THAI NGUYEN UNIVERSITY UNIVERSITY OF AGRICULTURE AND FORESTRY NGUYEN THI QUYNH LAM IDENTIFYING THE EFFECT OF EXPOSURE TO DIOXIN AND FURAN ON HUMAN HEALTH LEADING TO DIFFUSE LARGE B LYMPHOMA THROUGH GENE-NETWORK CONSTRUCTION BACHELOR THESIS Study Mode: Full-time Major: Environmental Science and Management Faculty: International Programs Office Batch: 2013 - 2017 Thai Nguyen, December 2017 n DOCUMENTATION PAGE WITH ABSTRACT Thai Nguyen University of Agriculture and Forestry Degree Program Bachelor of Environmental Science and Management Student name Nguyen Thi Quynh Lam Student ID DTN1353110372 Thesis Title Identifying the effect of exposure to dioxin and furans on human health leading to diffuse large B lymphoma through gene-network construction Supervisor(s) Prof ChunYu Chuang, Assoc Prof Tran Thi Thu Ha Abstract: Many studies indicated that exposure to dioxins and dioxins – compounds (e.g., 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) and polychlorinated dibenzofurans (furans) can induce several outcomes on human and animal in the long term period, and one of them is diffuse large B lymphoma which is considered as the most popular kind of lymphoma In order to identify the gene expression altered by TCDD and Furans potentially underlying DLBCL development, bioinformatics meta-analysis was applied in this study In this study, 10 datasets containing the information of gene expression of DLBCL, TCDD and Furans were obtained from Gene Expression Omnibus (GEO) and Array Express websites, and further analyzed using Cytoscape software and its plugins – ClueGO and CluePedia As a result, the most differentially expressed genes were found to construct genenetworks of DLBCL, TCDD and furans and hence the potential pathway presented how dioxins could cause the progress of lymphoma In addition, the analytical result i n reported that TCDD and furans have a possibility to induce the receptor AhR which promotes the appearance of protein TWIST1 and enhance the progress of DLBCL The result of this study has made a great contribution for further dioxins study, and it is also considered as the initial steps of future work for DLBCL diagnosis and treatment Keywords: TCDD, Furans, DBLCL, bioinformatics, GEO, Array Express Number of pages: 87 Date of Submission: 20/09/2017 Supervisor’s signature ii n ACKNOWLEDGEMENT First of all, I would like to use this opportunity to express my deepest gratitude and special thanks to Prof Chun-Yu Chuang for her patient to guide and keep me on the correct path and show me many of wonderful things during the time of my internship at the Department of Biomedical Engineering and Environmental Science at National Tsing Hua University I would like to express my deep thanks to Assoc Prof Tran Thi Thu Ha for giving me necessary advices and guidance in order to complete my thesis My sincere thanks are also given to all the members working in the Department of Biomedical Engineering and Environmental Science for supporting me all the materials and necessities when conducting experiments for my research Finally, I would like to thank my family and my friends encouraging me and advising me during completion of this thesis Thai Nguyen, October 2017 Nguyen Thi Quynh Lam iii n TABLE OF CONTENTS ACKNOWLEDGEMENT iii TABLE OF CONTENTS iv LIST OF FIGURES vii LIST OF TABLES viii LIST OF ABBREVIATIONS ix PART I INTRODUCTION 1.1 Research rationale 1.2 Research objectives PART II LITERATURE REVIEW .3 2.1 Persistent Organic Compounds (POPs) 2.2 Dioxins and dioxin – liked compounds 2.3 Lymphoma and non – Hodgkin lymphoma 2.3.1 Diffuse large B lymphoma 2.3.2 SNPs of Diffuse Large B lymphoma 2.4 Gene - network components 10 2.4.1 Microarray data 10 2.4.2 Gene network database: Array Express and GEO 11 2.4.3 Statistical analysis 13 2.4.4 Hub – proteins 15 2.4.5 GO term 15 iv n 2.5 Gene Network construction tools 16 2.5.1 Network Analyst website 16 2.5.2 Cytoscape software and plugins: ClueGO and CluePedia Apps 17 PART III METHODOLOGY 19 3.1 Data collection 19 3.2 Data processing 19 3.3 Network construction 21 PART IV RESULTS AND DISCUSSION 24 4.1 Results 24 4.1.1 Genetic datasets 24 4.1.2 Differentially genes expression 27 4.1.3 Gene-network construction of DLBCL, TCDD and Furans 33 4.1.4 Protein – protein interaction network of DLBCL, TCDD and Furans 35 4.1.5 Potential pathway showing the relation between TCDD and Furans and Diffuse Large B lymphoma 37 4.2 Discussion 39 4.2.1 AhR – mediated key factor of dioxins – like compounds 39 4.2.2 Key factors of hypoxia response and the risk of MYC – TP53 interaction 40 4.2.3 Inhibition of cancer cell apoptosis and tumorigenesis factor in DLBCL 42 PART V CONCLUSION 44 REFERENCES 46 v n APPENDICES 56 Appendix Differentially expressed genes of DLBCL versus normal cell 56 Appendix Differentially expressed genes of exposure to TCDD group and versus control group 63 Appendix Differentially expressed genes of exposure to FURANS group versus control group 67 Appendix Hub proteins of DLBCL network 74 Appendix Hub proteins of TCDD network 75 Appendix Hub proteins of FURANS network 76 vi n LIST OF FIGURES Figure 2.1: General molecular structure of polychlorinated dibenzo-p-dioxins (PCDD) and dibenzofurans (Source: Pereira, 2004) Figure 2.2: Representative structure of 2,3,7,8-tetrachhlorodibenzo-p-dioxins (TCDD) (Pereira, 2004) Figure 2.3: A schematic representation of signal transduction after TCDD/AHR interaction (Fracchiolla et al., 2016) 22 Figure 3.1: The flowchart of methodology Figure 4.1: Gene Ontology network showing the relationship of DLBCL, TCDD and Furans 32 Figure 4.2: Protein – protein interaction network constructed by CluePedia plugin in Cytoscape 36 Figure 4.3: Flowchart of proteins interaction and involved biological processes 37 vii n LIST OF TABLES 24 Table 4.1: Database of DLBCL 25 Table 4.2: Database of TCDD and Furans Table 4.3: Differentially expressed genes, including up-and down-regulated genes in Diffuse Large B lymphoma compared to normal cells 27 Table 4.4: Differentially expressed genes, including up-and down-regulated genes activated by TCDD compared to control group 29 Table 4.5: Differentially expressed genes, including up-and down-regulated genes activated by Furans compared to control group 30 Table 4.6: Lists of hub proteins containing in DLBCL, TCDD and Furans networks 34 viii n LIST OF ABBREVIATIONS ABC DLBCL activated B – cell like DLBCL AhR Aryl Hydrocarbon Receptor ARNT Aryl Hydrocarbon Receptor nuclear translocator B-NHL B cell non-Hodgkin lymphoma CRE CAMP response element DEG Differentially expressed genes DLBCL Diffuse large B cell lymphoma DNA Deoxyribonucleic acid DNMT1 DNA methyl transferase EGFR Epidermal growth factor receptor FDR False discovery rate GCB DLBCL Germinal center B-cell like DLBCL GEO Gene expression omnibus GO Gene ontology HAHs Halogenate aromatic hydrocarbon MAGE-ML Microarray and Gene Expression Markup Language MAGE-TAB Microarray Gene Expression - Tabular format MIAME Minimum information about microarray experiment MM Mismatch OC Organochlorine PCBs Polychlorinated biphenyls ix n ARHGDIB AQP9 DAZAP2 SLC6A6 B2M SMAP2 BCL2L1 SORL1 RAC2 FBXO7 PSAP FCN1 ND5 SLC25A37 TNFRSF10C TMBIM6 CD74 HLA-E -2.256 -2.285 -2.292 -2.437 -2.440 -2.534 -2.535 -2.655 -2.730 -2.741 -2.762 -2.874 -2.906 -3.031 -3.056 -3.224 -3.233 -3.265 6.91E-17 3.3E-08 3.52E-18 9.81E-22 2.59E-10 4.6E-19 2.52E-10 1.43E-30 4.49E-27 1.76E-14 6.6E-24 4.12E-16 3.24E-43 1.31E-08 3.3E-22 2.83E-22 4.45E-37 2.03E-20 SLC25A39 DCAF12 CX3CR1 RHOA CD53 XPO6 TAGLN2 FCGR2A MSN LYZ LAPTM5 MALAT1 TXNIP ACTB -3.273 -3.408 -3.451 -3.460 -3.530 -3.552 -4.353 -4.510 -5.876 -7.030 -7.697 -8.348 -9.649 -15.223 1.2E-09 4.96E-09 2.28E-24 1.17E-21 2.46E-19 2.5E-20 1.07E-20 7.8E-12 9.86E-33 3.06E-14 1.49E-32 5.37E-25 1.21E-22 8.11E-23 62 n Appendix 2: Differentially expressed genes of exposure to TCDD group and versus control group Name CYP1A1 TIPARP CYP1B1 TSKU SLC7A5 SIPA1L2 ST3GAL1 EDC3 RUNX2 LMCD1 AHRR HECW2 FZD7 SLC7A11 NEDD9 ABCG2 SLC22A4 MCOLN2 CEBPD ALDH1A3 CA8 NFE2L2 DDIT4 MYC MB21D2 ATP1B1 STC2 RND1 FOSL2 FAT1 TFAP2A Combine LogFC 2.594 1.284 0.801 0.700 0.593 0.578 0.524 0.520 0.511 0.494 0.483 0.483 0.465 0.461 0.457 0.445 0.442 0.422 0.418 0.406 0.395 0.395 0.371 0.368 0.363 0.352 0.350 0.336 0.329 0.320 0.313 Pval 1.62E-27 6.06E-46 2.20E-23 6.91E-27 8.98E-16 1.35E-25 1.41E-23 2.86E-25 2.50E-27 3.36E-21 3.37E-20 3.40E-25 8.55E-24 9.04E-16 3.91E-23 3.64E-15 1.67E-19 6.22E-17 2.95E-27 6.15E-28 1.70E-14 3.07E-26 2.16E-07 7.52E-17 2.72E-25 2.91E-14 3.52E-17 1.69E-25 2.38E-18 2.65E-14 2.43E-31 Name FAM174B IER3 SLC27A2 CDC25B ZIC2 RPP25 CSK RAB9A LAMA3 PYGL SLC4A7 SLC3A2 DLX1 TXNRD1 TNFRSF11B STC1 NR3C1 S100A16 RAMP3 PRSS23 GDAP1 ND1 CA2 TP53INP1 CXCR4 SLC6A14 CRIP2 NPY1R AGR3 YPEL3 DKK1 Combine LogFC 0.305 0.305 0.304 0.298 0.291 0.291 0.286 0.282 0.279 0.274 0.270 0.269 0.268 0.268 0.263 0.262 0.261 -0.260 -0.264 -0.265 -0.266 -0.272 -0.272 -0.272 -0.295 -0.318 -0.365 -0.375 -0.378 -0.400 -0.419 Pval 7.05E-16 1.50E-19 1.44E-10 3.15E-12 5.28E-20 1.33E-12 1.75E-09 5.21E-17 4.76E-16 1.06E-15 4.33E-11 2.09E-06 8.72E-25 5.37E-13 1.09E-03 5.44E-12 2.06E-14 6.78E-09 5.06E-07 2.35E-08 5.72E-12 1.37E-02 3.05E-08 1.80E-10 9.94E-14 1.93E-12 6.76E-09 3.43E-08 2.32E-07 2.01E-09 2.86E-17 63 n Name MYOF CTBP2 BASP1 GJB2 FGFBP1 PLEKHA1 PABPC1 SRXN1 CTNNA1 RPL11 DEGS1 STAG3L2 LGALS3 RPS7 DSP GLS SBDS GADD45A MBIP SOX17 PHLDA1 MALAT1 IL1R1 MAP3K1 CALY SLC9A3R1 TAGLN2 SYNGR2 PCBD1 SOX4 PHGDH FDFT1 CD81 MAL ASS1 JUP GNAS MT1X PHLDA2 Combine LogFC 0.729 0.569 0.534 0.530 0.524 0.509 0.398 0.395 0.375 0.362 0.346 0.344 0.334 0.333 0.329 0.321 0.321 0.314 0.310 0.308 0.299 0.290 0.274 -0.263 -0.267 -0.268 -0.268 -0.269 -0.270 -0.272 -0.276 -0.291 -0.298 -0.314 -0.329 -0.331 -0.338 -0.344 -0.344 Pval 2.35E-24 3.07E-18 2.46E-07 9.56E-20 1.25E-22 5.74E-31 1.06E-02 8.39E-10 7.50E-16 1.25E-02 2.81E-14 2.91E-11 3.88E-04 3.70E-02 2.51E-05 6.43E-05 5.00E-02 1.41E-17 2.56E-17 1.04E-23 2.17E-12 7.02E-03 4.27E-21 4.16E-06 9.25E-06 9.63E-05 2.74E-02 3.09E-04 1.33E-02 2.40E-12 6.31E-03 1.44E-03 5.79E-03 4.63E-03 4.65E-03 3.76E-03 4.88E-02 2.46E-06 2.89E-07 Name CAPNS1 AP2S1 SH3BGRL3 AP2M1 CLDN4 GPX4 TNNC1 ARL4C ATP6V0C ANKRD1 IGFBP2 MDK MT2A CFL1 KRT18 MSX1 ALDOA SFN IGFBP3 KRT8 ACTB S100A11 PFN1 HSPB1 KRT19 IGFBP1 SOS1 CCL20 NQO1 GDF15 ID2 SLC16A6 ETFB SLC2A8 CYB5A TMEM123 ESF1 SEPHS2 MRPS23 Combine LogFC -0.353 -0.360 -0.362 -0.369 -0.370 -0.377 -0.381 -0.389 -0.394 -0.404 -0.413 -0.414 -0.439 -0.474 -0.493 -0.495 -0.521 -0.532 -0.553 -0.869 -0.917 -0.928 -1.010 -1.088 -1.115 2.254 1.662 1.632 1.119 1.022 0.914 0.821 0.799 0.794 0.670 0.641 0.637 0.624 0.497 Pval 3.45E-03 1.14E-03 1.43E-03 2.67E-03 5.59E-06 8.37E-03 5.24E-03 2.57E-10 1.52E-02 1.69E-05 8.37E-03 1.40E-03 5.97E-06 1.65E-02 1.32E-02 1.13E-03 1.37E-02 4.71E-03 1.06E-03 1.98E-07 1.49E-03 6.27E-04 1.36E-03 1.49E-04 2.36E-13 1.47E-05 2.39E-06 1.58E-02 1.26E-04 1.41E-05 9.23E-05 9.49E-06 1.46E-03 2.39E-06 2.44E-06 1.03E-05 1.89E-06 5.80E-03 4.37E-06 64 n Name PNN SERTAD2 ID1 CYP24A1 ZBTB38 NDUFV2 AKAP12 TGFBR3 AJUBA IRF2BPL TBX3 DUSP6 SORL1 LRP11 APOC1 CYR61 C20orf24 FAM171A1 SNRPB2 SASH1 GPRC5C GLUL SLC19A2 RGS10 HSD17B11 DCDC2 NBPF1 CMTM3 ENAH PXDC1 ERRFI1 MOCOS CMTM6 ROBO1 ZFP36 CDK6 TESC COX8A CYBA Combine LogFC 0.485 0.461 0.457 0.453 0.439 0.433 0.430 0.425 0.425 0.381 0.377 0.371 0.364 0.354 0.350 0.339 0.332 0.323 0.322 0.317 0.314 0.312 0.311 0.309 0.307 0.298 0.294 0.294 0.294 0.285 0.283 0.279 0.269 0.267 0.264 0.261 0.260 -0.263 -0.274 Pvalue 1.94E-02 4.87E-06 3.22E-02 1.25E-02 1.05E-05 1.72E-03 7.96E-03 7.37E-04 1.65E-03 7.34E-05 1.03E-05 2.73E-03 1.93E-04 9.07E-06 1.00E-04 1.10E-04 4.25E-03 1.46E-05 2.50E-04 8.94E-06 1.10E-03 1.14E-03 5.29E-06 4.37E-06 7.40E-03 1.57E-03 1.94E-03 3.89E-03 8.44E-04 1.76E-03 2.94E-02 2.33E-05 3.88E-02 1.22E-04 4.48E-04 8.47E-03 2.23E-02 3.24E-02 1.13E-02 Name GPI GPT2 UQCR10 MIF CPB2 SERPINA7 ATP5G2 TRIM24 GAPDH IFITM3 IFITM2 VSNL1 CRLF1 RPL29 H2AFX TFPI MGST2 SP5 CST3 CHN2 SERPINB2 TMEM156 TAC1 HSD17B2 PFKP IL17RB FAM43A SLC37A2 DEPTOR VDR ADAMTS9 SULT1C2 AREG VEGFA JUN FAM107B ZNF395 ARMC9 AQP3 Combine LogFC -0.276 -0.278 -0.286 -0.287 -0.293 -0.302 -0.325 -0.344 -0.355 -0.372 -0.376 -0.409 -0.420 -0.436 -0.437 -0.510 -0.514 -0.720 -0.789 1.413 0.716 0.273 2.119 0.793 0.784 0.768 0.727 0.697 0.677 0.650 0.595 0.573 0.514 0.499 0.495 0.482 0.468 0.461 0.442 Pval 2.74E-03 3.90E-03 3.94E-02 4.98E-02 4.31E-02 1.41E-02 6.14E-03 1.14E-03 7.69E-03 6.26E-03 2.25E-02 2.39E-06 1.62E-02 2.92E-02 4.11E-02 2.84E-04 8.46E-04 3.43E-05 1.30E-02 2.02E-37 1.30E-03 2.96E-04 2.14E-15 1.89E-06 3.14E-02 3.36E-09 1.13E-02 4.23E-14 2.02E-04 2.18E-09 3.53E-06 1.71E-03 2.98E-04 4.36E-03 2.86E-02 1.46E-14 1.42E-02 8.34E-05 2.93E-04 65 n Name RAP1GAP SLC9A9 TPRA1 UGCG PTPRE ST3GAL5 CLMP EREG IL15RA KIAA0930 NKD2 ZMIZ1 EIF1AD FAM210A KRT23 KCTD9 GNAZ WDR43 S1PR2 TMCC1 DNMBP RBPMS RAI14 SCG5 MLLT1 SOWAHC VWCE EIF2S2 CARD10 SLC20A2 CDK5RAP2 PLEKHF1 PHACTR2 NFKBIE PITPNC1 TRIM55 Combine LogFC 0.440 0.435 0.432 0.431 0.430 0.419 0.411 0.406 0.399 0.383 0.366 0.364 0.360 0.351 0.342 0.339 0.339 0.337 0.332 0.331 0.325 0.324 0.323 0.321 0.321 0.318 0.315 0.312 0.311 0.308 0.298 0.298 0.294 0.294 0.285 0.283 Pval 1.47E-05 1.81E-08 2.14E-08 3.53E-06 2.25E-04 3.98E-03 1.63E-02 5.74E-07 1.63E-02 8.75E-09 7.92E-06 2.62E-06 3.50E-02 4.29E-02 1.25E-04 6.07E-03 4.38E-04 2.64E-02 2.26E-02 2.28E-03 2.32E-02 6.63E-05 3.82E-04 1.08E-03 1.71E-03 5.37E-03 5.52E-05 2.92E-02 3.25E-04 2.39E-02 8.74E-03 7.31E-04 1.22E-02 2.46E-02 4.75E-04 1.52E-06 Name NCEH1 C17orf58 RDH10 EGFR MCCC1 TLR2 FAM46C SS18 EML1 BAZ1A NAV3 SHB C2CD2 KLF6 KLHL4 PDK4 TBC1D9 KITLG FKBP5 NR1H4 ETNK2 BLNK MUM1L1 APBB2 ANK3 ZBED3 BBS10 KCNB1 PLCXD3 PEG10 KLHDC7A KIAA0040 NRXN3 CTGF Combine LogFC 0.283 0.282 0.280 0.280 0.278 0.278 0.274 0.273 0.271 0.266 0.265 0.263 0.263 0.263 -0.270 -0.276 -0.287 -0.290 -0.293 -0.297 -0.300 -0.304 -0.320 -0.320 -0.340 -0.350 -0.374 -0.377 -0.408 -0.413 -0.423 -0.461 -0.509 -0.596 PValue 2.04E-02 1.10E-02 4.66E-02 8.61E-03 4.34E-03 4.93E-03 4.55E-03 7.92E-06 8.90E-05 3.48E-02 9.51E-03 1.02E-02 2.46E-03 4.90E-03 3.68E-02 8.46E-03 3.22E-04 1.81E-03 2.03E-04 3.99E-02 4.62E-03 3.17E-02 3.41E-02 9.22E-06 1.93E-03 3.60E-02 2.19E-02 4.71E-03 4.44E-02 5.36E-03 1.91E-03 1.24E-03 4.34E-09 1.98E-08 66 n Appendix 3: Differentially expressed genes of exposure to FURANS group versus control group Name G6PC AGTR1 C5AR1 SLC26A3 LRRC17 PLSCR4 IGFBP3 SLC38A4 MEP1A HMGCS2 FRZB VNN1 INHBE SLC17A2 RORA HAL RBM24 LGSN RALGPS1 FXYD1 VLDLR TNS1 ATP2B2 ADSSL1 CA9 HIST2H2BE LRRTM4 TMEM178 PLG SLC22A15 DNAJC12 TFF1 GSDMB Combine LogFC 1.178 1.136 1.123 1.091 1.030 1.025 1.010 0.985 0.939 0.927 0.859 0.838 0.822 0.796 0.792 0.783 0.781 0.780 0.779 0.779 0.772 0.763 0.756 0.744 0.732 0.728 0.706 0.684 0.680 0.678 0.659 0.655 0.654 Pval 2.02E-02 1.55E-02 2.29E-03 4.40E-02 4.65E-03 7.42E-03 1.14E-02 1.46E-02 3.93E-02 7.09E-03 4.65E-03 2.29E-03 4.11E-02 1.84E-02 1.31E-02 3.75E-02 9.23E-03 1.20E-02 4.65E-03 1.31E-02 6.76E-03 1.46E-02 3.17E-03 9.23E-03 1.06E-02 4.65E-03 1.12E-02 8.37E-03 1.85E-02 8.51E-03 7.42E-03 8.55E-03 1.99E-02 Name C10orf10 ANGPTL2 CTSK PDE4D KLHL24 ALPK2 EGLN3 PTPRH ASNS C5orf41 TMEM140 FAM13A TCP11L2 EDN1 IFITM1 NT5E NDRG1 MAGI2 OSTalpha SLC7A11 SERPINE1 TNFSF4 RAB37 UTRN TMC8 KCNE1L SPAG4 BDH1 ARSG STC2 GATM CYP27B1 MAOA Combine LogFC 0.632 0.622 0.619 0.617 0.605 0.601 0.590 0.589 0.585 0.577 0.572 0.571 0.560 0.560 0.556 0.548 0.547 0.547 0.542 0.541 0.537 0.537 0.535 0.535 0.526 0.526 0.525 0.520 0.519 0.517 0.506 0.506 0.503 Pval 1.07E-02 1.33E-02 4.65E-03 9.23E-03 7.42E-03 1.93E-02 1.04E-02 7.21E-03 7.42E-03 6.98E-03 4.65E-03 3.44E-02 2.38E-02 3.16E-02 7.42E-03 1.68E-02 2.39E-02 1.63E-02 4.19E-02 2.09E-02 4.16E-02 1.12E-02 1.72E-02 4.72E-02 7.42E-03 2.88E-02 1.84E-02 6.26E-03 1.06E-02 4.65E-03 3.97E-02 1.12E-02 1.66E-02 67 n Name FILIP1L DDIT3 HS3ST5 SHC2 CHST15 SPON2 LOC375190 TTR PIM1 CBS N4BP2L1 FUT1 HIVEP2 XAF1 F7 HPN PPP1R15A PFKFB3 SORL1 DDIT4 PPARG TMEM27 HMHA1 SLC22A9 ACSM3 CYP3A5 ADAMTS6 RAB17 TP53INP2 LGALS8 SCN9A GK TAT C5orf4 SLCO6A1 BAAT PAQR5 HK1 VEGFA Combine LogFC 0.502 0.499 0.498 0.497 0.491 0.486 0.483 0.480 0.475 0.473 0.468 0.466 0.460 0.460 0.460 0.459 0.459 0.458 0.457 0.455 0.453 0.449 0.448 0.447 0.446 0.446 0.445 0.444 0.443 0.440 0.439 0.438 0.437 0.431 0.431 0.427 0.427 0.417 0.416 Pval 1.59E-02 7.42E-03 1.96E-02 4.65E-03 1.84E-02 1.31E-02 2.72E-02 3.40E-02 2.88E-02 1.19E-02 1.55E-02 2.77E-02 2.24E-02 7.42E-03 1.07E-02 1.59E-02 1.59E-02 3.34E-02 4.04E-02 4.71E-03 1.90E-02 2.62E-02 2.19E-02 3.45E-02 1.93E-02 2.50E-02 1.19E-02 2.88E-02 1.46E-02 4.40E-02 1.33E-02 9.14E-03 8.91E-03 1.31E-02 2.57E-02 1.12E-02 1.83E-02 1.35E-02 4.57E-02 Name GLDN FLRT3 CYP2J2 ENPP1 ARG1 FHL2 PTP4A3 CCDC17 JHDM1D TM4SF5 CPEB3 YPEL2 C1orf87 TMCC1 NAGS SLC7A2 YPEL3 SERINC2 TBXAS1 VN1R1 GEM PHKA2 MAFF UNC5B F13B TNFRSF10D MUC15 ROBO4 WIPI1 IVL SIRT4 ABCA7 FLJ37644 CLDN14 ZNF22 CLIC2 SLC6A8 IFITM2 EFNA1 Combine LogFC 0.414 0.413 0.413 0.413 0.412 0.410 0.408 0.408 0.407 0.407 0.406 0.404 0.403 0.403 0.401 0.401 0.400 0.400 0.399 0.398 0.398 0.398 0.388 0.388 0.387 0.387 0.386 0.385 0.385 0.383 0.381 0.381 0.380 0.378 0.377 0.376 0.376 0.374 0.372 Pval 1.11E-02 3.61E-02 1.37E-02 8.98E-03 8.37E-03 3.44E-02 1.31E-02 2.92E-02 3.34E-02 1.96E-02 1.07E-02 8.75E-03 2.40E-02 2.84E-02 3.81E-02 1.59E-02 2.09E-02 4.44E-02 1.37E-02 2.72E-02 1.34E-02 1.67E-02 8.45E-03 2.57E-02 7.42E-03 1.67E-02 4.16E-02 4.48E-02 1.04E-02 1.43E-02 1.04E-02 1.84E-02 1.84E-02 2.38E-02 2.27E-02 2.21E-02 2.17E-02 1.59E-02 1.33E-02 68 n Name SORBS1 OPTN APOF CTGF IRAK2 F10 FLJ39639 SUPT3H HSD17B6 CCDC68 KIAA0513 SLC26A6 KLF15 F5 PTPN14 FEZ1 P4HA1 NUDT9P1 PXK PFKM ZNF75A CFB PMM1 SULT2A1 LGALS4 TMEM45B GNG7 USP13 FBXO32 MTHFD2L PPARGC1A MXI1 QSOX1 CP RNASE4 ELF3 FNIP2 KLF6 C3orf32 Combine LogFC 0.370 0.370 0.368 0.368 0.367 0.365 0.364 0.363 0.363 0.362 0.361 0.360 0.360 0.359 0.357 0.357 0.356 0.356 0.355 0.354 0.353 0.353 0.352 0.351 0.350 0.349 0.348 0.347 0.345 0.345 0.345 0.342 0.340 0.339 0.339 0.339 0.338 0.338 0.338 Pval 1.65E-02 2.24E-02 2.24E-02 3.95E-02 1.28E-02 2.21E-02 2.23E-02 8.37E-03 2.80E-02 3.79E-02 1.88E-02 3.97E-02 1.10E-02 1.07E-02 3.30E-02 8.98E-03 3.60E-02 1.20E-02 1.37E-02 1.99E-02 1.93E-02 4.04E-02 1.56E-02 3.78E-02 1.70E-02 1.82E-02 1.20E-02 3.44E-02 4.91E-02 1.37E-02 2.71E-02 3.42E-02 3.61E-02 3.49E-02 4.19E-02 1.84E-02 1.67E-02 2.50E-02 1.91E-02 Name CLK1 CTDSPL KIAA1908 ZSWIM5 ARG2 SH3YL1 DNASE1L3 CSGALNACT1 SLCO2A1 GPRC5C PLXDC2 ANG ALOX12 CEACAM1 CACNA2D4 REC8 ZNF83 APOM HBEGF SERPINI1 FITM1 RNASET2 IL2RG L3MBTL4 CBLB HDAC5 C5 ALDH6A1 FER1L4 IL1RN DOK6 PDHA2 SHANK2 MYO10 PTTG3P LOC440288 ACPL2 CDC20 ZNF124 Combine LogFC 0.337 0.336 0.336 0.336 0.335 0.334 0.334 0.334 0.334 0.333 0.333 0.331 0.330 0.329 0.329 0.328 0.327 0.327 0.327 0.326 0.326 0.326 0.325 0.325 0.325 0.325 0.324 0.323 0.322 0.322 0.322 0.322 0.321 0.320 -0.321 -0.321 -0.321 -0.321 -0.322 Pval 1.84E-02 2.17E-02 1.93E-02 2.19E-02 1.84E-02 1.46E-02 1.28E-02 3.25E-02 1.89E-02 1.20E-02 4.50E-02 1.19E-02 8.28E-03 2.88E-02 4.68E-02 2.38E-02 1.98E-02 2.72E-02 1.72E-02 2.49E-02 2.72E-02 1.37E-02 3.07E-02 1.27E-02 1.47E-02 1.46E-02 1.44E-02 2.34E-02 3.34E-02 1.85E-02 2.72E-02 1.83E-02 1.22E-02 2.03E-02 1.37E-02 2.27E-02 1.96E-02 1.96E-02 2.10E-02 69 n Name C9orf46 BIRC5 DTYMK HNRNPC RNASEH2A CASP8AP2 NUF2 SMC4 TBCCD1 ARNTL2 RECQL ATP8B1 CSRP2 NUP35 ASF1B CCDC113 ARL13B CDK2 MCM6 UNG SNN DCK MRAS LSM5 WDR34 RPP30 ANP32E C11orf65 ABHD13 PIGX SKAP2 FAM108C1 NIPSNAP3A IFI30 RSRC1 BRCA1 C3orf26 DEPDC1 SULF2 Combine LogFC -0.323 -0.324 -0.324 -0.325 -0.325 -0.325 -0.325 -0.325 -0.325 -0.326 -0.326 -0.326 -0.327 -0.327 -0.328 -0.329 -0.329 -0.330 -0.330 -0.331 -0.332 -0.332 -0.332 -0.334 -0.335 -0.335 -0.336 -0.337 -0.337 -0.337 -0.337 -0.339 -0.339 -0.340 -0.340 -0.341 -0.341 -0.342 -0.342 Pval 2.71E-02 1.67E-02 1.82E-02 3.54E-02 3.94E-02 1.55E-02 2.42E-02 1.96E-02 1.07E-02 1.64E-02 2.92E-02 3.84E-02 2.19E-02 1.28E-02 3.90E-02 4.36E-02 3.34E-02 1.63E-02 1.37E-02 1.12E-02 3.64E-02 2.92E-02 4.51E-02 1.85E-02 3.85E-02 1.37E-02 1.91E-02 2.92E-02 4.78E-02 2.06E-02 3.66E-02 2.10E-02 4.11E-02 1.65E-02 1.59E-02 3.16E-02 2.21E-02 1.84E-02 2.07E-02 Name BUB1B PGBD1 LEF1 SLC25A10 UCHL5 KBTBD6 SDF2L1 TMEM107 ZWINT CEP152 GPNMB CENPA POLR3G ZNRF2 POLH FBXO5 GINS2 VAMP4 YEATS4 GK5 IMMP1L H2AFX ALG10B C12orf4 CDKN3 RRM2 CDR2L MYBL1 GUF1 KIAA1704 AURKB ZNF682 HDX HS3ST3B1 DBR1 UBR7 GTSE1 RRM1 SMC2 Combine LogFC -0.342 -0.342 -0.343 -0.345 -0.345 -0.345 -0.345 -0.346 -0.347 -0.347 -0.347 -0.347 -0.348 -0.350 -0.351 -0.351 -0.353 -0.354 -0.354 -0.355 -0.356 -0.356 -0.358 -0.358 -0.358 -0.361 -0.361 -0.361 -0.361 -0.361 -0.362 -0.362 -0.363 -0.364 -0.366 -0.366 -0.367 -0.367 -0.368 Pval 1.07E-02 3.51E-02 1.75E-02 2.53E-02 1.28E-02 2.41E-02 9.87E-03 1.07E-02 7.42E-03 3.57E-02 1.12E-02 1.28E-02 1.65E-02 4.37E-02 1.12E-02 2.04E-02 1.82E-02 3.51E-02 4.83E-02 2.17E-02 1.91E-02 1.50E-02 2.21E-02 3.80E-02 8.37E-03 1.04E-02 4.93E-02 1.14E-02 3.26E-02 1.88E-02 4.72E-02 3.64E-02 1.83E-02 1.18E-02 2.55E-02 7.42E-03 1.88E-02 1.31E-02 1.28E-02 70 n Name CKAP2 NUSAP1 TNFAIP8 DSN1 FLJ37201 LLPH FKBP5 KIAA1586 ANLN SKA3 ZNF43 QTRTD1 FDXR CHRNA5 CTPS C3orf52 SNHG10 EAF2 PLK1 CDC25A TRIP13 GBP3 CENPE CENPM FANCI POLQ OSR2 KIF14 BCHE SLC38A6 TTF2 FRK C12orf75 HAT1 LOC439949 SUV39H1 DTL ZNF267 C3orf64 Combine LogFC -0.369 -0.370 -0.370 -0.370 -0.372 -0.372 -0.372 -0.373 -0.374 -0.375 -0.375 -0.377 -0.378 -0.378 -0.379 -0.379 -0.380 -0.381 -0.381 -0.382 -0.382 -0.383 -0.384 -0.384 -0.385 -0.386 -0.387 -0.389 -0.390 -0.390 -0.391 -0.391 -0.391 -0.391 -0.392 -0.392 -0.392 -0.393 -0.394 Pval 8.82E-03 1.12E-02 2.41E-02 1.92E-02 1.92E-02 2.85E-02 1.96E-02 2.00E-02 1.37E-02 1.14E-02 8.07E-03 2.06E-02 2.25E-02 2.92E-02 1.60E-02 1.72E-02 2.71E-02 4.11E-02 1.65E-02 1.07E-02 1.07E-02 3.44E-02 1.07E-02 2.88E-02 1.47E-02 1.92E-02 3.47E-02 1.05E-02 1.10E-02 1.92E-02 1.65E-02 2.72E-02 1.65E-02 9.23E-03 3.44E-02 1.78E-02 1.65E-02 3.85E-02 1.20E-02 Name CCDC34 CEP120 UEVLD SVIP RP2 MCM9 GALNT7 MND1 C1orf216 CDCA2 PTGR1 POLE3 RFC2 CEP70 CASP6 FAM102B GINS4 HMMR C14orf142 XRCC4 UBE2T NCAPG ZWILCH CENPN SGOL2 CENPH CCDC99 ZNF107 GINS1 COQ3 TMEM194A WDR67 KIF15 STIL NDC80 CHML RBL1 SMTNL2 RFC3 Combine LogFC -0.395 -0.396 -0.398 -0.398 -0.399 -0.399 -0.400 -0.400 -0.401 -0.402 -0.403 -0.404 -0.404 -0.404 -0.405 -0.410 -0.411 -0.411 -0.413 -0.414 -0.415 -0.416 -0.416 -0.417 -0.417 -0.418 -0.419 -0.419 -0.419 -0.420 -0.420 -0.422 -0.424 -0.425 -0.426 -0.426 -0.426 -0.426 -0.426 Pval 1.30E-02 1.24E-02 4.58E-02 9.23E-03 2.30E-02 4.91E-02 2.26E-02 1.35E-02 4.48E-02 6.87E-03 1.92E-02 2.12E-02 1.59E-02 1.17E-02 1.07E-02 1.91E-02 2.50E-02 1.65E-02 2.07E-02 2.24E-02 1.07E-02 1.04E-02 8.28E-03 8.82E-03 1.20E-02 2.06E-02 7.42E-03 1.35E-02 7.84E-03 1.07E-02 1.67E-02 1.24E-02 2.72E-02 1.83E-02 2.69E-02 1.83E-02 6.48E-03 3.25E-02 1.06E-02 71 n Name SPARC CCDC15 PIK3R3 NCBP1 OBFC2B TCF19 ZNF597 NUPL1 RFC5 RAD51AP1 CENPK C12orf32 KIAA1009 KIF23 RPGRIP1L MDM1 TEX15 C3orf14 PBK C3orf70 DUSP19 CEP78 HELLS PIH1D2 KIF11 CENPI MICAL2 TK1 KIF20A GPR32 OIP5 POLE2 CCDC138 EXO1 PTPN2 CXorf57 ASPM APITD1 ID4 Combine LogFC -0.427 -0.427 -0.433 -0.434 -0.437 -0.437 -0.438 -0.438 -0.439 -0.441 -0.442 -0.445 -0.445 -0.447 -0.451 -0.452 -0.453 -0.453 -0.453 -0.454 -0.455 -0.457 -0.459 -0.461 -0.462 -0.465 -0.465 -0.472 -0.473 -0.478 -0.478 -0.478 -0.479 -0.481 -0.482 -0.483 -0.483 -0.484 -0.486 Pval 1.85E-02 1.59E-02 2.29E-02 1.37E-02 2.91E-02 2.83E-02 2.24E-02 1.07E-02 1.31E-02 1.07E-02 1.33E-02 2.07E-02 3.55E-02 1.25E-02 4.40E-02 2.31E-02 2.80E-02 2.92E-02 4.65E-03 4.65E-03 4.65E-03 4.65E-03 1.35E-02 2.48E-02 9.23E-03 1.20E-02 2.10E-02 1.12E-02 9.98E-03 1.82E-02 8.28E-03 4.65E-03 1.27E-02 2.39E-02 1.06E-02 4.40E-02 4.09E-03 1.12E-02 2.42E-02 Name ANKRD32 SPIN4 HSPA4L CCNB1 SUV39H2 ERCC6L ZNF273 PLK4 ALG10 CDC7 C12orf60 DLGAP5 CASC5 FAS SOX18 C4orf46 NCAPG2 TRIM59 FANCM C18orf54 RIBC2 CENPL ZNF326 CENPQ GINS3 NPNT E2F7 DNMT3B LOC100128191 TTC26 SGOL1 CEP55 CCNA2 DSCC1 C1orf124 CLUL1 FPGT ZNF114 SALL1 Combine LogFC -0.488 -0.489 -0.489 -0.490 -0.491 -0.492 -0.493 -0.493 -0.493 -0.495 -0.499 -0.501 -0.502 -0.504 -0.504 -0.505 -0.509 -0.513 -0.514 -0.515 -0.518 -0.521 -0.528 -0.529 -0.533 -0.536 -0.536 -0.537 -0.537 -0.539 -0.540 -0.540 -0.544 -0.546 -0.547 -0.548 -0.550 -0.550 -0.550 Pval 1.88E-02 1.75E-02 1.28E-02 1.06E-02 1.28E-02 1.04E-02 2.21E-02 1.06E-02 2.50E-02 2.40E-02 1.96E-02 1.67E-02 4.65E-03 4.44E-02 1.64E-02 1.17E-02 1.12E-02 8.91E-03 4.65E-03 4.65E-03 2.53E-02 2.90E-02 9.23E-03 5.36E-03 1.28E-02 4.80E-02 1.06E-02 9.87E-03 9.23E-03 9.55E-03 2.39E-02 8.28E-03 1.07E-02 1.04E-02 1.77E-02 3.17E-03 2.74E-02 3.79E-02 1.35E-02 72 n Name ZNF165 TMTC3 CCNE2 NUP62CL MORN2 SPA17 TIMM8A FAM64A FAM54A TTC39C DEPDC4 AGXT2L1 RAD18 F2R FIGNL1 TTC30A ZIK1 LMNB1 PACRGL BRCA2 FSCN1 PQLC3 C5orf34 SKA1 LIN9 COL1A1 C11orf82 CCDC18 VRK1 C1orf112 BIRC3 KIF18A MCM10 DKK1 SHCBP1 LRRIQ3 KIF20B CDC6 SPC25 Combine LogFC -0.555 -0.555 -0.555 -0.567 -0.567 -0.569 -0.570 -0.575 -0.580 -0.583 -0.585 -0.586 -0.588 -0.588 -0.589 -0.590 -0.590 -0.593 -0.593 -0.598 -0.598 -0.599 -0.600 -0.600 -0.601 -0.606 -0.608 -0.611 -0.615 -0.616 -0.620 -0.631 -0.632 -0.633 -0.651 -0.657 -0.670 -0.675 -0.679 Pval 4.59E-02 2.72E-02 3.39E-02 1.33E-02 9.98E-03 2.39E-02 8.91E-03 7.45E-03 1.46E-02 1.08E-02 4.65E-03 2.76E-02 7.42E-03 1.12E-02 8.37E-03 2.17E-02 6.76E-03 2.88E-02 1.37E-02 7.84E-03 1.84E-02 3.14E-02 7.42E-03 2.23E-02 8.37E-03 3.26E-02 8.75E-03 1.96E-02 9.23E-03 2.24E-02 3.17E-02 7.21E-03 7.61E-03 4.45E-02 9.98E-03 7.42E-03 1.07E-02 1.37E-02 6.87E-03 Name ZNF749 NEIL3 E2F8 AP1S3 WDHD1 RNASEH2B ARHGAP11A C4orf21 FAM111B LRRCC1 FANCB APOBEC3B TXNIP C6orf115 CHAC2 CMPK2 KBTBD8 TEX9 TTC30B GSTA1 ESCO2 STK17B MNS1 KIAA1524 ARRDC4 Combine LogFC -0.679 -0.681 -0.689 -0.694 -0.703 -0.717 -0.719 -0.727 -0.735 -0.809 -0.817 -0.830 -0.830 -0.833 -0.845 -0.858 -0.871 -0.950 -0.958 -0.966 -0.977 -1.008 -1.026 -1.173 -1.323 Pval 1.31E-02 6.87E-03 1.37E-02 4.40E-02 4.65E-03 4.65E-03 1.06E-02 1.05E-02 4.65E-03 1.46E-02 6.48E-03 1.66E-02 4.65E-03 3.84E-02 9.14E-03 4.65E-03 1.20E-02 1.72E-02 4.91E-03 1.37E-02 2.29E-03 7.42E-03 4.65E-03 4.65E-03 3.17E-03 73 n Appendix 4: Hub proteins of DLBCL network No 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Label UBC RPL11 RHOA MAPK1 PSMD10 STAT3 RPL18 RPS27A PSMC3 ALYREF UBA52 PSMC5 ACTB LYN CDKN1A PSMC4 RBX1 SNRPD3 EFTUD2 RAC2 NCBP2 CDK2 SNRPB TP53 NFKB1 SNU13 MRPL15 ARRB2 Degree 19 13 13 12 11 10 10 10 10 9 8 8 7 7 7 6 6 Betweeness 502.59 184.69 154.19 112.76 81.06 135.81 91.66 58.98 45.88 85.77 64.57 19.73 77.45 54.78 48.72 11.21 48 40.21 27.06 23.54 19.96 14.77 11.93 42.71 22.63 18.84 11.62 25.3 No 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 Label GNAQ MAGOH HSPB1 PRKCD MAPK14 PAK2 PIK3CA PLD2 IMP3 RPS5 TCF4 NPSR1 APEX1 NUP153 YBX1 EEF1A1 RACGAP1 CREBBP CDKN1B PARD6A PABPC1 TSHR MYOD1 NEDD8 MYH9 SNCA TWIST1 Degree 5 5 5 4 4 3 3 3 3 3 2 2 2 Betweeness 21.89 20.95 18.68 11.1 9.97 6.41 15.31 9.08 1.29 0.5 66.13 18.68 15.76 14.43 7.96 6.39 5.44 3.58 3.12 2.92 7.31 5.81 4.17 1.99 1.59 1.11 74 n Appendix 5: Hub proteins of TCDD network No 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 Label EGFR UBC JUN MYC SOS1 PABPC1 RPL11 RPS7 ACTB RUNX2 H2AFX EIF2S2 MAP3K1 CDK6 RPL29 NFE2L2 RPS27A SFN GAPDH TP53 CSK CTNNA1 MAPK1 RHOA RACK1 CREBBP CTNNB1 ESR1 PRKCA CCNB1 EIF4A1 Degree 19 18 17 16 12 11 11 10 7 7 7 6 6 6 6 5 5 4 Betweeness 329.9 579.93 234.17 260.94 113.18 190.36 174.17 60.49 101.85 109.39 71.68 61.92 60.98 43 31.1 76.21 43.06 36.6 31.54 29.46 28.79 27.61 20.92 13.7 42.47 21.66 21.56 11.71 13.88 12.59 11.92 No 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 62 Label FOS CDK4 AKT1 RPS12 CDC42 UBB PXN RUVBL1 SNRPB2 CDC37 STAT3 RAP1B SIRT1 RPS5 EIF5 TAGLN2 EFTUD2 RNPS1 SNRPF HSPA8 EIF2AK4 PRKCD PPM1D TJP1 EIF3G UBE2N TRIM28 CDC6 AHR GNAS Degree 4 4 3 3 3 3 3 2 2 2 2 2 2 1 Betweeness 10.33 8.76 7.24 5.18 3.51 18.54 15.23 11.23 9.06 7.26 5.24 2.67 1.99 1.41 0.57 59.21 31.48 24.23 8.36 5.34 4.39 2.9 2.86 2.84 2.81 2.31 2.25 1.02 0 75 n Appendix 6: Hub proteins of FURANS network No 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Label CDK2 PLK1 UBC CCNB1 BRCA1 CDC6 AURKB CDC20 RPS27A H2AFX UBB CCNA2 HDAC5 CENPA CDC25A UCHL5 AURKA ATR MCM6 CDK4 PPARG FANCM BUB1B TP53 NDC80 Degree 26 21 17 17 15 14 13 12 11 11 11 11 9 7 7 6 6 Betweeness 251.31 143.41 137.66 95.54 105.5 28.24 70.06 17.26 79.46 58.93 30.08 19.54 53.65 40.42 38.41 38.86 8.85 7.59 5.97 3.75 19.27 10.11 9.72 7.27 2.76 No 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 Label EP300 RB1 RPA1 NCBP1 KAT2B CREBBP RBL2 NPM1 PSMC4 PSMD10 HIST2H2AC HDAC3 CCNH STAG2 PSMA4 DMC1 PSMA3 RSRC1 RPS27 DDX20 YWHAH YWHAE RUVBL1 ESR1 Degree 5 4 4 4 3 3 3 2 2 2 Betweenness 19.45 5.05 4.62 27.49 11.51 9.75 8.34 4.87 3.42 3.12 12.38 6.63 4.32 3.94 2.69 1.73 1.23 4.2 3.92 3.53 3.45 2.3 1.73 0.74 76 n