Supplementary Table S1. Clinicopathological characteristics of HCC patients Discovery Set 1 Discovery Set 2 Validation Set 1 Validation Set 2 Total no. of patients 10 10 20 44 Age, years Mean (SD) 66.1 (5.9) 68 (8.9) 61.3 (10.9) 64.8 (9.9) Sex, no. of patients (%) Male 10 9 16 (80) 35 (79.5) Female 0 1 4 (20) 9 (20.5) Hepatitis virus infection, no. of patients (%) No 1 1 2 (10) 9 (20.5) B 2 5 7 (35) 12 (27.3) C 6 3 11 (55) 20 (45.5) B+C 1 1 0 3 (6.8) Background liver, no. of patients (%) Normal 0 0 1 (5) 5 (11.4) Chronic hepatitis (CH) 7 3 8 (40) 23 (52.3) Liver cirrhosis (LC) 2 4 8 (40) 8 (18.2) CH + LC 0 0 1 (5) 0 Precirrhosis 1 3 2 (10) 8 (18.2) Tumor size, cm3 mean (SD) 68.3 (42.0) 120.9 (218.1) 87.8 (111.9) 176.4 (256.7) Histology, no. of patients (%) Well 1 0 1 (5) 5 (11.4) Well to moderately 0 0 4 (20) 0 Moderately 5 10 8 (40) 27 (61.4) Moderately to poorly 1 0 1 (5) 0 Poorly 3 0 6 (30) 12 (27.3) Intrahepatic metastases, no. of patients (%) 0 7 7 17 (85) 30 (68.2) 1 1 1 2 (10) 14 (31.8) 2 2 2 0 0 3 0 0 1 (5) 0 Portal vein involvement, no. of patients (%) 0 4 1 10 (50) 17 (38.6) 1 5 8 7 (35) 24 (54.5) 2 0 1 0 1 (2.3) 3 1 0 3 (15) 2 (4.5) Supplementary Table S2. List of genes up-regulated in HCC (Discovery Set 1) Transcript Fold RefSeq Gene symbol P-value Gene description Cluster ID change 2337716 NM_006252 PRKAA2 6.71E-04 4.42 Protein kinase, AMP-activated, alpha 2 catalytic subunit 2379863 NM_016343 CENPF|TUBD1|P 1.05E-04 3.22 Centromere protein F, 350/400ka (mitosin) | tubulin, delta AK1 1 | p21/Cdc42/Rac1-activated kinase 1 (STE20 homolog, yeast) 2427007 NM_002959 SORT1|PSRC1|M 1.24E-04 3.14 Sortilin 1 | proline/serine-rich coiled-coil 1 | myosin YBPHL binding protein H-like 2441386 NM_003617 RGS5|UPK1B 5.06E-06 3.27 Regulator of G-protein signalling 5 | uroplakin 1B 2449559 NM_018136 ASPM 4.37E-05 3.03 Asp (abnormal spindle) homolog, microcephaly associated (Drosophila) 2469252 NM_001034 RRM2 6.68E-06 3.36 Ribonucleotide reductase M2 polypeptide 2544201 NM_004881|NM_147 TP53I3|PFN4 7.69E-06 3.67 Tumor protein p53 inducible protein 3 | profilin family, 184 member 4 2784113 NM_001237 CCNA2 4.01E-04 3.43 Cyclin A2 2813414 NM_031966 CCNB1 5.02E-06 3.53 Cyclin B1 2899102 NM_003531 HIST1H3C 5.21E-05 4.94 Histone cluster 1, H3c 2946215 NM_003537 HIST1H3B 3.73E-06 4.99 Histone cluster 1, H3b 2947077 NM_003533 HIST1H3I 2.49E-05 3.61 Histone cluster 1, H3i 2997376 NM_018685 ANLN 1.43E-05 3.39 Anillin, actin binding protein 3025433 NM_020299 AKR1B10|LOC34 4.50E-04 18.03 Aldo-keto reductase family 1, member B10 (aldose 0888|LOC441282 reductase) | similar to aldo-keto reductase family 1, member B10 3260586 NM_005063 SCD|LOC645313| 8.76E-05 3.43 Stearoyl-CoA desaturase (delta-9-desaturase) | similar to LOC651109 Acyl-CoA desaturase (Stearoyl-CoA desaturase) (Fatty acid desaturase) (Delta(9)-desaturase) 3329343 NM_002391|NM_001 MDK 4.38E-04 3.90 Midkine (neurite growth-promoting factor 2) 012334|NM_0010123 33 3375545 NM_013402 FADS1|FADS3 2.74E-04 3.34 Fatty acid desaturase 1 | fatty acid desaturase 3 3590388 NM_018454|NM_016 NUSAP1 1.62E-05 3.09 Nucleolar and spindle associated protein 1 359 3756193 NM_001067 TOP2A 7.29E-06 4.63 Topoisomerase (DNA) II alpha 170kDa 3881443 NM_012112 TPX2|TINAGL1 2.10E-06 3.11 TPX2, microtubule-associated, homolog (Xenopus laevis) | tubulointerstitial nephritis antigen-like 1 3639031 NM_199414|NM_199 PRC1 8.32E-06 3.17 Protein regulator of cytokinesis 1 413|NM_003981 Supplementary Table S3. List of genes down-regulated in HCC (Discovery Set 1) Transcript Fold RefSeq Gene symbol P-value Gene description Cluster ID change 2331679 NM_032793 MFSD2|LOC731362 1.37E-05 3.98 Major facilitator superfamily domain containing 2 | similar to ribosomal protein S2 2337786 NM_000562 C8A 6.13E-04 3.77 Complement component 8, alpha polypeptide 2377332 NM_000651|NM_000 CR1|LOC653907 3.69E-08 3.32 Complement component (3b/4b) receptor 1 (Knops blood 573 group) | similar to complement component (3b/4b) receptor 1 isoform F precursor 2388085 NM_003679 KMO 2.13E-04 3.96 Kynurenine 3-monooxygenase (kynurenine 3-hydroxylase) 2403080 NM_003665|NM_173 MAP3K6|FCN3 4.00E-09 18.47 Mitogen-activated protein kinase kinase kinase 6 | ficolin 452 (collagen/fibrinogen domain containing) 3 (Hakata antigen) 2439138 NM_005894 CD5L 1.52E-06 12.18 CD5 molecule-like 2443120 NM_001937 DPT 4.15E-07 5.63 Dermatopontin 2475911 NM_014600 EHD3 3.24E-09 3.30 EH-domain containing 3 2502686 NM_006770 MARCO 8.19E-10 6.79 Macrophage receptor with collagenous structure 2547231 NM_000348 SRD5A2 7.70E-05 4.20 Steroid-5-alpha-reductase, alpha polypeptide 2 (3-oxo-5 alpha-steroid delta 4-dehydrogenase alpha 2) 2678298 NM_004944 DNASE1L3|ACTB 5.72E-07 9.65 Deoxyribonuclease I-like 3 | actin, beta 2693620 NM_144639 UROC1 2.30E-06 6.38 Urocanase domain containing 1 2716124 NM_001528 HGFAC 9.54E-07 4.84 HGF activator 2729852 NM_005953 MT2A|MT1M|LOC4 1.53E-04 3.38 Metallothionein 2A | metallothionein 1M | hypothetical 41019|NUTF2 gene supported by X97260; BC070289 | nuclear transport factor 2 2745899 NM_022475 HHIP 7.34E-08 3.97 Hedgehog interacting protein 2772566 NM_144646 IGJ 4.02E-04 7.76 Immunoglobulin J polypeptide, linker protein for immunoglobulin alpha and mu polypeptides 2773434 NM_002089 CXCL2 1.94E-05 5.90 Chemokine (C-X-C motif) ligand 2 2775259 NM_152545 RASGEF1B|ALK|R 6.25E-05 3.25 RasGEF domain family, member 1B | anaplastic BM41 lymphoma kinase (Ki-1) | RNA binding motif protein 41 2775390 MOP-1 8.90E-04 3.53 2775909 NM_016619 PLAC8 7.54E-11 13.74 Placenta-specific 8 2792127 NM_000909 NPY1R|LOC729743| 6.08E-09 3.06 Neuropeptide Y receptor Y1 | similar to neuropeptide Y LOC731120 receptor Y1 2794584 NM_005277|NM_201 GPM6A|MPDU1 9.68E-09 3.47 Glycoprotein M6A | mannose-P-dolichol utilization defect 591|NM_201592 1 2807716 NM_000587 C7 2.60E-05 11.43 Complement component 7 2816536 NM_001882 CRHBP 3.45E-09 13.85 Corticotropin releasing hormone binding protein 2842624 NM_017675 PCLKC 6.73E-04 4.88 Protocadherin LKC 2853055 NM_031900 AGXT2 4.55E-04 3.61 Alanine-glyoxylate aminotransferase 2 2854092 NM_002310 LIFR 2.95E-07 7.18 Leukemia inhibitory factor receptor alpha 2854409 NM_001737 C9|ASTN2 7.35E-05 16.46 Complement component 9 | astrotactin 2 2876608 NM_004887 CXCL14 8.13E-08 4.89 Chemokine (C-X-C motif) ligand 14 2883283 NM_138379 TIMD4 3.38E-08 4.36 T-cell immunoglobulin and mucin domain containing 4 2907513 NM_018960 GNMT 1.61E-04 6.98 Glycine N-methyltransferase 2955761 NM_016593 CYP39A1 6.59E-04 3.97 Cytochrome P450, family 39, subfamily A, polypeptide 1 2975257 NM_022568|NM_170 ALDH8A1|HBS1L 7.13E-04 3.41 Aldehyde dehydrogenase 8 family, member A1 | 771 HBS1-like (S. cerevisiae) 2982630 NM_024492|NM_145 LPAL2|LOC732058| 5.06E-05 3.86 Lipoprotein, Lp(a)-like 2 | similar to Apolipoprotein(a) 727 PLGLB2 precursor (Apo(a)) (Lp(a)) | plasminogen-like B2 2982730 NM_005577 LPA|LOC732390|L 8.05E-06 7.98 Llipoprotein, Lp(a) | similar to Apolipoprotein(a) OC732436|PLGLB2| precursor (Apo(a)) (Lp(a)) | plasminogen-like B2 | TMEM166 transmembrane protein 166 2995476 INMT 1.51E-05 3.47 Indolethylamine N-methyltransferase 3049292 NM_001013398|NM_ IGFBP3 4.56E-05 4.96 Insulin-like growth factor binding protein 3 000598 3058944 NM_001010932|NM_ HGF 1.38E-05 5.69 Hepatocyte growth factor (hepapoietin A; scatter factor) 000601|NM_0010109 31|NM_001010933|N M_001010934 3060332 NM_024636 STEAP4 5.41E-06 3.70 STEAP family member 4 3065740 NM_173054|NM_005 RELN 3.74E-04 5.62 Reelin 045 3095257 NM_194294 INDOL1 2.39E-04 3.08 Indoleamine-pyrrole 2,3 dioxygenase-like 1 3095313 NM_020130 C8orf4 1.82E-07 3.76 Chromosome 8 open reading frame 4 3113133 NM_006438 COLEC10 1.37E-06 13.60 Collectin sub-family member 10 (C-type lectin) 3128817 NM_000680|NM_033 ADRA1A 1.87E-04 3.71 Adrenergic, alpha-1A-, receptor 303|NM_033304|NM_ 033302 3193631 NM_004108|NM_015 FCN2 1.70E-07 3.64 Ficolin (collagen/fibrinogen domain containing lectin) 2 837 (hucolin) 3204285 NM_006274 CCL19 4.46E-05 11.65 Chemokine (C-C motif) ligand 19 3204301 NM_002989 CCL21 1.51E-04 4.04 Chemokine (C-C motif) ligand 21 3215570 NM_000507 FBP1 2.86E-04 3.65 Fructose-1,6-bisphosphatase 1 3237286 NM_001009567 MRC1 1.08E-06 4.72 Mannose receptor, C type 1 3251566 NM_152635 OIT3|C1orf146 2.82E-08 10.95 Oncoprotein induced transcript 3 | chromosome 1 open reading frame 146 3286602 NM_000609|NM_199 CXCL12 3.57E-06 5.02 Chemokine (C-X-C motif) ligand 12 (stromal cell-derived 168|NM_001033886 factor 1) 3302533 NM_003015 SFRP5 1.38E-05 4.31 Secreted frizzled-related protein 5 3333811 NM_001039752 SLC22A10 3.50E-04 5.11 Solute carrier family 22 (organic anion/cation transporter), member 10 3348940 NM_031938|NM_001 KCTD9|BCDO2|LO 3.85E-05 4.40 Potassium channel tetramerisation domain containing 9 | 037290 C728291|LOC64251 beta-carotene dioxygenase 2 | similar to potassium 3|LOC728707|LOC7 channel tetramerisation domain containing 9 | 29404|LOC730942|L hypothetical protein LOC728707 OC650978|LOC6478 52|LOC731540 3349858 NM_006169 NNMT 2.28E-05 9.79 Nicotinamide N-methyltransferase 3359121 NR_003512|NM_0010 INS-IGF2 7.64E-04 13.10 Insulin- insulin-like growth factor 2 | insulin-like growth 07139|NM_000612 factor 2 (somatomedin A) 3360401 NM_000518 HBB 3.13E-06 3.35 Hemoglobin, beta 3362826 NM_006691 XLKD1 6.72E-09 8.65 Extracellular link domain containing 1 3365318 NM_006512 SAA4 9.90E-04 3.56 Serum amyloid A4, constitutive 3374934 NM_152852|NM_022 MS4A6A|LOC64368 2.47E-05 3.25 Membrane-spanning 4-domains, subfamily A, member 349|NM_152851 0 6A | hypothetical protein 3402786 NM_000616 CD4|S100PBP 1.43E-06 3.07