26.1 cg02622316 ZSCAN12 protein 96 6p21 cg08130265 LINC00597 long intergenic non-protein coding RNA 597 15q23-q24 cg19176447 AKAP2 A anchoring protein 2 9q31.3 cg12840719 CDKN2A -dependent kinase inhibitor 2A 9p21 cg21087137 GLIPR1L1 GLI pathogenesis-related 1 like 1 12q21.2 cg26189983 TNFRSF1B 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 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 activity 12p13 cg15343119 GALR1 type 1 18q23 cg09636671 LMOD1 leiomodin-1 1q32 cg15016628 BRS3 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 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 -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 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, 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- P 11q13 cg20261167 SPP1 Bone sialoprotein 1 4q22.1 cg05105069 TCEAL7 TCEA-like protein 7 Xq22.1 cg25802424 IRS2 receptor 2 13q34 cg06825142 DRD4 dopamine D4 receptor 11p15.5 cg05702774 SUCNR1 succinate receptor 1 3q25.1 cg21475402 BCAN 7 1q31 cg14998713 ETS1 v-ets erythroblastosis virus E26 oncogene homolog 1 (avian) 11q23.3 cg07895149 CALHM2 calcium homeostasis modulator protein 2 10q24.33 cg07536847 PAX7 paired box homeotic gene 7 1p36.13 cg25432696 CXCL6 small-inducible B6 4q13.3 cg02164046 SST somatostatin 3q28 cg02765328 CCND2 cyclin D2 12p13 cg25092328 PXMP4 peroxisomal 4 20q11.22 cg05022306 HOXC8 homeobox protein Hox-C8 12q13.3 cg26299767 REM1 RAS (RAD and GEM)-like GTP-binding 1 20q11.21 cg20209009 TBX21 T-box transcription factor TBX21 17q21.32 cg15134649 MT1E metallothionein D 16q13 cg03238797 ADAMTS18 A disintegrin and metalloproteinase with thrombospondin 16q23 motifs 18 cg00308665 HTR2A Serotonin receptor 2A 13q14-q21 cg00233307 MAP4K1 hematopoietic progenitor kinase 1 19q13.1-q13.4 cg16979445 NRM Nuclear rim protein 6p21.33 cg11011938 SEMA5A semaphorin-5A 5p15.2 cg04726446 CCDC164 coiled-coil domain containing 164 2p23.3 cg05899618 GDF7 growth differentiation factor 7 2p24.1 cg04062391 ZNF560 zinc finger protein 560 19p13.2 cg06960698 FGF14 Fibroblast homologous factor 4 13q34 cg09871315 HOXA2 homeobox protein Hox-A2 7p15.2 cg12061236 AKAP12 myasthenia gravis autoantigen gravin 6q24-q25 cg11584936 BNIPL BCL2/adenovirus E1B 19kD interacting protein like 1q21.3 cg11271605 STEAP4 Tumor necrosis factor, alpha-induced protein 9 7q21.12 cg11916609 IL1RL1 1 receptor-related protein 2q12 cg21269934 NAT8L Camello-like protein 3 4p16.3 cg18511007 COL1A2 collagen alpha-2(I) chain | 7q22.1 cg10919204 CDH6 -6 5p13.3 cg00250430 DMRT2 doublesex- and mab-3-related transcription factor 2 9p24.3 cg17475918 HLA-E HLA class I histocompatibility , E alpha chain 6p21.3 cg07730329 PCDHGA12 Cadherin-21 5q31 cg12711530 BMP10 bone morphogenetic protein 10 2p13.3 cg20892287 ARHGAP32 rac GTPase activating protein 11q24.3 cg17582777 EFNA3 EPH-related receptor tyrosine kinase ligand 3 1q21-q22 cg02335804 HNF1B Transcription factor 2 17q12 cg21458907 CADPS Calcium-dependent activator protein for secretion 1 3p14.2 cg02144933 AOX1 aldehyde oxidase 1 2q33 cg08768421 GDA guanine deaminase 9q21.13 cg00035347 NT5C2 cytosolic purine 5'-nucleotidase 10q24.32 cg13262687 POU4F2 POU domain class 4 transcription factor 2 4q31.2 cg21307628 CCDC80 down-regulated by oncogenes protein 1 3q13.2 cg00579393 REG1B Pancreatic stone protein 2 2p12 cg05194726 NRIP2 interacting protein 2 12p13.33 cg22619018 CSMD1 CUB and sushi domain-containing protein 1 8p23.2 cg00179446 UPF3B Up-frameshift suppressor 3 homolog on X Xq25-q26 cg21376883 ACTN2 alpha-actinin skeletal muscle 1q42-q43 cg25917510 HOXC8 homeobox protein Hox-C8 12q13.3 cg04528819 KLF14 Basic transcription element-binding protein 5 7q32.3 cg12163132 TBX2 T-box protein 2 17q23.2 cg15503752 ST6GALNAC1 Sialyltransferase 7A 17q25.1 cg09551147 SORCS3 sortilin-related VPS10 domain containing receptor 3 10q23-q25 cg01288089 CXCL10 small-inducible cytokine B10 4q21 cg25125453 SPTLC3 serine palmitoyltransferase 3 20p12.1 cg09009111 EMILIN2 Elastin microfibril interface-located protein 2 18p11.3 cg15873301 SYN2 synapsin II 3p25 cg10281002 TBX5 T-box transcription factor TBX5 12q24.1 cg25463409 COX7B2 Cytochrome c oxidase polypeptide VIIb2 4p12 cg16924616 DLX5 homeobox protein DLX-5 7q22 cg11536940 CPQ Plasma glutamate carboxypeptidase | 8q22.2 cg07903918 GABBR2 G-protein coupled receptor 51 9q22.1-q22.3 cg23694248 PTPRR protein tyrosine phosphatase Cr1PTPase 12q15 cg14289985 ZNF471 zinc finger protein 471 19q13.43 cg25692621 ASB4 ankyrin repeat and SOCS box protein 4 7q21-q22 cg08008403 LHX9 LIM homeobox protein 9 1q31.1 cg07080946 LUC7L putative SR protein LUC7B1 16p13.3 cg15604467 POU4F1 POU domain class 4, transcription factor 1 13q31.1 cg10883621 CCDC164 coiled-coil domain containing 164 2p23.3 cg20083730 MT1E metallothionein D 16q13 cg14785479 SCARF2 scavenger receptor class F, member 2 22q11.21 cg12601757 ST6GALNAC3 alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase 3 1p31.1 cg12827555 VSX2 homeobox protein CHX10 14q24.3 cg05885123 CRIP3 cysteine-rich protein 3 6p21.1 cg12493906 MMP26 matrix metalloproteinase 26 11p15 cg01367992 LY9 Cell surface molecule Ly-9 1q23.3 cg15642035 FAM135B family with sequence similarity 135, member B 8q24.23 cg06172871 HP , beta polypeptide 16q22.2 cg09816471 SNN stannin 16p13 cg18794577 GRIN3A ionotropic, NMDA 3A 9q31.1 cg03963198 IRX4 Homeodomain protein IRXA3 5p15.3 cg20881888 ZMYND10 zinc finger, MYND domain containing 10 3p21.3 cg22268164 TRHR thyroliberin receptor 8q23 cg17833578 LRIT1 Leucine-rich repeat-containing protein 21 10q23 cg10947146 XKR6 open reading frame 21 8p23.1 cg01546563 GATA4 GATA-binding factor 4 8p23.1-p22 cg10541755 EIF5A2 eukaryotic translation initiation factor 5A-2 3q26.2 cg22461018 MORF4 mortality factor 4 4q34.1 cg27257987 PSG4 pregnancy specific beta-1- 4 19q13.2 cg03064067 SLC6A15 Sodium- and chloride-dependent neurotransmitter transporter 12q21.3 NTT73 cg00891278 CCDC37 coiled-coil domain containing 37 3q21.3 cg20895028 CDH26 cadherin-like protein VR20 20q13.33 cg14726637 CR1 complement component receptor 1 1q32 cg05089968 PRR18 proline rich region 18 6q27 cg06851207 PNMAL1 PNMA-like protein 1 19q13.32 cg02599464 HIST1H4I histone family member 6p21.33 cg04845579 SULF1 sulfatase FP 8q13.1 cg21096399 MCAM melanoma-associated antigen A32 11q23.3 cg17589341 SLC14A1 Urea transporter, erythrocyte 18q11-q12 cg17132967 ZNF83 zinc finger protein 83 (HPF1) 19q13.3 cg15975283 SLC9C2 Solute carrier family 9 member C2 1q25.1 cg13323752 SLC2A14 Glucose transporter type 14 12p13.31 cg09697795 IZUMO2 izumo sperm-egg fusion protein 2 19q13.33 cg10175795 TCERG1L transcription elongation regulator 1-like 10q26.3 cg19896198 TNFRSF8 tumor necrosis factor receptor superfamily, member 8 1p36 cg21309147 STAC2 Src homology 3 and cysteine-rich domain-containing protein 2 17q12 cg14462830 TRDN triadin 6q22.31 cg00325491 C11orf75 Protein FN5 11q21 cg06268694 CELSR1 cadherin family member 9 22q13.3 cg25041439 HYLS1 hydrolethalus syndrome protein 1 11q24.2 cg12854483 CNN1 calponin H1, smooth muscle 19p13.2-p13.1 cg12717594 RECK reversion-inducing-cysteine-rich protein with kazal motifs 9p13.3 cg00884221 IGFBP7 IGF-binding protein 7 4q12 cg04574507 CD1B CD1b molecule 1q22-q23 cg09448880 PGLYRP3 recognition protein 3 1q21 cg06493930 GAS2 growth arrest-specific protein 2 11p14.3 cg11647681 PCDHGA12 gamma subfamily A, 12 5q31 cg06812844 TRPM2 Long transient receptor potential channel 2 21q22.3 cg24041453 CCDC11 coiled-coil domain-containing protein 11 18q21.1 cg02433671 RGL3 ral guanine nucleotide dissociation stimulator-like 3 19p13.2 cg24739326 CHST8 carbohydrate 8 19q13.1 cg02422694 HOXB4 homeo box B4 17q21.32 cg11902458 KCNN3 small conductance calcium-activated potassium channel protein 1q21.3 3 cg04660410 VILL villin-like protein 3p21.3 cg08474603 CRP C-reactive protein, pentraxin-related 1q21-q23 cg06313930 MAGEA5 melanoma-associated antigen 5 Xq28 cg01777397 CLIP4 restin-like protein 2 2p23.2 cg10569616 POT1 protection of telomeres 1 homolog 7q31.33 cg19917856 NCCRP1 non-specific cytotoxic cell receptor protein 1 homolog 19q13.2 () cg06276653 FAM135B protein FAM135B 8q24.23 cg00995327 CHST2 carbohydrate (chondroitin 6/keratan) sulfotransferase 2 3q24 cg20239740 SYT5 5 19q|11p cg08260959 HIST1H4F histone cluster 1, H4f 6p22.1 cg20542190 LILRA4 CD85 antigen-like family member G 19q13.4 cg07657236 KCNH8 potassium voltage-gated channel subfamily H member 8 3p24.3 cg24489015 LPO lactoperoxidase 17q23.1 cg17795586 P2RY13 G-protein coupled receptor 94 3q24 cg04411625 CRIP1 cysteine-rich intestinal protein 14q32.33 cg23881725 DLEC1 deleted in lung and esophageal cancer 1 transcript varient 2 3p21.3 cg05342835 SYNC syncoilin 1p35.1 cg03127334 ERG Transforming protein ERG 21q22.3 cg05307923 ADARB2 RED2 homolog 10p15.3 cg09952204 RASGRF2 ras-specific guanine nucleotide-releasing factor 2 5q13 cg00117172 RUNX3 transcription factor AML2 1p36 cg26353877 APCS pentaxin-related 1q21-q23 cg05248470 LILRB2 Immunoglobulin-like transcript 4 19q13.4 cg25239996 CD40 CD40 molecule, TNF receptor superfamily member 5 20q12-q13.2 cg19777470 CRABP1 cellular retinoic acid-binding protein I 15q24 cg18389752 AMOT angiomotin Xq23 cg12638745 LCA5L leber congenital amaurosis 5-like protein 21q22.2 cg07256847 TCP10 t-complex 10 homolog 6q27 cg13948987 HCRTR2 hypocretin receptor type 2 6p12 cg12621514 DKK1 dickkopf-1 like 10q11.2 cg18129786 ZNF445 zinc finger protein 445 3p21.32 cg07177852 CCDC68 cutaneous T-cell lymphoma associated antigen 18q21 cg10431340 MPZ protein zero 1q23.3 cg09682183 UNC93A unc93 homolog A 6q27 cg03294557 SERPINB4 squamous cell carcinoma antigen 2 18q21.3 cg18055007 DDAH2 dimethylarginine dimethylaminohydrolase 2 6p21.3 cg10978355 CKMT2 creatine kinase S-type, mitochondrial 5q13.3 cg11465971 GSX2 homeobox protein GSH-2 4q12 cg04052038 CLDN8 claudin 8 21q22.11 cg16321029 SNRPN Prader-Willi syndrome chromosome region 15q11.2 cg00842351 TJP2 Tight junction protein 2 9q13-q21 cg19162106 GPC5 proteoglycan 5 13q32 cg23303408 POU4F3 POU domain class 4, transcription factor 3 5q32 cg08762247 TMEM100 transmembrane protein 100 17q22 cg21907579 TBX5 T-box protein 5 12q24.1 cg01375871 TPSD1 delta 16p13.3 cg03020951 HMGA1 nonhistone chromosomal high-mobility group protein HMG- 6p21 I/HMG-Y cg27154163 KIT CD117 antigen 4q11-q12 cg17860158 CNTN2 contactin-2 1q32.1 cg02800334 ANXA13 -13 8q24.13 cg01637734 CD5L CD5 antigen-like 1q21-q23 cg00415164 ALX4 ALX homeobox 4 11p11.2 cg26390526 FLG epidermal filaggrin 1q21.3 cg01939443 RGSL1 regulator of G-protein signaling like 1 1q25 cg14542839 PAMR1 Peptidase domain-containing protein associated with muscle 11p13 regeneration 1 cg05767404 GCSAML germinal center-associated signaling and motility-like protein 1q44 cg16122592 MAGEB6 melanoma-associated antigen B6 Xp21.3 cg09848074 KLRG2 C-type lectin domain family 15 member B 7q34 cg09702010 KLK11 Hippostasin 19q13.33 cg02168291 CDH13 H-cadherin 16q23.3 cg20507276 OR2L13 2L13 1q44 cg06563300 SLC17A8 solute carrier family 17 member 8 12q23.1 cg01982833 MED21 mediator of RNA polymerase II transcription subunit 21 12p11.23 cg17886028 CCND2 cyclin D2 12p13 cg10377274 PATE1 prostate and testis expressed 1 11q24.2 cg07550362 TAC1 neuromedin L 7q21-q22 cg16792800 GPC6 glypican proteoglycan 6 13q32 cg00187686 TCN1 transcobalamin-1 11q11-q12 cg07070934 GJA4 connexin 37 1p35.1 cg21023001 CD93 CD93 molecule 20p11.21 cg01234133 COL1A1 collagen alpha-1(I) chain preproprotein 17q21.33 cg18277754 ALK ALK tyrosine kinase receptor 2p23 cg20415809 ITGA4 alpha 4 2q31.3 cg26482939 GNA15 G-protein subunit alpha-15 19p13.3 cg21696393 SOX8 transcription factor SOX-8 16p13.3 cg23158811 PBX4 homeobox protein PBX4 19p12 cg21577049 DAW1 dynein assembly factor with WDR repeat domains 1 2q36.3 cg13372488 KCNT2 sequence like an intermediate conductance potassium channel 1q31.3 subunit cg10849854 GREB1 gene regulated by estrogen in breast cancer 2p25.1 cg19601328 MAP3K14 Serine/threonine-protein kinase NIK 17q21 cg23629496 LRRN4 leucine-rich repeat neuronal protein 4 20p12.3 cg07752420 CDKN2A Cyclin-dependent kinase 4 inhibitor A 9p21 cg00768439 NAP1L3 nucleosome assembly protein 1-like 3 Xq21.3-q22 cg17241310 BARHL2 barH-like 2 homeobox protein 1p22.2 cg23807646 SLC26A8 Solute carrier family 26 member 8 6p21 cg02002676 APOBEC3B Phorbolin-1-related protein 22q13.1-q13.2 cg16112129 DRD1 dopamine D1 receptor 5q35.1 cg21991396 NLRP3 / AII/AVP-like 1q44 cg21269897 HIST1H4I histone 1, H4i 6p21.33 cg00729275 AQP4-AS1 chromosome 18 open reading frame 16 18q11.2 cg02624705 DCC deleted in colorectal cancer protein 18q21.3 cg10693071 TRIM36 Tripartite motif-containing protein 36 5q22.3 cg26721264 GALR1 galanin receptor type 1 18q23 cg13342558 TECTB tectorin beta 10q25-q26 cg21784940 REPIN1 Zinc finger protein 464 7q36.1 cg08537652 PRDM16 PR domain containing 16 1p36.23-p33 cg00405677 HAND1 heart and neural crest derivatives expressed 1 5q33 cg10757144 PCDHB15 protocadherin beta-15 5q31 cg05382123 CSMD2 CUB and sushi domain-containing protein 2 1p34.3 cg00903242 CHL1 molecule 2 3p26.1 cg16313343 BRF1 TATA box binding protein (TBP)-associated factor 3C 14q cg03574115 WDR65 WD repeat domain 65 1p34.2 cg08528984 PRDM16 PR domain zinc finger protein 16 1p36.23-p33 cg26113512 VILL villin-like protein 3p21.3 cg12205230 TPM3 Tropomyosin-5 1q21.2 cg12530080 PMCHL1 pro-melanin-concentrating hormone-like 1, 5p14.3 cg09022808 GAL3ST1 3'-phosphoadenylylsulfate:galactosylceramide 3'- 22q12.2 sulfotransferase cg09015232 SLC12A5 solute carrier family 12 (potassium/chloride transporter), 20q13.12 member 5 cg14106263 RBMX2 RNA-binding motif protein, X-linked 2 Xq26.1 cg02170525 CD8A CD8a molecule 2p12 cg25549459 POU3F3 octamer-binding protein 8 2q12.1 cg11122968 CD33 Sialic acid-binding Ig-like lectin 3 19q13.3 cg12331389 RBP4 retinol-binding protein 4, plasma 10q23-q24 cg20308679 -related protein 2qter cg23316360 EDNRB non-selective type 13q22 cg21226224 SOX17 transcription factor SOX-17 8q11.23 cg15543551 FGF12 homologous factor 1 3q28 cg11323198 CDH8 cadherin-8 16q22.1 cg08383315 RIC3 protein RIC-3 11p15.4 cg17356733 IFNGR2 gamma receptor beta chain 21q22.11 cg19596755 CPT1A Carnitine palmitoyltransferase 1A 11q13.2 cg00875272 TAL1 T-cell leukemia/lymphoma protein 5 1p32 cg24053587 PTPRO protein tyrosine phosphatase PTP-U2 12p13.3-p13.2 cg21137417 SPP2 Secreted phosphoprotein 2 2q37.1 cg17252960 ID4 DNA-binding protein inhibitor ID-4 6p22.3 cg27159719 TMEM71 transmembrane protein 71 8q24.22 cg09229912 CUX2 homeobox protein cux-2 12q24.12 cg16848873 HOXB6 homeobox protein Hox-B6 17q21.3 cg06954481 GBX2 gastrulation brain homeobox 2 2q37.2 cg26537639 CYBA cytochrome b, alpha polypeptide 16q24 cg11832722 DSC3 -4 18q12.1 cg20884362 FAM207A protein FAM207A 21q22.3 cg00795812 PDCD1 programmed cell death 1 2q37.3 cg12594641 LYPD6 ly6/PLAUR domain-containing protein 6 2q23.2 cg07837085 SLAMF7 SLAM family member 7 1q23.1-q24.1 cg11126134 MEDAG mesenteric estrogen-dependent adipogenesis 13q12.3 cg23400451 MYH4 Myosin heavy chain 2b 17p13.1 cg10818781 PHB2 Repressor of estrogen receptor activity 12p13 cg02192520 RDH5 retinol dehydrogenase 1 12q13-q14 cg09120035 CYP11B1 cytochrome P450C11 8q21 cg11500797 DLX5 homeobox protein DLX-5 7q22 cg14385738 PTPN22 PEST-domain phosphatase 1p13.2 cg15149645 CMC4 Mature T-cell proliferation-1 type A Xq28 cg18815943 FOXE3 forkhead box protein E3 1p32 cg26511321 HOXA7 homeobox protein Hox-A7 7p15.2 cg14015044 TNFRSF10C tumor necrosis factor receptor superfamily, member 10c, decoy 8p22-p21 without an intracellular domain cg22471346 GAS7 growth arrest-specific protein 7 17p13.1 cg05023691 RGS13 regulator of G-protein signaling 13 1q31.2 cg19378133 RBFOX1 ataxin 2-binding protein 1 16p13.3 cg08356693 ITLN1 intelectin-1 1q21.3 cg01078434 MAS1L MAS1 oncogene-like 6p21 cg05606799 KISS1 malignant melanoma metastasis-suppressor 1q32 cg05847038 ADAM7 sperm maturation-related glycoprotein GP-83 8p21.2 cg22680204 CRMP1 dihydropyrimidinase-related protein 1 4p16.1 cg03213216 PPM1N probable protein phosphatase 1N 19q13.32 cg25361106 TLX2 T-cell leukemia, homeobox 2 2p13.1 cg09873510 NLN Neurotensin 5q12.3 cg02345317 NLGN3 neuroligin-3 Xq13.1 cg04172348 SYN2 synapsin-2 3p25 cg17950095 HOXA11 homeobox protein Hox-A11 7p15.2 cg24800810 RGS7 regulator of G-protein signalling 7 1q43|1q23.1 cg07947016 KLK2 kallikrein 2, prostatic 19q13.41 cg07685034 PCBP3 poly(rC)-binding protein 3 21q22.3 cg18705301 NDUFAF1 NADH-ubiquinone 1 alpha subcomplex, 15q11.2-q21.3 assembly factor 1 cg07899016 PCDHB12 protocadherin beta 12 5q31 cg10207745 C12orf36 chromosome 12 open reading frame 36 12p13.1 cg14991487 HOXD9 homeobox protein Hox-D9 2q31.1 cg26750002 RASIP1 ras-interacting protein 1 19q13.33 cg01103730 IL20 interleukin-20 1q32 cg16744741 PRKG2 cGMP-dependent protein kinase 2 4q13.1-q21.1 cg17897879 TNFRSF8 tumor necrosis factor receptor superfamily, member 8 1p36 cg05345286 MDFI myoD family inhibitor 6p21 cg13302823 SCRT1 Scratch homolog 1 zinc finger protein 8q24.3 cg23349790 IGSF21 immunoglobin superfamily, member 21 1p36.13 cg09375488 ASB4 ankyrin repeat and SOCS box protein 4 7q21-q22 cg24512973 MUC1 tumor associated epithelial 1q21 cg24781100 MYBPC1 myosin binding , slow type 12q23.2 cg17651821 HIST1H4L histone 1, H4l 6p22.1 cg13492227 FGF11 fibroblast growth factor 11 17p13.1 cg05200628 CD48 CD48 molecule 1q21.3-q22 cg09837977 LRRN3 Neuronal leucine-rich repeat protein 3 7q31.1 cg05590294 CD69 CD69 antigen 12p13 cg17834752 KCNK9 TWIK-related acid-sensitive K(+) channel 3 8q24.3 cg13015534 ST6GALNAC1 GalNAc alpha-2,6-sialyltransferase I 17q25.1 cg02000005 CRIP1 cysteine-rich intestinal protein 14q32.33 cg02046017 SHANK2-AS3 SHANK2 Antisense RNA 3 11q13.4

cg15149938 C22orf34 Open Reading Frame 34 22q13.33 cg24068372 WDR86 WD Repeat Domain86 7q36.1 cg04564030 CDH7 Cadherin 7, Type 2 18q22.1 cg27032184 TRMU TRNA 5-Methylaminomethyl-2-Thiouridylate 22q13 Methyltransferase cg18499731 SNORD109B Small Nucleolar RNA, C/D Box 109B 15q11.2 cg01335367 FAM222A family with sequence similarity 222, member A 12q24.11 cg09495977 HTRA3 HtrA Serine Peptidase 3 4p16.1 cg26757793 MMP20 Matrix Metallopeptidase 20 11q22.3 cg19766460 C21orf128 chromosome 21 open reading frame 128 21q22.3 cg09847584 RIMBP2 RIMS binding protein 2 12q24.33 cg06352750 SDPR serum deprivation response 2q32.3

Supplementary Table 5: Ingenuity Pathway analysis of the 333 differentially methylated genes associated to treatment response with both drugs

Top Canonical Pathways overrepresented in P-value FDR Ratio Molecules associated with the pathway differentially methylated genes cAMP-mediated Signaling 3.52E-05 0.002 7/217 FPR1,GABBR2,HTR1B,LHCGR,P2RY14,PKIA, VIPR2 G-Protein Coupled Receptor 7.23 E-04 0.002 6/260 FPR1,GABBR2, HTR1B,LHCGR,P2RY14,VIPR2 Signaling Gai Signaling 1.72E-03 0.04 4/128 FPR1,GABBR2, HTR1B,P2RY14

Supplementary Table 6: Associations between methylation status and TP53 mutation status

FUMI TP53 before TP53 after Gene wt- % of mut- % of p-value wt- % of mut- % of p-value methylation methylation methylation methylation ALU 19.4 12.2 0.044 BRCA1 21.3 10.5 0.002

CDKN2A 21.1 12.9 0.022

CCND2 19.2 12 0.036 13.5 6.2 0.017 FOXC1 22.2 10.9 0.001 IGFBP3 20.7 13.4 0.041 LINE1 19.4 12.2 0.044 ABCB1 20.7 13.4 0.041 13.7 7.3 0.044 PPP2R2B 20.7 13.5 0.045 13.8 7 0.036