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Home , ACSS2, ADAM28, ADAMTS9, ALPI, Annexin A13, APOBEC3C

SUPPLEMENTARY INFORMATION

1. SUPPLEMENTARY FIGURE LEGENDS

Supplementary Figure 1. Long-term exposure to increases the expression of progenitor cell-like features. A) mRNA expression levels of PROM-1

(CD133), THY-1 (CD90), EpCAM, KRT19, and VIM assessed by quantitative real-time

PCR. Data represent the mean expression value for a in each phenotypic type of cells, displayed as fold-changes normalized to 1 (expression value of its corresponding parental non-treated cell line). Expression level is relative to the GAPDH gene. Bars indicate standard deviation. Significant statistical differences are set at p<0.05. B)

Immunocitochemical of CD90 and in Hep3B sorafenib resistant cell line and its parental cell line. C) Western blot analysis comparing levels in resistant Hu6 and Hep3B cells vs their corresponding parental cells lines.

Supplementary Figure 2. Efficacy of gene silencing of IGF1R and FGFR1 and evaluation of MAPK14 signaling activation. IGF1R and FGFR1 knockdown expression 48h after transient transfection with siRNAs (50 nM), in non-treated parental cells and sorafenib-acquired resistant tumor derived cells was assessed by quantitative

RT-PCR (A) and western blot (B). C) Activation status of MAPK14 signaling was evaluated by western blot analysis in vivo, in tumors with acquired resistance to sorafenib in comparison to non-treated tumors (right panel), as well as in in vitro, in sorafenib resistant cell lines vs parental non-treated.

Supplementary Figure 3. levels of several pro-angiogenic factors. mRNA expression levels of FGF1, FGF2, VEGFA, IL8, ANGPT2, KDR,

FGFR3, FGFR4 assessed by quantitative real-time PCR in tumors harvested from mice.

Plotted data represent the mean expression value for a gene in each experimental group, displayed as fold-changes normalized to 1 (mean expression value in non- treated animals). Expression level is relative to the GAPDH. Bars indicate standard deviation. Significant statistical differences are set at p<0.05.

Supplementary Figure 4. Increased expression and activation of FGFR1 and

IGF1R in acquired resistance tumors. A) Immunohistochemical analysis of FGFR1 and IGF1R protein levels in sorafenib-sensitive and sorafenib-acquired resistant tumors.

B) Immunostaining showing activation () of FGFR1 and IGF1R in viable clusters of cells close to necrotic areas in sorafenib-resistant tumors.

2. SUPPLEMENTARY MATERIAL & METHODS

Sphere formation assay

To obtain single cell suspension, subcutaneous Huh7-derived tumors were excised and mechanically dissociated by gentle pipetting in Ca/Mg-free PBS on ice, and filtered through a 40 µm cell strainer (BD Falcon). Then, cells were exposed to red cell lysis buffer (Sigma-Aldrich) to remove red blood cells. No enzymatic digestion was used to isolate cells. Cell viability was quantified in a Neubauer cytometer using the trypan blue

(1%; Sigma Aldrich) exclusion method. After tumor harvest and generation of single cell suspensions tumor cells where directly cultured into non-adherent conditions to allow the formation of spheroids as previously described(1). Briefly, cells were grown in serum free epithelial growth medium (MEGM, BioWhittaker) supplemented with B27

(Invitrogen), 20 ng/mL EGF and 20 ng/mL bFGF (BD Biosciences), and 4 μg/mL

(Sigma). Live cells were then plated in 96-well ultra-low attachment plates (Corning) at limiting dilution (10, 102, 103 and 104 cells) and sphere formation was assessed microscopically after 10 days of growth.

Cell culture, reagents and

Parental Huh7, Hep3B and H6 cell lines were cultured in DMEN with 10% fetal bovine serum (Gibco, Grand Island, NY). The Hep3B-sorafenib resistant cell line(2) and H6- sorafenib resistant cells line were kindly provided Dr. Desbois-Mouthon (INSERM,

Paris) and grown in the presence of sorafenib at a concentration of 4 µM and 3 µM, respectively. Tumor-derived spheres were grown under non-adherent culture conditions in serum free epithelial growth medium (MEGM, BioWhittaker) supplemented with B27 (Invitrogen), 20 ng/mL EGF and 20 ng/mL bFGF (BD

Biosciences), and 4 μg/mL insulin (Sigma). Cells from sorafenib-acquired resistant tumors were grown in the presence of 4 µM of sorafenib. Sorafenib was purchased from LC Laboratories (Woburn, MA). (IGF1R inhibitor) and BGJ398 (pan inhibitor of FGFR1, -2, -3) were purchased from BioVision (Milpitas, CA). Brivanib

(FGFR inhibitor) was provided by Bristol-Myers Squibb (BMS, New York, NY).

In vitro and the in vivo doses of the compounds were chosen after revision of published preclinical studies, as well as, by following the manufacturer’s recommendations(3-5).

For in vivo oral administration, sorafenib was dissolved in ethanol 95%/cremophor

EL/sterile water (12.5:12.5:75%) at 30 mg/kg/day dosage. Brivanib was dissolved following BMS recommendations and orally dosed at 100 mg/kg/day. For MTT assay dissociated spheres were plated at a density of 5,000 cells/well in 96-well ultra-low attachment. Huh7, Hep3B, Hep3B-sora, Huh6 and Huh6-sora cells were seeded at

2,500-3,000 cells/well density under adherent conditions. Then cell viability was evaluated after 48-72 hours in the presence of sorafenib or/and other inhibitors (0.1-10

M). Each experimental condition was measured in triplicate in 3 independent experiments.

siRNA transfection

Cells were plated on 96-well plates or 6-well plates and transiently transfected with

Silencer® Select siRNAs from Ambion (Life technologies, Inc.) (cat. #4390824 ID:

#s7211 for IGF1R siRNA, ID: #s5164 for FGFR1 siRNA, cat. # 4390649 for control

GAPDH siRNA, cat. 4390646 negative control #2) at 50 nM using Lipofectamine® 3000 tranfection reagent (Life technologies, Life Technologies) following manufacturer’s intructions. 4 hours post transfection sorafenib at 3 µM was added to the medium and cells were allowed to grown for additional 48 hours.

Protein extraction and Western blot analysis

Cells were plated into 15 cm culture dishes and grown to subconfluency. Total protein was quantified using Bradford Reagent (Sigma, Saint Louis, MO). To isolate cytoplasmic cells were lysed with RIPA buffer plus and inhibitors (50 mM Tris pH=7.4, 150 mM NaCl, 1% Trithon X-100, 0.1% SDS, 0.25 mM EDTA, 1% deoxycholate). A modified lysis buffer was used to better preserve

IGF1R and FGFR1 in whole lysates (Hepes pH=7.5 50 mM, NaCl 150 mM, MgCl2 1.5 mM, EDTA 1 mM, 10% Glycerol, 1% Trithon X-100). Both buffers contained a mixture of protease and phosphatase inhibitors; Cocktail Tablets (Roche, Mannheim, Germany),

NaF 1 mM, NaPiP 1 mM and Na3VO4 0.2 mM.

For western blot analysis equal amounts of total protein were resolved in polyacrylamide gels and transferred to nitrocellulose membranes (Pierce, Rockford, IL).

Membranes were BSA-blocked and hybridized overnight at 4ºC with the primary ; IGF1R, phospho-IGF1R, FGFR1, phospho-FGFR1, ERK, phospho-ERK,

Akt, phospho-Akt, MAPK14, phospho-MAPK14, EpCAM, vimentin, CK19 (Cell

Signaling) and later at room temperature with HRP-conjugated secondary antibodies.

To evaluate the activation status of FGFR1, immunoprecipitation with total anti-FGFR1 and western blot analysis using the anti-phosphotyrosine clone PY20 HRP (Santa Cruz) was performed as previously described(5). Signals were visualized with Amersham

ECL Prime (GE Healthcare, Buckinghamshire, UK) using a LAS-4000 imaging system

(Fujifilm, Tokyo, Japan).

Immunohistochemical analysis

For , 5-m paraffin-embedded sections of mice xenograft tumors were baked at 55 C for 1 hour, deparaffinized in xylene, and rehydrated in a graded series of ethanol solutions. Antigens were unmasked by microwave heating the samples in 10 mM sodium citrate buffer (pH 6.0) for 15 minutes (5 minutes, 3 times), and the reaction was quenched using 3%. After washing with PBS, samples were incubated with the following primary concentrations: p-FGFR1

(Tyr766) 1:50, FGFR1 1:100 (both from Abcam plc, Cambridge, UK), anti-p-RPS6

(phosphoSer240/244) 1:200, anti-pERK (phosphoThr202/Tyr204) 1:100, anti-ERK

1:100 (all from , Danvers, MA), and anti-p-IGF-1R (phosphoTyr1316)(6)

1:100, at 4ºC overnight. DAB (3,3'-diaminobenzidine) was used as a detection system (EnVision+ System-HRP, Dako). Samples were contrasted with Gill’s hematoxilyn

(Panreac, Castellar del Valles, Spain), dehydrated and mounted with DPX (Richmond,

IL). Immunoreactivity was graded by a pathologist (MS). The variables measured were immunostaining intensity and staining pattern.

For immunocytochemistry cells were seeded on poly-L treated coverslips on 24- well plates for 16h, fixed, permeabilized and incubated O/N at 4ºC with primary antibodies for CK19 (Dako), EpCAM, CD133, CD90 (Abcam), and vimentin (Cell

Signaling).

Gene expression analysis profiling

Briefly, 1 g of total RNA was hybridized to the Gene 1.0 ST platform.

Differential expression among experimental groups was analyzed using Array File

Maker 4.0 (AFM) software. Data was normalized by RMA method and analyzed with

GenePattern software (www.broadinstitute.org/genepattern). The dataset is deposited at GEO Omnibus (http://www.ncbi.nlm.nih.gov/geo) under accession number GEO

(GSE73571). For relative mRNA quantification TaqMan® Gene Expression Assays were used following manufacturer’s instructions (Applied Biosystems, Foster City, CA).

GAPDH and ribosomal RNA (18S) were chosen as endogenous reference .

TaqMan® probes are listed in Supplementary Table 2.

For the purpose of the study, we used data from the transcriptomic analysis of 442

HCCs performed by the HCC Genomic Consortium in previous studies (7-11).

Computation of sphere- and tumor-initiating cell frequencies

To compute the frequency of sphere- and tumor-initiating cells, the maximum-likelihood estimation method was used(4, 12). Similar results were obtained using a second method(13), and internal consistency was validated by chi-squared analysis (data not shown).

Bioinformatic and statistical analysis

Gene expression profiling among experimental groups was analyzed with the module

Comparative Marker Selection as implemented in Gene Pattern, and Array File Maker

4.0 (AFM) tools. Gene Set Enrichment Analysis (GSEA) was performed to identify differentially expressed gene sets from MSigDB databases

(www.broadinstitute.org/msigdb) and a collection of previously reported gene- expression signatures in liver cancer(14). Nearest template prediction method

(NTP)(15) was used to identify patients harboring the gene signature of sorafenib resistance. Genes with expression values higher than 1.5-fold change were uploaded into Gene Pattern and IPA software (http://www.ingenuity.com). Statistical significance was computed with Fisher’s exact test for categorical variables and with T-test or

Mann-Whitney U-test for continuous variables. Correlations were calculated with the parametric Pearson’s coefficient or the non-parametric Spearman’s correlation. Kaplan-

Meier curves and the log-rank test were applied to analyze survival. For multiple test correction significance was set at FDR<0.05. Statistical analysis was performed using

R (http://cran.r-project.org/) and SPSS 18.0 package (Chicago, IL).

Pilot study to analyze the development of acquired resistance to sorafenib in a mouse xenograft model.

5x106 Huh7 cells in PBS were inoculated in the right of a female 8-weeks Balb/C nude mouse. At 150 mm3 tumor volume, nude mouse started treatment with sorafenib at 30 mg/kg/day. After 4 weeks of growth the tumor was excised, cut into small pieces, and subcutaneously implanted in 10 additional nude mice. Tumor grafts were allowed to grow until they reach 100 mm3 and then, mice started daily treatment with sorafenib. As there is no clear and uniform definition of acquire resistance to TKIs, tumor growth was accurately monitored 3 times per week using a digital hand-caliper during 28 days. Tumor size was determined using the formula: volume= 0.5 x (width)2 x length. Body weight was also monitored thrice weekly to evaluate potential side effects associated to the administration of the . Accurate observation of tumor burden allowed us to define the criteria of development of acquired resistance to sorafenib which was defined as 1) a ≥30% tumor volume increase in 3 days and 2) in tumors responsive to sorafenib for ≥15 days. Tumors initially not responding to sorafenib were considered intrinsically resistant. Tumors exhibiting a slow growth rate (ratio<1.3) or regression during treatment time were considered sorafenib-responsive. The following graph shows tumor growth evolution in this set of 10 mice for 25 consecutive days.

2400 Intrisic resistance

Acquired resistance n=2 2000 n=2

sorafenib responsive

) ) )

3 3 3

1600

(mm(mm(mm

1200

volumevolume volume

800

tumortumor tumor n=6 400

0 1 5 10 15 20 25 days on sorafenib

Preparation of brivanib for in vivo administration

In brief, brivanib was dissolved in an acid citric/sodium citrate-based solution at pH of 1 at 100 mg/kg. Then, NaOH 12N was added very slowly to raise pH at 3.5, continuously stirring up the mixture to allow gummy precipitates to completely dissolve. This solution is stable for up to 2 weeks at room temperature and protected from light.

SUPPLEMENTARY REFERENCES

1. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008;133:704-715. 2. Blivet-Van Eggelpoel MJ, Chettouh H, Fartoux L, Aoudjehane L, Barbu V, Rey C, Priam S, et al. Epidermal and HER-3 restrict cell response to sorafenib in hepatocellular carcinoma cells. J Hepatol 2012;57:108- 115. 3. Huynh H, Ngo VC, Fargnoli J, Ayers M, Soo KC, Koong HN, Thng CH, et al. Brivanib alaninate, a dual inhibitor of vascular endothelial and receptor tyrosine , induces growth inhibition in mouse models of human hepatocellular carcinoma. Clin Cancer Res 2008;14:6146-6153. 4. Newell P, Toffanin S, Villanueva A, Chiang DY, Minguez B, Cabellos L, Savic R, et al. Ras pathway activation in hepatocellular carcinoma and anti- tumoral effect of combined sorafenib and rapamycin in vivo. J Hepatol 2009;51:725-733. 5. Sia D, Losic B, Moeini A, Cabellos L, Hao K, Revill K, Bonal D, et al. Massive parallel sequencing uncovers actionable FGFR2-PPHLN1 fusion and ARAF in intrahepatic cholangiocarcinoma. Nat Commun 2015;6:6087. 6. Rubini M, D'Ambrosio C, Carturan S, Yumet G, Catalano E, Shan S, et al. Characterization of an antibody that can detect an activated IGF-I receptor in human cancers. Exp Cell Res 1999;251:22-32. 7. Villanueva A, Portela A, Sayols S, Battiston C, Hoshida Y, Méndez- González J, Imbeaud S, et al. DNA Methylation-based prognosis and epidrivers in hepatocellular carcinoma. Hepatology (submitted) 2014. 8. Chiang DY, Villanueva A, Hoshida Y, Peix J, Newell P, Minguez B, LeBlanc AC, et al. Focal gains of VEGFA and molecular classification of hepatocellular carcinoma. Cancer Res 2008;68:6779-6788. 9. Villanueva A, Chiang DY, Newell P, Peix J, Thung S, Alsinet C, Tovar V, et al. Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastroenterology 2008;135:1972-1983, 1983 e1971-1911. 10. Villanueva A, Hoshida Y, Battiston C, Tovar V, Sia D, Alsinet C, Cornella H, et al. Combining clinical, pathology, and gene expression data to predict recurrence of hepatocellular carcinoma. Gastroenterology 2011;140:1501-1512 e1502. 11. Wurmbach E, Chen YB, Khitrov G, Zhang W, Roayaie S, Schwartz M, Fiel I, et al. Genome-wide molecular profiles of HCV-induced dysplasia and hepatocellular carcinoma. Hepatology 2007;45:938-947. 12. Cairo S, Armengol C, De Reynies A, Wei Y, Thomas E, Renard CA, Goga A, et al. Hepatic stem-like phenotype and interplay of Wnt/beta- and signaling in aggressive childhood liver cancer. Cancer Cell 2008;14:471-484. 13. Desbois-Mouthon C, Cacheux W, Blivet-Van Eggelpoel MJ, Barbu V, Fartoux L, Poupon R, Housset C, et al. Impact of IGF-1R/EGFR cross-talks on hepatoma cell sensitivity to . Int J Cancer 2006;119:2557-2566. 14. Hoshida Y, Toffanin S, Lachenmayer A, Villanueva A, Minguez B, Llovet JM. Molecular classification and novel targets in hepatocellular carcinoma: recent advancements. Semin Liver Dis 2010;30:35-51. 15. Hoshida Y. Nearest template prediction: a single-sample-based flexible class prediction with confidence assessment. PLoS One 2011;5:e15543.

Supplementary Table 1: Clinical characteristics of HCC patients in the two cohorts.

Variable Cohort A Cohort B (n=219) (n=223)

Median age 66 67

Gender (male) 172 (78%) 159 (71%)

Aetiology Hepatitis C 101 (45%) 136 (61%) Hepatitis B 44 (20%) 46 (21%) Alcohol 35 (16%) 12 (5%) Others 37 (17%) 29 (13%)

Child-Pugh score: A 216 (97%) 207 (93%) B 4 (2%) 2 (0.8%) C 3 (1%)

Tumour size (cm) <2 26 (12%) 24 (11%) 2-3 73 (33%) 75 (34%) >3 122 (55%) 123 (55%)

Multiple nodules Absent 166 (75%) 191 (86%) Present 55 (25%) 31(14%)

Micro-vascular invasion Absent 142 (64%) 127 (57%) Present 77 (35%) 89 (40%)

Satellites Absent 158 (71%) 163 (73%) Present 63 (29%) 41 (18%)

BCLC early stage (0-A) 191 (87%) 196 (88%)

Degree of tumour differentiation Well 34 (15%) 52 (23%) Moderately 105 (47%) 117 (52%) Poor 45 (20%) 36 (16%)

Bilirubin (≥1 mg/dL) 92 (42%) 81 (36%)

Albumin (<3.5 g/L) 25 (11%) 24 (11%)

Platelet count (<100,000/mm3) 43 (19%) 35 (16%)

AFP (>100 mg/dL) 51 (23%) 60 (27%)

Events Recurrence 151 (69%) 141 (63%) Death 139 (62%) 83 (37%)

Supplementary Table 2. Taqman probes used for the Quantitative real time RT-PCR expression analysis.

Target gene Taqman Assay ID 1 FGF1 Hs00265254_m1 2 FGF2 Hs00266645_m1 3 FGF19 Hs00391591_m1 4 FGFR1 Hs00241111_m1 5 FGFR3 Hs00179829_m1 6 FGFR4 Hs01106908_m1 7 IGF1R Hs00181385_m1 8 VEGFA Hs00900055_m1 9 KDR Hs00911700_m1 10 IL8 Hs00174103_m1 11 ANGTP1 Hs00375822_m1 12 PROM1 Hs01009250_m1 13 ANPEP Hs00174265_m1 14 THY-1 Hs00264235_s1 15 EpCAM Hs00901885_m1 16 KRT19 Hs00761767_s1 17 VIM Hs00185584_m1 18 GAPDH Hs03929097_g1 19 18S Hs99999901_s1

Supplementary Table 3. List of 528 differentially expressed genes in sorafenib-resistant tumors vs sorafenib-responsive tumors (≥1.5-fold, p<0.05)

Symbol Accession Gene name//Description Fold change p value

Upregulated EYS NM_001142800 eyes shut homolog (Drosophila) 2,48 0,030 ZNF257 NM_033468 protein 257 2,34 0,000 LRP12 NM_013437 low density lipoprotein receptor-related protein 12 2,24 0,001 SNRPA1 NM_003090 small nuclear ribonucleoprotein polypeptide A 2,17 0,002 FGF18 NM_003862 fibroblast growth factor 18 2,17 0,003 SNORD44 NR_002750 small nucleolar RNA, C/D box 44 2,13 0,001 MMP16 NM_005941 matrix metallopeptidase 16 (membrane-inserted) 2,13 0,002 LAMA4 NM_001105206 laminin, alpha 4 1,98 0,002 GUSBP3 NR_027386 glucuronidase, beta 3 1,98 0,014 FREM1 NM_144966 FRAS1 related 1 1,97 0,000 SNORD12C NR_002433 small nucleolar RNA, C/D box 12C 1,97 0,018 TRIM52 NM_032765 tripartite motif containing 52 1,97 0,006 SNORD78 NR_003944 small nucleolar RNA, C/D box 78 1,97 0,001 FAM5C NM_199051 family with sequence similarity 5, member C 1,96 0,010 SNORD21 NR_000006 small nucleolar RNA, C/D box 21 1,94 0,006 ARHGAP29 NM_004815 Rho GTPase activating protein 29 1,93 0,001 CBWD5 NM_001024916 COBW domain containing 5 1,93 0,003 SLC16A6 NM_001174166 16, member 6 (monocarboxylic acid transporter 7) 1,93 0,004 FAM60A NM_001135811 family with sequence similarity 60, member A 1,92 0,000 SNORD22 NR_000008 small nucleolar RNA, C/D box 22 1,90 0,007 CDC6 NM_001254 cell division cycle 6 homolog (S. cerevisiae) 1,88 0,002 SNORA62 NR_002324 small nucleolar RNA, H/ACA box 62 1,87 0,001 SNORD31 NR_002560 small nucleolar RNA, C/D box 31 1,87 0,013 HELLS NM_018063 helicase, lymphoid-specific 1,86 0,000 SNORD73A NR_000007 small nucleolar RNA, C/D box 73A 1,85 0,006 DNA2 NM_001080449 DNA replication helicase 2 homolog (yeast) 1,84 0,001 SNORD4A NR_000010 small nucleolar RNA, C/D box 4A 1,84 0,002 SNORA74A NR_002915 small nucleolar RNA, H/ACA box 74A 1,83 0,011 RING1 NM_002931 ring finger protein 1 1,82 0,021 DRD5 NM_000798 receptor D5 1,80 0,000 RNU5E NR_002754 RNA, U5E small nuclear 1,80 0,035 GCLC NM_001498 glutamate-cysteine , catalytic subunit 1,79 0,031 MMP16 NM_005941 matrix metallopeptidase 16 (membrane-inserted) 1,78 0,000 SNORD30 NR_002561 small nucleolar RNA, C/D box 30 1,78 0,007 CENPE NM_001813 protein E, 312kDa 1,78 0,006 SNORA75 NR_002921 small nucleolar RNA, H/ACA box 75 1,77 0,002 ZNHIT6 NM_017953 zinc finger, HIT-type containing 6 1,76 0,004 SNORD75 NR_003941 small nucleolar RNA, C/D box 75 1,76 0,002 VCAN NM_004385 1,76 0,010 DUSP6 NM_001946 dual specificity phosphatase 6 1,76 0,003 SNORD27 NR_002563 small nucleolar RNA, C/D box 27 1,75 0,010 PDE4D NM_001165899 4D, cAMP-specific 1,75 0,001 SNORD36B NR_000017 small nucleolar RNA, C/D box 36B 1,75 0,002 NETO2 NM_018092 neuropilin (NRP) and tolloid (TLL)-like 2 1,75 0,009 IGF1R NM_000875 insulin-like growth factor 1 receptor 1,75 0,035 FERMT1 NM_017671 fermitin family member 1 1,74 0,000 KLRAP1 NR_028045 killer cell lectin-like receptor subfamily A pseudogene 1 1,74 0,003 TSPAN12 NM_012338 tetraspanin 12 1,73 0,030 PANK2 NM_153638 pantothenate 2 1,72 0,010 HOMER1 NM_004272 homer homolog 1 (Drosophila) 1,72 0,002 SNORD49A NR_002744 small nucleolar RNA, C/D box 49A 1,71 0,014 DDX21 NM_004728 DEAD (Asp-Glu-Ala-Asp) box polypeptide 21 1,70 0,001 BRCA2 NM_000059 2, early onset 1,70 0,004 SNORD20 NR_002908 small nucleolar RNA, C/D box 20 1,70 0,006 SLC7A11 NM_014331 solute carrier family 7, (cationic transporter) member 11 1,70 0,014 CHN1 NM_001822 chimerin (chimaerin) 1 1,70 0,010 UTP20, small subunit (SSU) processome component, homolog UTP20 NM_014503 1,69 0,005 (yeast) CLSPN NM_022111 claspin 1,69 0,009 SNORD52 NR_002742 small nucleolar RNA, C/D box 52 1,69 0,003 POLQ NM_199420 polymerase (DNA directed), theta 1,69 0,007 LRRFIP1 NM_001137552 rich repeat (in FLII) interacting protein 1 1,68 0,012 CCDC41 NM_016122 coiled-coil domain containing 41 1,68 0,006 ADAMTS9 NM_182920 ADAM metallopeptidase with type 1 motif, 9 1,67 0,019 SNORD50B NR_003044 small nucleolar RNA, C/D box 50B 1,67 0,030 EIF1AX NM_001412 eukaryotic translation initiation factor 1A, X-linked 1,67 0,042 RBM14 NM_006328 RNA binding motif protein 14 1,67 0,006 SNORD80 NR_003940 small nucleolar RNA, C/D box 80 1,66 0,041 CCDC144C NR_023380 coiled-coil domain containing 144C 1,65 0,022 SNORD59B NR_003046 small nucleolar RNA, C/D box 59B 1,65 0,013 BAGE2 NM_182482 B melanoma antigen family, member 2 1,64 0,019 LOC100130876 AK130278 hypothetical LOC100130876 1,64 0,046 GPD2 NM_001083112 glycerol-3-phosphate dehydrogenase 2 (mitochondrial) 1,64 0,006 CEP290 NM_025114 centrosomal protein 290kDa 1,64 0,013 ARHGAP11A NM_014783 Rho GTPase activating protein 11A 1,64 0,010 LOC100130428 BC040288 IGYY565 1,64 0,012 FAM169A NM_015566 family with sequence similarity 169, member A 1,63 0,023 GALNT5 NM_014568 D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 5 1,63 0,026 PRPF4B NM_003913 PRP4 pre-mRNA processing factor 4 homolog B (yeast) 1,63 0,007 FANCM NM_020937 Fanconi anemia, complementation group M 1,63 0,016 LOC80154 NR_026811 hypothetical LOC80154 1,63 0,001 METTL2B NM_018396 methyltransferase like 2B 1,62 0,011 ROCK2 NM_004850 Rho-associated, coiled-coil containing 2 1,62 0,000 LYAR NM_017816 Ly1 antibody reactive homolog (mouse) 1,62 0,013 CRIPAK NM_175918 cysteine-rich PAK1 inhibitor 1,62 0,010 SNORD34 NR_000019 small nucleolar RNA, C/D box 34 1,61 0,026 CLSPN NM_022111 claspin 1,61 0,018 TCEB3CL NM_001100817 elongation factor B polypeptide 3C-like 1,61 0,013 C12orf48 AK302724 12 48 1,61 0,016 POLR3G NM_006467 polymerase (RNA) III (DNA directed) polypeptide G (32kD) 1,61 0,026 FAM72D AB096683 family with sequence similarity 72, member D 1,61 0,007 BCAT1 NM_005504 branched chain amino-acid transaminase 1, cytosolic 1,60 0,007 ZNF322A NM_024639 zinc finger protein 322A 1,60 0,007 TFAM NM_003201 A, mitochondrial 1,59 0,009 PDGFD NM_025208 derived growth 1,59 0,020 OR4F16 NM_001005277 , family 4, subfamily F, member 16 1,59 0,011 NAA25 NM_024953 N(alpha)-acetyltransferase 25, NatB auxiliary subunit 1,59 0,012 RPL7L1 NM_198486 ribosomal protein L7-like 1 1,58 0,028 CLIP4 NM_024692 CAP-GLY domain containing linker , member 4 1,58 0,027 sema domain, (Ig), secreted, () SEMA3D NM_152754 1,58 0,004 3D KIF20B NM_016195 family member 20B 1,58 0,002 UTP15 NM_032175 UTP15, U3 small nucleolar ribonucleoprotein, homolog (S. cerevisiae) 1,58 0,011 WDHD1 NM_007086 WD repeat and HMG-box DNA binding protein 1 1,58 0,012 FGFR1 NM_023110 fibroblast growth factor receptor 1 1,57 0,001 SNORD58A NR_002571 small nucleolar RNA, C/D box 58A 1,57 0,050 KDM1B NM_153042 lysine (K)-specific 1B 1,57 0,013 NCAPG2 NM_017760 non-SMC condensin II complex, subunit G2 1,57 0,000 ATR NM_001184 ataxia telangiectasia and Rad3 related 1,57 0,007 ATAD5 NM_024857 ATPase family, AAA domain containing 5 1,56 0,030 BIVM NM_017693 basic, immunoglobulin-like variable motif containing 1,56 0,017 ZFC3H1 NM_144982 zinc finger, C3H1-type containing 1,56 0,013 MIR32 NR_029506 microRNA 32 1,56 0,030 CHRNA5 NM_000745 receptor, nicotinic, alpha 5 1,56 0,001 SNORA6 NR_002325 small nucleolar RNA, H/ACA box 6 1,56 0,006 RBL1 NM_002895 retinoblastoma-like 1 (p107) 1,56 0,007 PLCXD1 NM_018390 phosphatidylinositol-specific C, X domain containing 1 1,56 0,001 TAS2R20 NM_176889 receptor, type 2, member 20 1,56 0,022 SNORA70 NR_000011 small nucleolar RNA, H/ACA box 70 1,56 0,005 CCPG1 NM_004748 cell cycle progression 1 1,56 0,042 GOLGA6L1 NM_001001413 golgin A6 family-like 1 1,56 0,025 NCRNA00266 BC118988 non-protein coding RNA 266 1,55 0,023 SSR1 NM_003144 signal sequence receptor, alpha 1,55 0,032 MYC NM_002467 v-myc myelocytomatosis viral oncogene homolog (avian) 1,55 0,005 ME1 NM_002395 malic 1, NADP(+)-dependent, cytosolic 1,55 0,018 C12orf5 NM_020375 open reading frame 5 1,54 0,001 GOLGA8F NR_033351 golgin A8 family, member F 1,54 0,005 SNORD26 NR_002564 small nucleolar RNA, C/D box 26 1,54 0,026 DUSP5 NM_004419 dual specificity phosphatase 5 1,54 0,012 VPS13A NM_033305 vacuolar protein sorting 13 homolog A (S. cerevisiae) 1,54 0,033 EIF5B NM_015904 eukaryotic translation initiation factor 5B 1,54 0,007 RBM28 NM_018077 RNA binding motif protein 28 1,53 0,005 ERCC6L NM_017669 excision repair cross-complementing repair deficiency 1,53 0,028 TBC1D30 AB449914 TBC1 domain family, member 30 1,53 0,049 LYRM7 NM_181705 Lyrm7 homolog (mouse) 1,53 0,023 ATM NM_000051 ataxia telangiectasia mutated 1,53 0,006 NR2F2 NM_021005 subfamily 2, group F, member 2 1,53 0,003 SEPT14 NM_207366 septin 14 1,53 0,039 RANBP2 NM_006267 RAN binding protein 2 1,53 0,020 SNORD103A NR_004054 small nucleolar RNA, C/D box 103A 1,53 0,020 HSPH1 NM_006644 heat shock 105kDa/110kDa protein 1 1,53 0,019 FKBP14 NM_017946 FK506 binding protein 14, 22 kDa 1,52 0,046 SMCHD1 NM_015295 structural maintenance of hinge domain containing 1 1,52 0,013 PRKDC NM_006904 protein kinase, DNA-activated, catalytic polypeptide 1,52 0,003 BTAF1 NM_003972 BTAF1 RNA polymerase II, B-TFIID transcription factor-associated 1,52 0,001 KIF14 NM_014875 kinesin family member 14 1,52 0,014 TAS2R31 NM_176885 , type 2, member 31 1,52 0,038 SNORD96A NR_002592 small nucleolar RNA, C/D box 96A 1,52 0,001 MYCBP2 NM_015057 MYC binding protein 2 1,52 0,005 PNPT1 NM_033109 polyribonucleotide nucleotidyltransferase 1 1,52 0,006 AP1S3 NM_001039569 adaptor-related protein complex 1, sigma 3 subunit 1,51 0,003 SLC7A1 NM_003045 solute carrier family 7 (cationic amino acid transporter), member 1 1,51 0,034 SYCP2L NM_001040274 synaptonemal complex protein 2-like 1,51 0,024 NAA15 NM_057175 N(alpha)-acetyltransferase 15, NatA auxiliary subunit 1,51 0,004 SNORD42B NR_000013 small nucleolar RNA, C/D box 42B 1,51 0,003 NOLC1 NM_004741 nucleolar and coiled-body phosphoprotein 1 1,51 0,027 SNORD79 NR_003939 small nucleolar RNA, C/D box 79 1,51 0,008 GPCPD1 NM_019593 glycerophosphocholine phosphodiesterase GDE1 homolog 1,51 0,002 LOC100129112 AK123839 hypothetical protein LOC100129112 1,51 0,018 LZIC NM_032368 and CTNNBIP1 domain containing 1,51 0,012 OR8G2 NM_001007249 olfactory receptor, family 8, subfamily G, member 2 1,51 0,046 KIF11 NM_004523 kinesin family member 11 1,51 0,007 FN1 NM_212482 fibronectin 1 1,50 0,010 CLEC2D NM_001004419 C-type lectin domain family 2, member D 1,50 0,013 ATAD2 NM_014109 ATPase family, AAA domain containing 2 1,50 0,002 PPM1E NM_014906 , Mg2+/Mn2+ dependent, 1E 1,50 0,010 TAS2R14 NM_023922 taste receptor, type 2, member 14 1,50 0,035 SPATA5 NM_145207 spermatogenesis associated 5 1,50 0,016 SVIP NM_148893 small VCP/p97-interacting protein 1,50 0,026 C4orf21 NM_018392 open reading frame 21 1,50 0,010 CCDC88C NM_001080414 coiled-coil domain containing 88C 1,50 0,023 TGFBR2 NM_001024847 transforming growth factor, beta receptor II (70/80kDa) 1,50 0,003 Downregulated IGHA1 AK128476 immunoglobulin heavy constant alpha 1 -7,55 0,050 CDH17 NM_004063 17, LI cadherin (liver-intestine) -4,49 0,003 FXYD3 NM_021910 FXYD domain containing ion transport regulator 3 -4,01 0,000 DPEP1 NM_004413 1 (renal) -4,00 0,001 NPNT NM_001033047 nephronectin -3,96 0,000 PRR15L NM_024320 proline rich 15-like -3,91 0,001 TBX4 NM_018488 T-box 4 -3,77 0,000 MUC13 NM_033049 13, cell surface associated -3,76 0,008 UBD NM_006398 ubiquitin D -3,58 0,001 IGLJ3 AB001736 immunoglobulin lambda joining 3 -3,54 0,025 ANXA13 NM_001003954 A13 -3,47 0,004 PPP1R3C NM_005398 , regulatory (inhibitor) subunit 3C -3,31 0,000 ERP27 NM_152321 protein 27 -3,16 0,008 GUCY2C NM_004963 2C (heat stable enterotoxin receptor) -3,08 0,012 APOA4 NM_000482 A-IV -2,92 0,002 KNG1 NM_000893 kininogen 1 -2,89 0,003 DPYSL3 NM_001387 -like 3 -2,77 0,011 SPARC NM_003118 secreted protein, acidic, cysteine-rich () -2,66 0,002 LCN15 NM_203347 lipocalin 15 -2,63 0,002 INHBE NM_031479 inhibin, beta E -2,61 0,000 HHLA2 NM_007072 HERV-H LTR-associating 2 -2,59 0,007 HPX NM_000613 -2,56 0,000 PTGIS NM_000961 prostaglandin I2 (prostacyclin) synthase -2,55 0,002 CTSE NM_001910 E -2,53 0,010 AQP10 NM_080429 10 -2,53 0,001 MS4A10 NM_206893 membrane-spanning 4-domains, subfamily A, member 10 -2,47 0,031 FXYD1 NM_005031 FXYD domain containing ion transport regulator 1 -2,46 0,000 UNC93A NM_018974 unc-93 homolog A (C. elegans) -2,45 0,000 ACE2 NM_021804 angiotensin I converting enzyme (peptidyl-dipeptidase A) 2 -2,45 0,033 PADI2 NM_007365 peptidyl deiminase, type II -2,45 0,037 PIGR NM_002644 polymeric immunoglobulin receptor -2,45 0,017 LGALS14 NM_203471 lectin, galactoside-binding, soluble, 14 -2,44 0,000 ADH1C NM_000669 alcohol dehydrogenase 1C (class I), gamma polypeptide -2,43 0,000 DKK1 NM_012242 dickkopf homolog 1 (Xenopus laevis) -2,43 0,023 NOX1 NM_007052 NADPH oxidase 1 -2,39 0,005 FMO1 NM_002021 flavin containing 1 -2,38 0,001 AADAC NM_001086 arylacetamide deacetylase () -2,36 0,000 TNFSF10 NM_003810 () superfamily, member 10 -2,34 0,001 HEPH NM_138737 hephaestin -2,33 0,032 VCAM1 NM_001078 vascular 1 -2,30 0,040 KLHDC8B NM_173546 kelch domain containing 8B -2,30 0,000 DUOX2 NM_014080 dual oxidase 2 -2,29 0,046 GPR133 NM_198827 G protein-coupled receptor 133 -2,28 0,003 SERPINA7 NM_000354 serpin peptidase inhibitor, clade A (antitrypsin), member 7 -2,27 0,000 APOBEC3B NM_004900 apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3B -2,27 0,000 SNORA38B NR_003706 small nucleolar RNA, H/ACA box 38B (retrotransposed) -2,23 0,018 GPR56 NM_201524 G protein-coupled receptor 56 -2,20 0,003 LGR5 NM_003667 leucine-rich repeat containing G protein-coupled receptor 5 -2,16 0,023 LGALS3BP NM_005567 lectin, galactoside-binding, soluble, 3 binding protein -2,14 0,005 SFXN3 NM_030971 sideroflexin 3 -2,13 0,000 CYP27A1 NM_000784 P450, family 27, subfamily A, polypeptide 1 -2,11 0,000 SNORA60 NR_002986 small nucleolar RNA, H/ACA box 60 -2,09 0,005 UNC5CL NM_173561 unc-5 homolog C (C. elegans)-like -2,08 0,002 RBP1 NM_002899 retinol binding protein 1, cellular -2,07 0,000 C6 NM_001115131 -2,06 0,048 APOBEC3C NM_014508 apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3C -2,06 0,017 AMOT NM_133265 angiomotin -2,05 0,001 NKAIN2 NM_001040214 Na+/K+ transporting ATPase interacting 2 -2,03 0,025 APOA4 NM_000482 apolipoprotein A-IV -2,03 0,004 TM4SF18 NM_138786 transmembrane 4 L six family member 18 -2,02 0,002 CAV1 NM_001753 , caveolae protein, 22kDa -2,01 0,017 CDHR5 NM_021924 cadherin-related family member 5 -2,01 0,019 C19orf21 BC052236 open reading frame 21 -2,01 0,001 MPP1 NM_002436 , palmitoylated 1, 55kDa -2,01 0,000 SERPINA5 NM_000624 serpin peptidase inhibitor, clade A ( antitrypsin), member 5 -2,00 0,000 RASL11A NM_206827 RAS-like, family 11, member A -1,99 0,002 APOC3 NM_000040 apolipoprotein C-III -1,97 0,001 SLC44A4 NM_025257 solute carrier family 44, member 4 -1,97 0,015 SLC5A9 NM_001135181 solute carrier family 5 (sodium/ ), member 9 -1,97 0,005 PIK3IP1 NM_052880 phosphoinositide-3-kinase interacting protein 1 -1,97 0,000 GDPD3 NM_024307 glycerophosphodiester phosphodiesterase domain containing 3 -1,96 0,002 CPT1A NM_001876 carnitine palmitoyltransferase 1A (liver) -1,96 0,003 FOLH1 NM_004476 (prostate-specific membrane antigen) 1 -1,95 0,013 EPHX1 NM_000120 epoxide hydrolase 1, microsomal (xenobiotic) -1,95 0,003 KLKB1 NM_000892 B, plasma (Fletcher factor) 1 -1,95 0,006 HPN NM_182983 -1,95 0,001 TCN2 NM_000355 transcobalamin II -1,95 0,002 LASS4 NM_024552 LAG1 homolog, ceramide synthase 4 -1,95 0,001 HAO2 NM_001005783 hydroxyacid oxidase 2 (long chain) -1,95 0,001 CYFIP2 NM_001037332 cytoplasmic FMR1 interacting protein 2 -1,94 0,009 INHBC NM_005538 inhibin, beta C -1,94 0,011 MPPED2 NM_001584 metallophosphoesterase domain containing 2 -1,93 0,043 SLC44A3 NM_001114106 solute carrier family 44, member 3 -1,92 0,004 MTMR11 NM_001145862 related protein 11 -1,92 0,004 PIPOX NM_016518 pipecolic acid oxidase -1,92 0,010 OSBP2 NM_030758 binding protein 2 -1,92 0,001 C4A NM_007293 complement component 4A (Rodgers blood group) -1,91 0,008 RND1 NM_014470 Rho family GTPase 1 -1,90 0,001 TMEM45B NM_138788 transmembrane protein 45B -1,88 0,007 GLYATL1 NM_080661 glycine-N-acyltransferase-like 1 -1,88 0,000 RRAS NM_006270 related RAS viral (r-ras) oncogene homolog -1,88 0,002 APOC3 NM_000040 apolipoprotein C-III -1,88 0,004 VTN NM_000638 -1,87 0,000 DHRS11 NM_024308 dehydrogenase/reductase (SDR family) member 11 -1,87 0,002 STAP2 NM_017720 signal transducing adaptor family member 2 -1,87 0,002 CX3CL1 NM_002996 chemokine (C-X3-C motif) ligand 1 -1,87 0,003 SGK2 NM_016276 serum/glucocorticoid regulated kinase 2 -1,87 0,018 HSD17B2 NM_002153 hydroxysteroid (17-beta) dehydrogenase 2 -1,87 0,005 DLL4 NM_019074 delta-like 4 (Drosophila) -1,86 0,001 TIMP2 NM_003255 TIMP metallopeptidase inhibitor 2 -1,86 0,006 TMPRSS6 NM_153609 transmembrane protease, 6 -1,86 0,000 VIM NM_003380 vimentin -1,85 0,001 TNFAIP3 NM_006290 tumor necrosis factor, alpha-induced protein 3 -1,85 0,007 SAA2 NM_030754 serum amyloid A2 -1,84 0,032 RBP2 NM_004164 retinol binding protein 2, cellular -1,84 0,007 LEAP2 NM_052971 liver expressed antimicrobial 2 -1,84 0,000 APOD NM_001647 apolipoprotein D -1,84 0,034 UBD NM_006398 ubiquitin D -1,84 0,000 HLA-A NM_002116 major histocompatibility complex, class I, A -1,84 0,001 HSPB8 NM_014365 heat shock 22kDa protein 8 -1,82 0,028 GOLGA8C NR_027411 golgin A8 family, member C -1,81 0,014 SLCO2A1 NM_005630 solute carrier organic anion transporter family, member 2A1 -1,81 0,011 ERBB2 NM_001005862 v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 -1,81 0,003 ACSL5 NM_016234 acyl-CoA synthetase long-chain family member 5 -1,81 0,004 CD9 NM_001769 CD9 molecule -1,81 0,013 REEP6 NM_138393 receptor accessory protein 6 -1,81 0,000 ELFN1 NM_001128636 extracellular leucine-rich repeat and fibronectin type III domain 1 -1,80 0,001 HMGCS2 NM_005518 3-hydroxy-3-methylglutaryl-CoA synthase 2 (mitochondrial) -1,80 0,013 TFR2 NM_003227 2 -1,80 0,009 PON3 NM_000940 3 -1,80 0,018 UPK1B NM_006952 uroplakin 1B -1,79 0,029 OLFML3 NM_020190 olfactomedin-like 3 -1,79 0,001 SLC2A2 NM_000340 solute carrier family 2 (facilitated ), member 2 -1,78 0,029 HLA-J NR_024240 major histocompatibility complex, class I, J (pseudogene) -1,78 0,001 AGPAT2 NM_006412 1-acylglycerol-3-phosphate O-acyltransferase 2 -1,78 0,001 CD24 NM_013230 CD24 molecule -1,78 0,008 S100A14 NM_020672 S100 binding protein A14 -1,78 0,002 WIF1 NM_007191 WNT inhibitory factor 1 -1,78 0,009 IFITM1 NM_003641 induced transmembrane protein 1 (9-27) -1,77 0,022 PARP3 NM_001003931 poly (ADP-ribose) polymerase family, member 3 -1,77 0,012 EFNA1 NM_004428 -A1 -1,77 0,001 ALPK2 NM_052947 alpha-kinase 2 -1,76 0,012 NYNRIN NM_025081 NYN domain and retroviral integrase containing -1,76 0,005 ASS1 NM_000050 argininosuccinate synthase 1 -1,76 0,000 SPINT1 NM_181642 serine peptidase inhibitor, Kunitz type 1 -1,76 0,000 PDGFA NM_002607 platelet-derived growth factor alpha polypeptide -1,74 0,004 GSN NM_000177 -1,74 0,002 HNF1B NM_000458 HNF1 B -1,74 0,002 CAV2 NM_001233 caveolin 2 -1,74 0,021 FABP1 NM_001443 binding protein 1, liver -1,74 0,001 LIPH NM_139248 , member H -1,74 0,027 EPHA1 NM_005232 EPH receptor A1 -1,74 0,002 YPEL2 NM_001005404 yippee-like 2 (Drosophila) -1,74 0,015 IFITM3 NM_021034 interferon induced transmembrane protein 3 (1-8U) -1,73 0,017 F7 NM_000131 coagulation factor VII (serum prothrombin conversion accelerator) -1,73 0,002 ZG16 NM_152338 zymogen granule protein 16 homolog () -1,73 0,001 EDNRB NM_001122659 receptor type B -1,73 0,000 SLC30A10 NM_018713 solute carrier family 30, member 10 -1,73 0,007 CFHR1 NM_002113 complement -related 1 -1,72 0,021 GPRC5B NM_016235 G protein-coupled receptor, family C, group 5, member B -1,72 0,040 KLHL24 NM_017644 kelch-like 24 (Drosophila) -1,72 0,028 TMEM141 NM_032928 transmembrane protein 141 -1,71 0,000 AIG1 NM_016108 -induced 1 -1,71 0,015 ID2 NM_002166 inhibitor of DNA binding 2, dominant negative helix-loop-helix protein -1,71 0,000 TMEM176A NM_018487 transmembrane protein 176A -1,71 0,009 TP53INP1 NM_033285 tumor protein inducible nuclear protein 1 -1,71 0,004 C1orf168 NM_001004303 open reading frame 168 -1,71 0,006 MAOB NM_000898 monoamine oxidase B -1,71 0,002 UBA7 NM_003335 ubiquitin-like modifier activating enzyme 7 -1,71 0,000 SHC2 NM_012435 SHC (Src 2 domain containing) transforming protein 2 -1,71 0,002 APOBEC3F NM_001006666 apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3F -1,70 0,005 AKT3 NM_181690 v-akt murine thymoma viral oncogene homolog 3 -1,70 0,024 F10 NM_000504 coagulation -1,70 0,002 SERPING1 NM_000062 serpin peptidase inhibitor, clade G (C1 inhibitor), member 1 -1,70 0,011 RARRES3 NM_004585 responder (tazarotene induced) 3 -1,70 0,000 PFKFB3 NM_004566 6-phosphofructo-2-kinase/-2,6-biphosphatase 3 -1,69 0,001 TRIM29 NM_012101 tripartite motif containing 29 -1,69 0,000 DGAT2 NM_032564 diacylglycerol O-acyltransferase 2 -1,69 0,000 F2R NM_001992 coagulation factor II () receptor -1,69 0,010 B3GNT7 NM_145236 UDP-GlcNAc:betaGal beta-1,3-N-acetylglucosaminyltransferase 7 -1,69 0,003 SLC46A1 NM_080669 solute carrier family 46 (folate transporter), member 1 -1,68 0,005 GBP3 NM_018284 guanylate binding protein 3 -1,68 0,007 TRIM21 NM_003141 tripartite motif containing 21 -1,68 0,012 SLC22A7 NM_006672 solute carrier family 22 (organic anion transporter), member 7 -1,68 0,039 AKR1D1 NM_005989 aldo-keto reductase family 1, member D1 -1,68 0,025 OTUD1 NM_001145373 OTU domain containing 1 -1,68 0,007 ZG16 NM_152338 zymogen granule protein 16 homolog (rat) -1,68 0,005 NPPB NM_002521 natriuretic peptide B -1,68 0,005 FMO5 NM_001461 flavin containing monooxygenase 5 -1,68 0,025 AHSG NM_001622 alpha-2-HS- -1,67 0,001 GXYLT2 NM_001080393 glucoside 2 -1,67 0,006 CIDEC NM_022094 cell death-inducing DFFA-like effector c -1,67 0,036 CLDN6 NM_021195 claudin 6 -1,67 0,000 FSTL1 NM_007085 -like 1 -1,67 0,009 HLA-A NM_002116 major histocompatibility complex, class I, A -1,67 0,007 LGI4 NM_139284 leucine-rich repeat LGI family, member 4 -1,67 0,001 ECE1 NM_001397 endothelin converting enzyme 1 -1,67 0,005 NYNRIN NM_025081 NYN domain and retroviral integrase containing -1,67 0,015 SLC2A3 NM_006931 solute carrier family 2 (facilitated glucose transporter), member 3 -1,66 0,027 TIMP4 NM_003256 TIMP metallopeptidase inhibitor 4 -1,66 0,008 SEMA6A NM_020796 sema domain, transmembrane and cytoplasmic (semaphorin) 6A -1,66 0,047 HEY1 NM_012258 hairy/enhancer-of-split related with YRPW motif 1 -1,66 0,002 KCNMB4 NM_014505 potassium large conductance calcium-activated channel, member 4 -1,66 0,044 TMEM140 NM_018295 transmembrane protein 140 -1,66 0,001 HOXC10 NM_017409 homeobox C10 -1,65 0,001 EPB49 NM_001978 erythrocyte membrane protein band 4.9 (dematin) -1,65 0,002 ARMCX6 NM_019007 containing, X-linked 6 -1,65 0,005 PPP1R1A NM_006741 protein phosphatase 1, regulatory (inhibitor) subunit 1A -1,65 0,001 TAPBP NM_003190 TAP binding protein (tapasin) -1,65 0,005 LCT NM_002299 lactase -1,65 0,039 F2RL1 NM_005242 coagulation factor II (thrombin) receptor-like 1 -1,65 0,047 TMEM27 NM_020665 transmembrane protein 27 -1,65 0,000 KLHL13 NM_033495 kelch-like 13 (Drosophila) -1,65 0,007 MOGAT3 NM_178176 monoacylglycerol O-acyltransferase 3 -1,64 0,001 MOSC2 NM_017898 MOCO sulphurase C-terminal domain containing 2 -1,64 0,006 RBP5 NM_031491 retinol binding protein 5, cellular -1,64 0,000 SAA2 NM_030754 serum amyloid A2 -1,64 0,007 POLD4 NM_021173 polymerase (DNA-directed), delta 4 -1,64 0,000 HLA-B BC013187 major histocompatibility complex, class I, B -1,64 0,002 PRF1 NM_005041 perforin 1 (pore forming protein) -1,63 0,000 MAGED2 NM_014599 melanoma antigen family D, 2 -1,63 0,017 AGBL2 NM_024783 ATP/GTP binding protein-like 2 -1,63 0,037 KLHL38 NM_001081675 kelch-like 38 (Drosophila) -1,63 0,000 NUPR1 NM_001042483 nuclear protein, transcriptional regulator, 1 -1,63 0,013 C5orf4 NM_032385 open reading frame 4 -1,63 0,026 AQP1 NM_198098 (Colton blood group) -1,63 0,021 NUAK1 NM_014840 NUAK family, SNF1-like kinase, 1 -1,63 0,008 HDHD3 NM_031219 haloacid dehalogenase-like hydrolase domain containing 3 -1,62 0,000 GPR157 NM_024980 G protein-coupled receptor 157 -1,62 0,003 ENPP3 NM_005021 ectonucleotide pyrophosphatase/ -1,62 0,017 SLC38A3 NM_006841 solute carrier family 38, member 3 -1,62 0,003 TMSB4X NM_021109 thymosin beta 4, X-linked -1,62 0,020 SLC39A5 NM_001135195 solute carrier family 39 (metal ), member 5 -1,62 0,001 RNU4-1 NR_003925 RNA, U4 small nuclear 1 -1,62 0,006 HEPACAM2 NM_001039372 HEPACAM family member 2 -1,62 0,034 A1BG NM_130786 alpha-1-B glycoprotein -1,62 0,002 EFEMP2 NM_016938 EGF containing -like extracellular matrix protein 2 -1,62 0,001 SLC39A4 NM_017767 solute carrier family 39 (zinc transporter), member 4 -1,61 0,043 MFI2 NM_005929 antigen p97 (melanoma associated) -1,61 0,005 SLC36A1 NM_078483 solute carrier family 36 (/amino acid symporter), member 1 -1,61 0,039 TMSB4X NM_021109 thymosin beta 4, X-linked -1,61 0,020 ELF3 NM_001114309 E74-like factor 3 (ets domain transcription factor, epithelial-specific ) -1,61 0,002 FLVCR2 NM_017791 feline leukemia virus subgroup C cellular receptor family, member 2 -1,61 0,001 TBX15 NM_152380 T-box 15 -1,61 0,005 SLC13A5 NM_177550 solute carrier family 13, member 5 -1,61 0,000 ALPI NM_001631 , intestinal -1,60 0,005 ITGA3 NM_002204 , alpha 3 (antigen CD49C, alpha 3 subunit of VLA-3 receptor) -1,60 0,008 TMSB4X NM_021109 thymosin beta 4, X-linked -1,60 0,018 LRMP NM_006152 lymphoid-restricted membrane protein -1,60 0,000 NBPF6 NM_001143987 neuroblastoma breakpoint family, member 6 -1,60 0,009 SYT11 NM_152280 XI -1,60 0,038 CALCOCO1 NM_020898 calcium binding and coiled-coil domain 1 -1,60 0,013 INPP5D NM_001017915 inositol polyphosphate-5-phosphatase, 145kDa -1,60 0,003 SLC7A7 NM_003982 solute carrier family 7, member 7 -1,60 0,021 NFKBIA NM_020529 nuclear factor of kappa gene enhancer in B-cells inhibitor -1,60 0,013 PLEKHG6 NM_018173 pleckstrin homology domain containing, family G, member 6 -1,60 0,001 FOXO3B NR_026718 forkhead box O3B pseudogene -1,60 0,045 SMAD7 NM_005904 SMAD family member 7 -1,59 0,001 CFB NM_001710 -1,59 0,005 C1orf210 NM_182517 chromosome 1 open reading frame 210 -1,59 0,001 UCP2 NM_003355 uncoupling protein 2 (mitochondrial, proton carrier) -1,59 0,005 KCTD21 NM_001029859 tetramerisation domain containing 21 -1,59 0,016 UPK3A NM_006953 uroplakin 3A -1,59 0,001 LOXL4 NM_032211 lysyl oxidase-like 4 -1,59 0,007 CCL16 NM_004590 chemokine (C-C motif) ligand 16 -1,59 0,021 NFIB NM_005596 /B -1,59 0,009 CFB NM_001710 complement factor B -1,59 0,001 ITM2C NM_030926 integral membrane protein 2C -1,59 0,009 GBP1 NM_002053 guanylate binding protein 1, interferon-inducible -1,59 0,006 SELM NM_080430 selenoprotein M -1,58 0,003 PGLYRP2 NM_052890 recognition protein 2 -1,58 0,019 PPP1R14A NM_033256 protein phosphatase 1, regulatory (inhibitor) subunit 14A -1,58 0,000 DAO NM_001917 D-amino-acid oxidase -1,58 0,000 CFI NM_000204 -1,58 0,021 YPEL3 NM_031477 yippee-like 3 (Drosophila) -1,58 0,000 HLA-A NM_002116 major histocompatibility complex, class I, A -1,58 0,002 HLA-H NR_001434 major histocompatibility complex, class I, H (pseudogene) -1,58 0,002 THRA NM_003250 thyroid receptor, alpha oncogene -1,58 0,001 NR1I2 NM_003889 nuclear receptor subfamily 1, group I, member 2 -1,58 0,010 LRRC31 NM_024727 leucine rich repeat containing 31 -1,58 0,005 AMHR2 NM_020547 anti-Mullerian , type II -1,57 0,000 CDX2 NM_001265 caudal type homeobox 2 -1,57 0,002 BCL11A NM_022893 B-cell CLL/lymphoma 11A (zinc finger protein) -1,57 0,013 FUT2 NM_000511 2 (secretor status included) -1,57 0,004 MEP1A NM_005588 , alpha (PABA peptide hydrolase) -1,57 0,009 CD151 NM_004357 CD151 molecule (Raph blood group) -1,57 0,002 TSPAN7 NM_004615 tetraspanin 7 -1,57 0,004 RGN NM_152869 (senescence marker protein-30) -1,56 0,013 CKB NM_001823 creatine kinase, -1,56 0,000 SLC2A14 NM_153449 solute carrier family 2 (facilitated glucose transporter), member 14 -1,56 0,005 SERPINF2 NM_001165920 serpin peptidase inhibitor, clade F, member 2 -1,56 0,000 CYP19A1 NM_031226 , family 19, subfamily A, polypeptide 1 -1,56 0,018 WBP1 NM_012477 WW domain binding protein 1 -1,56 0,006 IL32 NM_001012631 32 -1,56 0,003 KIAA1161 NM_020702 KIAA1161 -1,56 0,003 MYOM3 NM_152372 myomesin family, member 3 -1,56 0,001 KLF5 NM_001730 Kruppel-like factor 5 (intestinal) -1,56 0,002 ITIH3 NM_002217 inter-alpha (globulin) inhibitor H3 -1,56 0,004 PTPRM NM_001105244 protein tyrosine phosphatase, receptor type, M -1,55 0,040 C8orf49 BC132945 open reading frame 49 -1,55 0,020 GRAMD1A NM_020895 GRAM domain containing 1A -1,55 0,041 AOC3 NM_003734 oxidase, copper containing 3 (vascular adhesion protein 1) -1,55 0,006 MALL NM_005434 mal, T-cell differentiation protein-like -1,55 0,018 NRG3 NM_001010848 3 -1,55 0,008 B3GNT5 NM_032047 UDP-GlcNAc:betaGal beta-1,3-N-acetylglucosaminyltransferase 5 -1,55 0,008 CCL14-CCL15 NR_027921 CCL14-CCL15 readthrough -1,55 0,002 MGST3 NM_004528 microsomal S- 3 -1,55 0,004 SYP NM_003179 synaptophysin -1,55 0,038 ANGPTL2 NM_012098 -like 2 -1,55 0,002 C8B NM_000066 complement component 8, beta polypeptide -1,55 0,017 RAB5B NM_002868 RAB5B, member RAS oncogene family -1,54 0,030 AQP3 NM_004925 (Gill blood group) -1,54 0,001 LOC146336 NR_027242 hypothetical LOC146336 -1,54 0,036 PRKAB2 NM_005399 protein kinase, AMP-activated, beta 2 non-catalytic subunit -1,54 0,007 FETUB NM_014375 fetuin B -1,54 0,001 ZDHHC12 NM_032799 zinc finger, DHHC-type containing 12 -1,54 0,021 PLP2 NM_002668 proteolipid protein 2 (colonic -enriched) -1,54 0,000 USH1C NM_153676 Usher syndrome 1C (autosomal recessive, severe) -1,54 0,011 SERPINA4 NM_006215 serpin peptidase inhibitor, clade A (antitrypsin), member 4 -1,54 0,000 ZNF827 NM_178835 zinc finger protein 827 -1,54 0,015 ABCG8 NM_022437 ATP-binding cassette, sub-family G (WHITE), member 8 -1,54 0,011 FBXO32 NM_058229 F-box protein 32 -1,54 0,005 CTSL1 NM_001912 cathepsin L1 -1,54 0,002 ADH1A NM_000667 alcohol dehydrogenase 1A (class I), alpha polypeptide -1,54 0,001 DAB1 NM_021080 disabled homolog 1 (Drosophila) -1,54 0,019 CPE NM_001873 E -1,54 0,048 C3 NM_000064 complement component 3 -1,54 0,019 RASGEF1B NM_152545 RasGEF domain family, member 1B -1,54 0,001 AQP7P1 NR_002817 aquaporin 7 pseudogene 1 -1,54 0,048 C6orf123 AB016901 open reading frame 123 -1,53 0,001 RHOU NM_021205 ras homolog , member U -1,53 0,002 HEBP1 NM_015987 binding protein 1 -1,53 0,002 JUP NM_002230 junction -1,53 0,032 CCDC159 NM_001080503 coiled-coil domain containing 159 -1,53 0,005 GAL3ST1 NM_004861 galactose-3-O- 1 -1,53 0,002 PLA2G12B NM_032562 , group XIIB -1,53 0,034 PID1 NM_017933 phosphotyrosine interaction domain containing 1 -1,53 0,001 DNAH17 NM_173628 , axonemal, heavy chain 17 -1,53 0,026 PIGZ NM_025163 phosphatidylinositol glycan anchor biosynthesis, class Z -1,53 0,035 GPER NM_001039966 G protein-coupled receptor 1 -1,53 0,003 ACY3 NM_080658 (aminocyclase) 3 -1,53 0,011 DUOXA2 NM_207581 dual oxidase maturation factor 2 -1,52 0,018 MT1F NM_005949 metallothionein 1F -1,52 0,000 FSTL3 NM_005860 follistatin-like 3 (secreted glycoprotein) -1,52 0,002 OR7E14P BC008657 olfactory receptor, family 7, subfamily E, member 14 pseudogene -1,52 0,032 SLC43A3 NM_017611 solute carrier family 43, member 3 -1,52 0,029 CLDN7 NM_001307 claudin 7 -1,52 0,017 TGFBI NM_000358 transforming growth factor, beta-induced, 68kDa -1,52 0,008 LPCAT3 NM_005768 lysophosphatidylcholine acyltransferase 3 -1,52 0,004 IGSF9 NM_001135050 immunoglobulin superfamily, member 9 -1,52 0,030 SPATA20 NM_022827 spermatogenesis associated 20 -1,52 0,034 VDR NM_001017535 D (1,25- dihydroxyvitamin D3) receptor -1,51 0,001 GCNT4 NM_016591 glucosaminyl (N-acetyl) transferase 4, core 2 -1,51 0,030 SLC16A12 NM_213606 solute carrier family 16, member 12 -1,51 0,006 C1S NM_201442 complement component 1, s subcomponent -1,51 0,013 TMEM8B NM_016446 transmembrane protein 8B -1,51 0,004 C2 NM_000063 -1,51 0,014 PEMT NM_148172 phosphatidylethanolamine N-methyltransferase -1,51 0,003 SERPIND1 NM_000185 serpin peptidase inhibitor, clade D ( ), member 1 -1,51 0,001 TMOD1 NM_003275 1 -1,51 0,022 ANO3 NM_031418 anoctamin 3 -1,51 0,001 LOC440173 NR_027471 hypothetical LOC440173 -1,51 0,025 NELL2 NM_006159 NEL-like 2 (chicken) -1,51 0,038 DUSP18 NM_152511 dual specificity phosphatase 18 -1,50 0,013 DTX4 NM_015177 deltex homolog 4 (Drosophila) -1,50 0,000 C9orf103 NM_001001551 open reading frame 103 -1,50 0,003 SNAP25 NM_003081 synaptosomal-associated protein, 25kDa -1,50 0,036

Supplementary Table 4. List of differentially expressed genes in sorafenib-resistant tumors associated with the 15-top biological functions.

CATEGORY MOLECULES p-VALUE

F2R, VTN, ASS1, FOLH1, PRR15L, F7, HOXC10, ZG16, PRF1, ELF3, EIF1AX, NR1I2, C12orf48, CAV1, FABP1, TIMP2, ATM, MFI2, MALL, PTGIS, TP53INP1, TSPAN12, RRAS, ANGPTL2, TBX4, AIG1, RBM28, LASS4, KLKB1, TIMP4, CTSL1, CD9, AKR1D1, TMEM27, CFHR1, EPHX1, APOD, SERPING1, FN1, GUCY2C, GBP1, PPP1R3C, DUSP6, HSPB8, TNFSF10, ZNF827, POLD4, VCAN, AQP3, ADH1A, DUSP5, CLEC2D, HLA-A, MT1F, FGF18, LEAP2, SLC2A14, HLA-B, IGF1R, CD24, IFITM1, VDR, CHRNA5, TRIM29, AMOT, HEY1, PRKDC, LIPH, TMSB10/TMSB4X, CDC6, DGAT2, OLFML3, DRD5, VIM, NETO2, Cancer ITGA3, S100A14, HPN, HNF1B, BCL11A, KIF20B, CTSE, LOXL4, SLC7A11, IL32, CLDN7, RBP1, PDE4D, 1,33E-12-2,72E-02 SLC39A5, IGSF9, MYC, TGFBR2, ROCK2, WIF1, ACSL5, CFI, SLC39A4, JUP, FAM5C, KIF14, CPT1A, mir-32, FSTL3, PGLYRP2, FGFR1, C1S, CDX2, MUC13, SYP, AQP1, MAGED2, THRA, SGK2, ADAMTS9, GSN, F10, KNG1, TFAM, FERMT1, NUAK1, CX3CL1, HSD17B2, CD151, AOC3, FXYD3, ID2, PDGFA, ADH1C, RANBP2, SLC7A1, SLC2A3, SERPIND1, AADAC, NFKBIA, CYP19A1, AGPAT2, CFB, AKT3, ERBB2, PIK3IP1, WBP1, HPX, VCAM1, DPEP1, EDNRB, SMAD7, FAM72D, SNAP25, LYAR, A1BG, LAMA4, SERPINA5, LGALS3BP, CDH17, C4B (includes others), BRCA2, SPARC, MEP1A, DKK1 ABCG8, SLC7A11, PEMT, F2R, IL32, FOLH1, F7, CLDN7, RBP1, PDE4D, SLC39A5, HOXC10, IGSF9, TGFBR2, MYC, ZG16, C12orf48, ACSL5, CAV1, FABP1, TIMP2, TP53INP1, CPT1A, FSTL3, C1S, FGFR1, CDX2, ANGPTL2, MUC13, TBX4, GSN, SGK2, KNG1, F10, TFAM, CTSL1, CD9, AKR1D1, FERMT1, NUAK1, HSD17B2, MGST3, CFHR1, EPHX1, AOC3, DDX21, ID2, FN1, GUCY2C, PDGFA, DUSP6, Gastrointestinal Disease 2,47E-11-2,72E-02 SEMA6A, ADH1C, TNFSF10, POLD4, SLC2A3, AQP3, DUSP5, MT1F, LEAP2, SLC2A14, AGPAT2, IGF1R, CD24, IFITM1, VDR, ERBB2, CHRNA5, LIPH, VCAM1, HPX, DPEP1, UCP2, CYP27A1, CDC6, OLFML3, SMAD7, DGAT2, VIM, DRD5, FAM72D, A1BG, LYAR, HNF1B, LAMA4, SERPINA5, CDH17, DKK1, MEP1A ABCG8, UPK3A, ASS1, FOLH1, GCLC, CCDC88C, DAB1, SYCP2L, SLC44A3, GPCPD1, ZG16, ELF3, NR1I2, GPD2, CENPE, CAV1, FABP1, HEPACAM2, AMHR2, MFI2, PTGIS, TP53INP1, TRIM21, CIDEC, TBX4, FREM1, PIGR, LASS4, CTSL1, DUOX2, APOD, EPHX1, SERPING1, APOA4, GUCY2C, GBP1, IGLJ3, HSPB8, ZNF827, POLD4, TBX15, MPPED2, AQP3, DUSP5, APOC3, TMPRSS6, VDR, BTAF1, TRIM29, PLA2G12B, ALPK2, SERPINA4, LIPH, PRKDC, WDR36, UCP2, DGAT2, DRD5, VIM, SLCO2A1, HPN, INPP5D, HNF1B, BCL11A, YPEL2, VPS13A, HMGCS2, PDE4D, USH1C, MYC, TGFBR2, IGSF9, DAO, MAOB, WIF1, UBA7, CYFIP2, NUPR1, SLC39A4, C1orf168, CPT1A, FXYD1, MUC13, AQP1, THRA, SGK2, ADAMTS9, ATAD2, PTPRM, FERMT1, SMCHD1, SLC7A7, MGST3, CD151, DPYSL3, ADH1C, ME1, SLC2A3, CYP19A1, PADI2, AGPAT2, SLC16A12, ECE1, ERBB2, VCAM1, EDNRB, CCHCR1, Genetic Disorder 3,85E-08-2,72E-02 SNAP25, SLC16A6, GPR56, LAMA4, NRG3, LGALS3BP, SERPINA5, KLF5, SLC36A1, CDH17, SPARC, BRCA2, ANO3, DKK1, MEP1A, OSBP2, PEMT, F2R, TFR2, F7, BCAT1, PRF1, C12orf48, PRPF4B, KDM1B, TIMP2, ATM, MALL, CHN1, RRAS, SSR1, AIG1, RBM28, UBD, KLKB1, TIMP4, AKR1D1, CD9, TMEM27, PDGFD, FN1, TSPAN7, DUSP6, PPP1R3C, TMEM45B, TNFSF10, RASGEF1B, VCAN, ATAD5, HLA-A, MT1F, F2RL1, FGF18, LRRFIP1, SLC2A14, LEAP2, IGF1R, HLA-B, CD24, IFITM1, CHRNA5, RING1, TMSB10/TMSB4X, TGFBI, NELL2, DTX4, CDC6, FETUB, ITGA3, SERPINF2, NPPB, PLEKHG6, LCT, ATR, ITIH3, SLC7A11, MMP16, SLC39A5, ROCK2, SPATA5, SEMA3D, CFI, GPR133, LYRM7, JUP, FAM5C, KIF14, mir-32, C1S, FGFR1, SYP, GSN, F10, RARRES3, CPE, CX3CL1, HSD17B2, KIF11, AOC3, FXYD3, SLC46A1, PDGFA, PPP1R1A, LGR5, TNFAIP3, FMO5, CLIP4, SERPIND1, CEP290, NFKBIA, SLC2A2, CFB, AKT3, FMO1, HHLA2, PIK3IP1, HPX, CYP27A1, PANK2, EFEMP2, HSPH1, SMAD7, FAM72D, LYAR, FLVCR2, NKAIN2, C4B , HOMER1

AOC3, SERPING1, FN1, APOA4, RND1, F2R, PPP1R1A, PDGFA, IL32, VTN, HSPB8, MYC, ROCK2, Cell-To-Cell Signaling and TGFBR2, ELF3, CYFIP2, NFKBIA, HLA-A, IGF1R, CAV1, CD24, GTPBP4, JUP, ERBB2, CCL16, VCAM1, 4,42E-08-2,72E-02 Interaction TGFBI, RRAS, THRA, ITGA3, PTPRM, PIGR, INPP5D, SERPINF2, NPPB, F10, GPR56, KNG1, CD9, FERMT1, LGALS3BP, C4B (includes others), SPARC, IGHA1, PDGFD, TMOD1, CX3CL1, CD151 AOC3, SERPING1, RND1, APOA4, FN1, F2R, IL32, VTN, TGFBR2, ROCK2, CEP290, NFKBIA, CYFIP2, Tissue Development ELF3, IGF1R, ERBB2, JUP, GTPBP4, CCL16, TIMP2, VCAM1, TGFBI, RRAS, ITGA3, GSN, PIGR, 4,42E-08-2,72E-02 PTPRM, INPP5D, F10, GPR56, KNG1, CD9, FERMT1, C4B, IGHA1, CX3CL1, TMOD1, CD151 F2R, VTN, FOLH1, F7, HEBP1, ROCK2, TGFBR2, MYC, ELF3, CAV1, JUP, CCL16, FAM5C, MFI2, TIMP2, FGFR1, GSN, PIGR, PTPRM, F10, KNG1, CTSL1, CD9, FERMT1, CX3CL1, CD151, AOC3, ID2, FN1, GBP1, PDGFA, TNFSF10, VCAN, Cellular Movement 1,07E-07-2,72E-02 NFKBIA, F2RL1, IGF1R, ERBB2, GTPBP4, AMOT, HEY1, VCAM1, EDNRB, SMAD7, VIM, S100A14, ITGA3, SERPINF2, NPPB, PLEKHG6, DKK1 F2R, ASS1, FOLH1, PDE4D, ROCK2, MYC, TGFBR2, BCAT1, WIF1, NR1I2, CFI, CAV1, SLC39A4, CCL16, AMHR2, TIMP2, APOBEC3B, PFKFB3, mir-32, FSTL3, RRAS, TSPAN12, C1S, EPHA1, FGFR1, MAGED2, GSN, AIG1, F10, TIMP4, CTSL1, PDGFD, CX3CL1, HSD17B2, APOD, SERPING1, FN1, PDGFA, HSPB8, SLC7A1, ZNF827, Reproductive System Disease 8,23E-06-2,72E-02 SLC2A3, VCAN, MPPED2, MT1F, HLA-A, FGF18, CYP19A1, AGPAT2, RHOU, IGF1R, CFB, HLA-B, CD24, AKT3, VDR, ERBB2, CAV2, CHRNA5, VCAM1, TMSB10/TMSB4X, TGFBI, EDNRB, SMAD7, DRD5, VIM, FAM72D, ITGA3, SNAP25, HPN, HNF1B, LAMA4, SERPINA5, C4B (includes others), SPARC, BRCA2, DKK1, MEP1A FN1, PDGFA, VTN, IL32, HSPB8, TNFAIP3, TNFSF10, F7, RBP1, MYC, TGFBR2, AQP3, PRF1, ELF3, Cell Death NFKBIA, APOC3, CAV1, NUPR1, 2,36E-05-2,72E-02 IGF1R, ERBB2, TRIM29, TIMP2, ATM, VCAM1, FGFR1, SMAD7, KLF5, NUAK1, BRCA2, ATR, CX3CL1 PEMT, TCN2, F2R, VTN, NR2F2, RBL1, PDE4D, HOXC10, TGFBR2, MYC, BCAT1, WIF1, ELF3, NUPR1, CAV1, JUP, FAM5C, TIMP2, ATM, FSTL3, EPHA1, FGFR1, FXYD1, MAGED2, AQP1, GSN, SSR1, PTPRM, KNG1, CTSL1, CD9, FERMT1, RARRES3, SLC7A7, CLSPN, PDGFD, CX3CL1, KIF11, Cellular Growth and Proliferation CD151, ID2, FN1, GBP1, ACE2, PDGFA, DUSP6, SEMA6A, HSPB8, TNFSF10, TNFAIP3, POLD4, VCAN, 5,9E-05-2,72E-02 DUSP5, NFKBIA, F2RL1, CYP19A1, FGF18, IGF1R, CD24, IFITM1, ERBB2, VDR, GTPBP4, CAV2, HEY1, NOX1, VCAM1, TMSB10/TMSB4X, EDNRB, TGFBI, UTP20, AHSG, CDC6, SMAD7, ITGA3, SERPINF2, HPN, EFNA1, GPR56, GPER, KIF20B, KLF5, PNPT1, BRCA2, SPARC, DKK1, DLL4 FN1, F2R, TGFBI, EDNRB, RRAS, VTN, TNFSF10, VIM, THRA, F7, ITGA3, RBL1, HPN, MYC, TGFBR2, Cell Morphology AQP3, MT1F, LAMA4, IGF1R, 7,35E-05-2,72E-02 CAV1, ERBB2, TIMP2 Cellular Response to Therapeutics PRKDC, ATR, ATM 7,79E-05-7,79E-05

Tumor Morphology ID2, FN1, F2R, VTN, FGFR1, TNFSF10, VIM, HPN, MYC, CTSL1, CAV1, IGF1R, CDH17, JUP, ERBB2 8,88E-05-2,72E-02 FN1, DUSP6, ADH1C, POLD4, PDE4D, SERPIND1, TGFBR2, CYP19A1, IGF1R, CAV1, AKT3, CD24, ERBB2, VDR, CHRNA5, PTGIS, Respiratory Disease 9,87E-05-8,25E-03 TMSB10/TMSB4X, FGFR1, CDC6, VIM, SYP, FAM72D, THRA, GSN, ITGA3, LASS4, F10, FERMT1, BRCA2, TMEM27, EPHX1 LOXL4, UPK3A, FN1, F2R, PDE4D, MYC, CEP290, WIF1, NFKBIA, AGPAT2, CFB, CFI, FABP1, ERBB2, VDR, CHRNA5, TIMP2, VCAM1, Renal and Urological Disease 1,23E-04-2,72E-02 EDNRB, FGFR1, SMAD7, DRD5, GSN, SNAP25, PIGR, NPPB, KNG1, HNF1B, F10, CTSL1, KIF20B, BRCA2, CD151 AOC3, SERPING1, FN1, F2R, VTN, IL32, HSPB8, F7, HEBP1, IFITM3, APOBEC3F, HLA-A, F2RL1, IGF1R, HLA-B, POLR3G, CD24, Inflammatory Response ERBB2, CCL16, TAPBP, ATM, TIMP2, NOX1, VCAM1, EDNRB, PGLYRP2, AHSG, GSN, ITGA3, S100A14, 1,65E-04-2,72E-02 PIGR, F10, KNG1, CTSL1, DUOX2, CD9, C8B, IGHA1, CX3CL1, CFHR1, CD151

27

Supplementary Table 5: Representative list of gene sets associated with sorafenib-resistant tumors by GSEA (FDR<0.05). * 40 representative top scored gene sets is shown

NAME SIZE NES FDR q-val Reference

LIVER CANCER GENE SETS BOYAULT_LIVER_CANCER_SUBCLASS_G3 128 2,60 0,000 MsigDB v5.0 Villanueva et al. VILLANUEVA_CK19_SIGNATURE 144 2,32 0,000 Gastroenterology. 2011 CAIRO_HEPATOBLASTOMA_CLASSES_UP 538 2,58 0,000 MsigDB v5.0 LEE_LIVER_CANCER_POOR_SURVIVAL 113 1,87 0,003 MsigDB v5.0 CHIANG_LIVER_CANCER_SUBCLASS_PROLIFERATION 128 1,75 0,007 MsigDB v5.0 Tovar et al. J TOVAR_IGFR1_ACTIVATION 181 1,75 0,008 Hepatology. 2010 FUNCTIONAL GENE SETS (C CURATED ) 2 Biological states and cancer-related* MANALO_HYPOXIA_DN 253 3,12 0,000 MsigDB v5.0 RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP 553 3,05 0,000 MsigDB v5.0 WINNEPENNINCKX_MELANOMA_METASTASIS_UP 135 2,87 0,000 MsigDB v5.0 SCHLOSSER_MYC_TARGETS_REPRESSED_BY_SERUM 150 2,81 0,000 MsigDB v5.0 GARY_CD5_TARGETS_DN 391 2,80 0,000 MsigDB v5.0 PUJANA_BRCA2_PCC_NETWORK 388 2,79 0,000 MsigDB v5.0 PUJANA_CHEK2_PCC_NETWORK 694 2,78 0,000 MsigDB v5.0 KOBAYASHI_EGFR_SIGNALING_24HR_DN 225 2,68 0,000 MsigDB v5.0 ROSTY_CERVICAL_CANCER_PROLIFERATION_CLUSTER 127 2,68 0,000 MsigDB v5.0 PUJANA_BRCA_CENTERED_NETWORK 88 2,67 0,000 MsigDB v5.0 SOTIRIOU_BREAST_CANCER_GRADE_1_VS_3_UP 136 2,67 0,000 MsigDB v5.0 FERREIRA_EWINGS_SARCOMA_UNSTABLE_VS_STABLE_UP 134 2,67 0,000 MsigDB v5.0 MITSIADES_RESPONSE_TO_APLIDIN_DN 227 2,63 0,000 MsigDB v5.0 RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP 641 2,63 0,000 MsigDB v5.0 KANG_DOXORUBICIN_RESISTANCE_UP 48 2,62 0,000 MsigDB v5.0 SHEDDEN_LUNG_CANCER_POOR_SURVIVAL_A6 408 2,59 0,000 MsigDB v5.0 PYEON_CANCER_HEAD_AND_NECK_VS_CERVICAL_UP 162 2,57 0,000 MsigDB v5.0 CROONQUIST_IL6_DEPRIVATION_DN 73 2,55 0,000 MsigDB v5.0 WEI_MYCN_TARGETS_WITH_E_BOX 702 2,55 0,000 MsigDB v5.0 BIDUS_METASTASIS_UP 194 2,51 0,000 MsigDB v5.0 ZHANG_BREAST_CANCER_PROGENITORS_UP 346 2,51 0,000 MsigDB v5.0 KAUFFMANN_MELANOMA_RELAPSE_UP 54 2,49 0,000 MsigDB v5.0 WONG_EMBRYONIC_STEM_CELL_CORE 309 2,46 0,000 MsigDB v5.0 SCHLOSSER_MYC_TARGETS_AND_SERUM_RESPONSE_DN 43 2,45 0,000 MsigDB v5.0 TOYOTA_TARGETS_OF_MIR34B_AND_MIR34C 398 2,41 0,000 MsigDB v5.0 MILI_PSEUDOPODIA_HAPTOTAXIS_UP 424 2,40 0,000 MsigDB v5.0 PUJANA_BREAST_CANCER_WITH_BRCA1_MUTATED_UP 53 2,37 0,000 MsigDB v5.0 DACOSTA_UV_RESPONSE_VIA_ERCC3_COMMON_DN 398 2,36 0,000 MsigDB v5.0 FARMER_BREAST_CANCER_CLUSTER_2 29 2,35 0,000 MsigDB v5.0 MOLENAAR_TARGETS_OF_CCND1_AND_CDK4_DN 48 2,34 0,000 MsigDB v5.0 SCHUHMACHER_MYC_TARGETS_UP 64 2,34 0,000 MsigDB v5.0 ODONNELL_TARGETS_OF_MYC_AND_TFRC_DN 41 2,34 0,000 MsigDB v5.0 MOREAUX_MULTIPLE_MYELOMA_BY_TACI_DN 109 2,33 0,000 MsigDB v5.0 BENPORATH_PROLIFERATION 127 2,33 0,000 MsigDB v5.0 DAZARD_RESPONSE_TO_UV_NHEK_DN 247 2,33 0,000 MsigDB v5.0 BENPORATH_CYCLING_GENES 583 2,33 0,000 MsigDB v5.0 BENPORATH_ES_1 342 2,22 0,000 MsigDB v5.0 28

RAMALHO_STEMNESS_UP 184 2,10 0,000 MsigDB v5.0 MISSIAGLIA_REGULATED_BY_METHYLATION_DN 90 2,03 0,001 MsigDB v5.0 COLDREN_GEFITINIB_RESISTANCE_UP 70 1,83 0,007 MsigDB v5.0

Reactome* REACTOME_MITOTIC_PROMETAPHASE 83 2,66 0,000 MsigDB v5.0 REACTOME_CELL_CYCLE_MITOTIC 282 2,59 0,000 MsigDB v5.0 REACTOME_PROCESSING_OF_CAPPED_INTRON_CONTAINING_PRE_MRNA 129 2,53 0,000 MsigDB v5.0 REACTOME_MITOTIC_M_M_G1_PHASES 146 2,49 0,000 MsigDB v5.0

REACTOME_TRANSPORT_OF_MATURE_MRNA_DERIVED_FROM_AN_INTRON 48 2,45 0,000 MsigDB v5.0 _CONTAINING_TRANSCRIPT

REACTOME_SNRNP_ASSEMBLY 45 2,42 0,000 MsigDB v5.0 REACTOME_G2_M_CHECKPOINTS 37 2,41 0,000 MsigDB v5.0 REACTOME_ACTIVATION_OF_ATR_IN_RESPONSE_TO_REPLICATION_STRES 33 2,41 0,000 MsigDB v5.0 S REACTOME_FORMATION_AND_MATURATION_OF_MRNA_TRANSCRIPT 140 2,39 0,000 MsigDB v5.0 REACTOME_DOUBLE_STRAND_BREAK_REPAIR 20 2,35 0,000 MsigDB v5.0 REACTOME_E2F_MEDIATED_REGULATION_OF_DNA_REPLICATION 28 2,34 0,000 MsigDB v5.0 REACTOME_MRNA_SPLICING 100 2,30 0,000 MsigDB v5.0 REACTOME_HIV_LIFE_CYCLE 95 2,28 0,000 MsigDB v5.0 REACTOME_METABOLISM_OF_RNA 88 2,28 0,000 MsigDB v5.0 REACTOME_ELONGATION_AND_PROCESSING_OF_CAPPED_TRANSCRIPTS 123 2,26 0,000 MsigDB v5.0 REACTOME_RNA_POLYMERASE_II_TRANSCRIPTION 85 2,24 0,000 MsigDB v5.0 REACTOME_LATE_PHASE_OF_HIV_LIFE_CYCLE 82 2,23 0,000 MsigDB v5.0 REACTOME_TRANSPORT_OF_THE_SLBP_INDEPENDENT_MATURE_MRNA 30 2,21 0,000 MsigDB v5.0 REACTOME_MRNA_3_END_PROCESSING 33 2,20 0,000 MsigDB v5.0 REACTOME_ACTIVATION_OF_THE_PRE_REPLICATIVE_COMPLEX 29 2,19 0,000 MsigDB v5.0 REACTOME_TRNA_AMINOACYLATION 36 2,19 0,000 MsigDB v5.0 REACTOME_NEP_NS2_INTERACTS_WITH_THE_CELLULAR_EXPORT_MACHI 27 2,17 0,000 MsigDB v5.0 NERY REACTOME_CELL_CYCLE_CHECKPOINTS 101 2,14 0,000 MsigDB v5.0 REACTOME_CYTOSOLIC_TRNA_AMINOACYLATION 21 2,14 0,000 MsigDB v5.0 REACTOME_REV_MEDIATED_NUCLEAR_EXPORT_OF_HIV1_RNA 29 2,12 0,000 MsigDB v5.0 REACTOME_TRANSPORT_OF_RIBONUCLEOPROTEINS_INTO_THE_HOST_NU 27 2,11 0,000 MsigDB v5.0 CLEUS REACTOME_VPR_MEDIATED_NUCLEAR_IMPORT_OF_PICS 29 2,09 0,000 MsigDB v5.0 REACTOME_NUCLEAR_IMPORT_OF_REV_PROTEIN 28 2,08 0,001 MsigDB v5.0 REACTOME_G1_S_TRANSITION 96 2,08 0,001 MsigDB v5.0 REACTOME_E2F_TRANSCRIPTIONAL_TARGETS_AT_G1_S 17 2,07 0,001 MsigDB v5.0 REACTOME_DNA_REPAIR 90 2,05 0,001 MsigDB v5.0 REACTOME_G2_M_TRANSITION 75 2,04 0,001 MsigDB v5.0 REACTOME_REGULATION_OF_GLUCOKINASE_BY_GLUCOKINASE_REGULAT 27 2,03 0,001 MsigDB v5.0 ORY_PROTEIN REACTOME_INFLUENZA_LIFE_CYCLE 121 1,99 0,001 MsigDB v5.0 REACTOME_S_PHASE 100 1,97 0,001 MsigDB v5.0 REACTOME_DNA_STRAND_ELONGATION 29 1,95 0,002 MsigDB v5.0 REACTOME_GENE_EXPRESSION 382 1,94 0,002 MsigDB v5.0 REACTOME_HIV_INFECTION 171 1,94 0,002 MsigDB v5.0 REACTOME_DNA_REPLICATION_PRE_INITIATION 74 1,91 0,003 MsigDB v5.0 REACTOME_EXTENSION_OF_TELOMERES 27 1,89 0,003 MsigDB v5.0

Biocarta BIOCARTA_MCM_PATHWAY 18 1,92 0,028 MsigDB v5.0 BIOCARTA_ATRBRCA_PATHWAY 18 1,93 0,050 MsigDB v5.0

GENE ONTOLOGY (GO) GENE SETS* RNA_PROCESSING 144 2,48 0,000 MsigDB v5.0 NUCLEOLUS 105 2,46 0,000 MsigDB v5.0 29

HELICASE_ACTIVITY 46 2,34 0,000 MsigDB v5.0 RIBONUCLEOPROTEIN_COMPLEX_BIOGENESIS_AND_ASSEMBLY 72 2,32 0,000 MsigDB v5.0 M_PHASE 103 2,30 0,000 MsigDB v5.0 RNA_SPLICING 76 2,26 0,000 MsigDB v5.0 M_PHASE_OF_MITOTIC_CELL_CYCLE 77 2,26 0,000 MsigDB v5.0 RNA_HELICASE_ACTIVITY 23 2,24 0,000 MsigDB v5.0 DNA_RECOMBINATION 41 2,22 0,000 MsigDB v5.0 RIBONUCLEOPROTEIN_COMPLEX 117 2,20 0,000 MsigDB v5.0 NUCLEAR_PART 503 2,20 0,000 MsigDB v5.0 ATP_DEPENDENT_HELICASE_ACTIVITY 24 2,19 0,000 MsigDB v5.0 75 2,19 0,000 MsigDB v5.0 CONDENSED_CHROMOSOME 30 2,19 0,000 MsigDB v5.0 DNA_REPAIR 107 2,18 0,000 MsigDB v5.0 DNA_DEPENDENT_DNA_REPLICATION 51 2,18 0,000 MsigDB v5.0 CELL_CYCLE_PROCESS 176 2,17 0,000 MsigDB v5.0 NUCLEAR_LUMEN 341 2,17 0,000 MsigDB v5.0 SPLICEOSOME 40 2,17 0,000 MsigDB v5.0 DOUBLE_STRAND_BREAK_REPAIR 20 2,15 0,000 MsigDB v5.0 CHROMOSOMEPERICENTRIC_REGION 29 2,15 0,000 MsigDB v5.0 CELL_CYCLE_CHECKPOINT_GO_0000075 43 2,13 0,000 MsigDB v5.0 MRNA_PROCESSING_GO_0006397 66 2,12 0,000 MsigDB v5.0 RESPONSE_TO_DNA_DAMAGE_STIMULUS 137 2,12 0,000 MsigDB v5.0 ATP_DEPENDENT_RNA_HELICASE_ACTIVITY 16 2,11 0,000 MsigDB v5.0 DNA_HELICASE_ACTIVITY 22 2,11 0,000 MsigDB v5.0 HISTONE_ACETYLTRANSFERASE_ACTIVITY 15 2,10 0,001 MsigDB v5.0 MITOTIC_CELL_CYCLE 140 2,08 0,001 MsigDB v5.0 CHROMOSOME 114 2,07 0,001 MsigDB v5.0 MRNA_METABOLIC_PROCESS 76 2,07 0,001 MsigDB v5.0 RNA_DEPENDENT_ATPASE_ACTIVITY 17 2,07 0,001 MsigDB v5.0 DNA_REPLICATION 95 2,05 0,001 MsigDB v5.0 DNA_METABOLIC_PROCESS 232 2,05 0,001 MsigDB v5.0 CELL_CYCLE_PHASE 158 2,04 0,001 MsigDB v5.0 RESPONSE_TO_ENDOGENOUS_STIMULUS 174 2,03 0,002 MsigDB v5.0 PROTEIN_RNA_COMPLEX_ASSEMBLY 58 2,03 0,002 MsigDB v5.0 ORGANELLE_LUMEN 399 2,03 0,002 MsigDB v5.0 MEMBRANE_ENCLOSED_LUMEN 399 2,03 0,001 MsigDB v5.0 TRANSLATION_FACTOR_ACTIVITY_NUCLEIC_ACID_BINDING 36 2,00 0,002 MsigDB v5.0 RNA_SPLICINGVIA_TRANSESTERIFICATION_REACTIONS 30 1,99 0,002 MsigDB v5.0

H HALLMARKS GENE SETS

HALLMARK_E2F_TARGETS 181 2,92 0,000 MsigDB v5.0

HALLMARK_MYC_TARGETS_V1 183 2,64 0,000 MsigDB v5.0

HALLMARK_MTORC1_SIGNALING 197 1,79 0,001 MsigDB v5.0

30

Supplementary Table 6: List of gene sets associated with sorafenib-responsive tumors by GSEA (FDR<0.05). *40 representative top scored gene sets are shown.

FDR q- Reference/MsigDB NAME SIZE NES val collection

LIVER CANCER GENE SETS HOSHIDA_S3 241 2,28 0,000 MsigDB v5.0 BOYAULT_LIVER_CANCER_SUBCLASS_G3_DN 49 2,27 0,000 MsigDB v5.0 CAIRO_HEPATOBLASTOMA_DN 248 2,25 0,000 MsigDB v5.0 YAMASHITA_LIVER_CANCER_STEM_CELL_DN 67 2,21 0,000 MsigDB v5.0 CHIANG_LIVER_CANCER_SUBCLASS_PROLIFERATION_DN 145 2,19 0,000 MsigDB v5.0 WOO_LIVER_CANCER_RECURRENCE_DN 78 2,14 0,000 MsigDB v5.0 CHIANG_LIVER_CANCER_SUBCLASS_CTNNB1_DN 137 2,12 0,000 MsigDB v5.0 HOSHIDA_S1 213 1,82 0,006 MsigDB v5.0 CHIANG_LIVER_CANCER_SUBCLASS_POLYSOMY7 56 1,77 0,009 MsigDB v5.0

FUNCTIONAL GENE SETS (C2 CURATED ) Reactome, keggs, cancer-related*

KEGG_COMPLEMENT_AND_COAGULATION_CASCADES 65 2,55 0,000 MsigDB v5.0

HSIAO_LIVER_SPECIFIC_GENES 221 2,53 0,000 MsigDB v5.0 KOBAYASHI_EGFR_SIGNALING_24HR_UP 89 2,50 0,000 MsigDB v5.0 COLDREN_GEFITINIB_RESISTANCE_DN 205 2,33 0,000 MsigDB v5.0 CAIRO_LIVER_DEVELOPMENT_DN 200 2,33 0,000 MsigDB v5.0 KEGG_PPAR_SIGNALING_PATHWAY 64 2,31 0,000 MsigDB v5.0 KEGG_DRUG_METABOLISM_CYTOCHROME_P450 53 2,31 0,000 MsigDB v5.0 BROWNE_INTERFERON_RESPONSIVE_GENES 63 2,26 0,000 MsigDB v5.0 RODWELL_AGING_KIDNEY_UP 294 2,25 0,000 MsigDB v5.0 DAVICIONI_MOLECULAR_ARMS_VS_ERMS_DN 165 2,25 0,000 MsigDB v5.0 SANA_RESPONSE_TO_IFNG_UP 57 2,24 0,000 MsigDB v5.0 CERVERA_SDHB_TARGETS_1_UP 98 2,23 0,000 MsigDB v5.0 SANA_TNF_SIGNALING_UP 71 2,21 0,000 MsigDB v5.0 PICCALUGA_ANGIOIMMUNOBLASTIC_LYMPHOMA_UP 188 2,20 0,000 MsigDB v5.0 RADAEVA_RESPONSE_TO_IFNA1_UP 31 2,19 0,000 MsigDB v5.0 RODWELL_AGING_KIDNEY_NO_BLOOD_UP 135 2,19 0,000 MsigDB v5.0 RICKMAN_METASTASIS_DN 224 2,19 0,000 MsigDB v5.0 MARKEY_RB1_ACUTE_LOF_UP 193 2,18 0,000 MsigDB v5.0 LINDGREN_BLADDER_CANCER_CLUSTER_2B 353 2,18 0,000 MsigDB v5.0 BERENJENO_TRANSFORMED_BY_RHOA_DN 337 2,16 0,000 MsigDB v5.0 REACTOME_COMPLEMENT_CASCADE 22 2,15 0,000 MsigDB v5.0 REACTOME_METABOLISM_OF_LIPIDS_AND_LIPOPROTEINS 214 2,15 0,000 MsigDB v5.0 KINSEY_TARGETS_OF_EWSR1_FLII_FUSION_DN 284 2,15 0,000 MsigDB v5.0 MOHANKUMAR_TLX1_TARGETS_DN 134 2,14 0,000 MsigDB v5.0 ICHIBA_GRAFT_VERSUS_HOST_DISEASE_D7_UP 82 2,14 0,000 MsigDB v5.0 SCHUETZ_BREAST_CANCER_DUCTAL_INVASIVE_UP 321 2,14 0,000 MsigDB v5.0 MCLACHLAN_DENTAL_CARIES_DN 216 2,14 0,000 MsigDB v5.0 BIOCARTA_LAIR_PATHWAY 16 2,14 0,000 MsigDB v5.0 CHARAFE_BREAST_CANCER_BASAL_VS_MESENCHYMAL_UP 109 2,12 0,000 MsigDB v5.0 LINDGREN_BLADDER_CANCER_HIGH_RECURRENCE 41 2,12 0,000 MsigDB v5.0 CHARAFE_BREAST_CANCER_LUMINAL_VS_MESENCHYMAL_UP 394 2,11 0,000 MsigDB v5.0 YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_0 64 2,11 0,000 MsigDB v5.0 COLIN_PILOCYTIC_ASTROCYTOMA_VS_GLIOBLASTOMA_UP 34 2,10 0,000 MsigDB v5.0 31

KEGG_TYPE_I_DIABETES_MELLITUS 34 2,10 0,000 MsigDB v5.0 EINAV_INTERFERON_SIGNATURE_IN_CANCER 26 2,08 0,000 MsigDB v5.0 CROMER_TUMORIGENESIS_UP 43 2,08 0,000 MsigDB v5.0 SU_LIVER 54 2,07 0,000 MsigDB v5.0 MISHRA_CARCINOMA_ASSOCIATED_FIBROBLAST_DN 22 2,06 0,000 MsigDB v5.0 MANALO_HYPOXIA_UP 189 1,99 0,001 MsigDB v5.0 ELVIDGE_HYPOXIA_UP 156 1,78 0,011 MsigDB v5.0

GENE ONTOLOGY (GO) GENE SETS

SERINE_TYPE_ENDOPEPTIDASE_ACTIVITY 35 2,10 0,006 MsigDB v5.0 SERINE_HYDROLASE_ACTIVITY 40 2,05 0,012 MsigDB v5.0 CYTOKINE_BINDING 43 2,04 0,010 MsigDB v5.0 SERINE_TYPE_PEPTIDASE_ACTIVITY 39 2,03 0,008 MsigDB v5.0 ANION_TRANSPORT 30 2,02 0,008 MsigDB v5.0 PROTEASE_INHIBITOR_ACTIVITY 41 1,98 0,010 MsigDB v5.0 SERINE_TYPE_ENDOPEPTIDASE_INHIBITOR_ACTIVITY 25 1,98 0,009 MsigDB v5.0 MONOOXYGENASE_ACTIVITY 26 1,97 0,008 MsigDB v5.0 ION_TRANSPORT 179 1,94 0,012 MsigDB v5.0 INORGANIC_ANION_TRANSPORT 18 1,93 0,012 MsigDB v5.0 FATTY_ACID_OXIDATION 17 1,92 0,014 MsigDB v5.0 EXTRACELLULAR_SPACE 221 1,91 0,014 MsigDB v5.0 LIPID_CATABOLIC_PROCESS 35 1,90 0,017 MsigDB v5.0 LIPID_TRANSPORTER_ACTIVITY 27 1,90 0,016 MsigDB v5.0 DEFENSE_RESPONSE 239 1,89 0,017 MsigDB v5.0 HEMATOPOIETIN_INTERFERON_CLASSD200_DOMAIN_CYTOKINE_RECEPTOR_ACTIVITY 31 1,89 0,016 MsigDB v5.0 CALCIUM_INDEPENDENT_CELL_CELL_ADHESION 19 1,89 0,015 MsigDB v5.0 INTRAMOLECULAR_OXIDOREDUCTASE_ACTIVITY 17 1,88 0,017 MsigDB v5.0 RECEPTOR_SIGNALING_PROTEIN_ACTIVITY 77 1,88 0,016 MsigDB v5.0 LIPID_METABOLIC_PROCESS 289 1,86 0,018 MsigDB v5.0 LIPID_TRANSPORT 26 1,86 0,018 MsigDB v5.0 ANION_TRANSMEMBRANE_TRANSPORTER_ACTIVITY 58 1,86 0,018 MsigDB v5.0 SKELETAL_DEVELOPMENT 98 1,86 0,018 MsigDB v5.0 REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS 141 1,84 0,021 MsigDB v5.0 EXTRACELLULAR_REGION 400 1,83 0,024 MsigDB v5.0 CELL_CELL_ADHESION 80 1,82 0,028 MsigDB v5.0 REGULATION_OF_BODY_FLUID_LEVELS 53 1,82 0,028 MsigDB v5.0 COAGULATION 42 1,80 0,031 MsigDB v5.0 INTERLEUKIN_BINDING 23 1,80 0,030 MsigDB v5.0 DIGESTION 38 1,80 0,031 MsigDB v5.0 RESPONSE_TO_WOUNDING 175 1,80 0,030 MsigDB v5.0 EXCRETION 34 1,79 0,031 MsigDB v5.0 MEMBRANE_FRACTION 320 1,79 0,032 MsigDB v5.0 RESPONSE_TO_EXTERNAL_STIMULUS 287 1,78 0,033 MsigDB v5.0 INTERLEUKIN_RECEPTOR_ACTIVITY 19 1,78 0,033 MsigDB v5.0 INTRINSIC_TO_PLASMA_MEMBRANE 905 1,77 0,036 MsigDB v5.0 TISSUE_REMODELING 29 1,77 0,036 MsigDB v5.0 CELLULAR_LIPID_METABOLIC_PROCESS 227 1,77 0,036 MsigDB v5.0 INTEGRAL_TO_PLASMA_MEMBRANE 891 1,76 0,038 MsigDB v5.0 PEPTIDASE_ACTIVITY 157 1,76 0,038 MsigDB v5.0

H HALLMARKS GENE SETS

HALLMARK_EPITHELIAL_MESENCHYMAL_TRANSITION 189 2,34 0,000 MsigDB v5.0

HALLMARK_INTERFERON_ALPHA_RESPONSE 97 2,28 0,000 MsigDB v5.0

HALLMARK_INTERFERON_GAMMA_RESPONSE 188 2,26 0,000 MsigDB v5.0 32

HALLMARK_IL6_JAK_STAT3_SIGNALING 85 2,23 0,000 MsigDB v5.0

HALLMARK_HYPOXIA 199 2,02 0,000 MsigDB v5.0

HALLMARK_KRAS_SIGNALING_UP 192 1,97 0,000 MsigDB v5.0

HALLMARK_APOPTOSIS 161 1,88 0,003 MsigDB v5.0

HALLMARK_INFLAMMATORY_RESPONSE 199 1,86 0,004 MsigDB v5.0

33

Supplementary Table 7. List of 342 differentially expressed genes in spheres from sorafenib-resistant tumors vs spheres of non-treated tumors (≥1.5-fold, FDR<0.05)

Symbol Accession Gene name//Description Fold change FDR value Upregulated TXNIP NM_006472 thioredoxin interacting protein 8,61 0,010 DLK1 NM_003836 delta-like 1 homolog (Drosophila) 5,30 0,010 PGC NM_002630 progastricsin (pepsinogen C) 5,27 0,023 MYLK4 NM_001012418 light chain kinase family, member 4 4,59 0,033 SULT1E1 NM_005420 sulfotransferase family 1E, estrogen-preferring, member 1 4,45 0,004 HP NM_005143 4,34 0,043 NQO1 NM_000903 NAD(P)H dehydrogenase, quinone 1 4,25 0,012 DIO1 NM_000792 deiodinase, iodothyronine, type I 4,17 0,019 VCAM1 NM_001078 vascular cell adhesion molecule 1 3,82 0,006 ABCB11 NM_003742 ATP-binding cassette, sub-family B (MDR/TAP), member 11 3,61 0,008 UGT1A1 NM_000463 UDP 1 family, polypeptide A1 3,32 0,008 LEAP2 NM_052971 liver expressed antimicrobial peptide 2 3,26 0,009 OTC NM_000531 ornithine carbamoyltransferase 2,99 0,023 HLF NM_002126 hepatic leukemia factor 2,75 0,022 APOC3 NM_000040 apolipoprotein C-III 2,72 0,010 SLCO1B3 NM_019844 solute carrier organic anion transporter family, member 1B3 2,70 0,020 SLC22A7 NM_006672 solute carrier family 22 (organic anion transporter), member 7 2,70 0,020 FAM49A NM_030797 family with sequence similarity 49, member A 2,60 0,006 ACSS2 NM_018677 acyl-CoA synthetase short-chain family member 2 2,57 0,008 GPX2 NM_002083 glutathione peroxidase 2 (gastrointestinal) 2,56 0,012 ACSM2A NM_001010845 acyl-CoA synthetase medium-chain family member 2A 2,54 0,013 IGFBP2 NM_000597 insulin-like growth factor binding protein 2, 36kDa 2,50 0,032 ETNK2 NM_018208 ethanolamine kinase 2 2,49 0,006 MEST NM_002402 mesoderm specific transcript 2,48 0,018 CES1 NM_001025195 1 2,44 0,020 TMSB4X NM_021109 thymosin beta 4, X-linked 2,39 0,004 PRSS8 NM_002773 protease, serine, 8 2,36 0,004 UGT2B10 NM_001075 UDP glucuronosyltransferase 2 family, polypeptide B10 2,35 0,038 HK1 NM_033500 hexokinase 1 2,35 0,004 LRP8 NM_004631 low density lipoprotein receptor-related protein 8, apolipoprotein e receptor 2,31 0,004 MICB NM_005931 MHC class I polypeptide-related sequence B 2,30 0,006 TMSB4XP8 NM_183049 thymosin beta 4, X-linked pseudogene 8 2,27 0,009 ECM2 NM_001393 extracellular matrix protein 2, female organ and adipocyte specific 2,21 0,023 KYNU NM_003937 kynureninase 2,20 0,008 MYO18B NM_032608 myosin XVIIIB 2,18 0,004 ARG1 NM_000045 , liver 2,17 0,039 TINAG NM_014464 tubulointerstitial nephritis antigen 2,16 0,008 TDRD1 NM_198795 tudor domain containing 1 2,16 0,009 CYP19A1 NM_031226 cytochrome P450, family 19, subfamily A, polypeptide 1 2,15 0,009 34

TMSB4X NM_021109 thymosin beta 4, X-linked 2,15 0,013 SALL4 NM_020436 sal-like 4 (Drosophila) 2,14 0,004 ATP11C NM_173694 ATPase, class VI, type 11C 2,13 0,004 HSD17B7 NM_016371 hydroxysteroid (17-beta) dehydrogenase 7 2,12 0,008 TRIM31 NM_007028 tripartite motif containing 31 2,12 0,008 ALDOC NM_005165 aldolase C, fructose-bisphosphate 2,09 0,006 HSD17B7P2 NR_003086 hydroxysteroid (17-beta) dehydrogenase 7 pseudogene 2 2,09 0,011 TRIM31 NM_007028 tripartite motif containing 31 2,08 0,016 ATP2B2 NM_001001331 ATPase, Ca++ transporting, plasma membrane 2 2,07 0,017 APOH NM_000042 (beta-2-glycoprotein I) 2,05 0,016 INSIG1 NM_005542 insulin induced gene 1 2,04 0,018 SLC6A8 NM_005629 solute carrier family 6 (neurotransmitter transporter, creatine), member 8 2,04 0,010 PNCK NM_001039582 pregnancy up-regulated non-ubiquitously expressed CaM kinase 2,04 0,016 TET1 NM_030625 tet methylcytosine dioxygenase 1 2,02 0,012 TM4SF4 NM_004617 transmembrane 4 L six family member 4 2,01 0,032 C8orf58 NM_001013842 chromosome 8 open reading frame 58 2,01 0,004 CLEC2B NM_005127 C-type lectin domain family 2, member B 2,01 0,024 myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila); MLLT11 NM_006818 translocated to, 11 1,99 0,022 ALDH1L1 NM_012190 aldehyde dehydrogenase 1 family, member L1 1,98 0,034 NXPE3 NM_145037 neurexophilin and PC-esterase domain family, member 3 1,98 0,018 LOC151009 AK095678 uncharacterized LOC151009 1,97 0,026 DPPA2 NM_138815 developmental pluripotency associated 2 1,96 0,007 DPYS NM_001385 dihydropyrimidinase 1,95 0,015 PRICKLE1 NM_153026 prickle homolog 1 (Drosophila) 1,95 0,029 SLC27A2 NM_003645 solute carrier family 27 (fatty acid transporter), member 2 1,93 0,020 SLC2A9 NM_020041 solute carrier family 2 (facilitated glucose transporter), member 9 1,91 0,007 MB21D2 NM_178496 Mab-21 domain containing 2 1,91 0,010 LY75 NM_002349 lymphocyte antigen 75 1,91 0,010 PCP4L1 NM_001102566 protein 4 like 1 1,90 0,015 CNKSR1 NM_006314 connector enhancer of kinase suppressor of Ras 1 1,89 0,004 SLC25A18 NM_031481 solute carrier family 25 (glutamate carrier), member 18 1,88 0,019 RNFT2 NM_001109903 ring finger protein, transmembrane 2 1,87 0,024 MVK NM_000431 1,86 0,007 IGSF1 NM_001555 immunoglobulin superfamily, member 1 1,86 0,009 SYT2 NM_177402 synaptotagmin II 1,86 0,015 serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member SERPINA11 NM_001080451 11 1,85 0,004 CES1P1 NR_003276 carboxylesterase 1 pseudogene 1 1,84 0,044 ISYNA1 NM_016368 inositol-3-phosphate synthase 1 1,83 0,010 GSTA2 NM_000846 glutathione S-transferase alpha 2 1,83 0,039 MBL2 NM_000242 mannose-binding lectin () 2, soluble 1,82 0,016 HMGA1 NM_145905 high mobility group AT-hook 1 1,82 0,019 CENPI NM_006733 centromere protein I 1,82 0,008 PNPLA3 NM_025225 patatin-like phospholipase domain containing 3 1,81 0,025 ATP2B4 NM_001001396 ATPase, Ca++ transporting, plasma membrane 4 1,81 0,010 35

GAL NM_015973 galanin/GMAP prepropeptide 1,81 0,021 ACSM3 NM_005622 acyl-CoA synthetase medium-chain family member 3 1,80 0,040 TRIM16 NM_006470 tripartite motif containing 16 1,80 0,039 NUAK1 NM_014840 NUAK family, SNF1-like kinase, 1 1,80 0,018 FXYD1 NM_005031 FXYD domain containing ion transport regulator 1 1,80 0,021 SPAG5 NM_006461 sperm associated antigen 5 1,80 0,008 KIF20A NM_005733 kinesin family member 20A 1,79 0,004 LOC151009 NR_027244 uncharacterized LOC151009 1,78 0,014 UGT2B10 NM_001075 UDP glucuronosyltransferase 2 family, polypeptide B10 1,78 0,016 UPK1A NM_007000 uroplakin 1A 1,78 0,008 FAM72D AB096683 family with sequence similarity 72, member D 1,77 0,009 serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member SERPINA6 NM_001756 6 1,76 0,022 CSF3R NM_156039 colony stimulating factor 3 receptor (granulocyte) 1,75 0,007 STARD4 NM_139164 StAR-related transfer (START) domain containing 4 1,75 0,015 PGA5 NM_014224 pepsinogen 5, group I (pepsinogen A) 1,75 0,036 CDH9 NM_016279 cadherin 9, type 2 (T1-cadherin) 1,75 0,016 INSIG2 NM_016133 insulin induced gene 2 1,75 0,018 GSTM4 NM_000850 glutathione S-transferase mu 4 1,75 0,009 TMSB4X NM_021109 thymosin beta 4, X-linked 1,74 0,033 NUDT16P1 NR_027766 nudix (nucleoside diphosphate linked moiety X)-type motif 16 pseudogene 1 1,73 0,022 ZP3 NM_001110354 zona pellucida glycoprotein 3 (sperm receptor) 1,73 0,032 MVD NM_002461 mevalonate (diphospho) decarboxylase 1,72 0,008 FOXG1 NM_005249 forkhead box G1 1,71 0,020 TRIM16L NM_001037330 tripartite motif containing 16-like 1,71 0,010 NUF2 NM_145697 NUF2, NDC80 kinetochore complex component, homolog (S. cerevisiae) 1,71 0,008 SLC6A4 NM_001045 solute carrier family 6 (neurotransmitter transporter, serotonin), member 4 1,69 0,008 GNB4 NM_021629 guanine binding protein (G protein), beta polypeptide 4 1,69 0,016 CPEB2 NM_182485 cytoplasmic polyadenylation element binding protein 2 1,68 0,011 PIR NM_003662 pirin (-binding nuclear protein) 1,68 0,009 CDA NM_001785 1,67 0,011 APOC3 NM_000040 apolipoprotein C-III 1,67 0,018 SULT1B1 NM_014465 sulfotransferase family, cytosolic, 1B, member 1 1,66 0,017 AGXT2 NM_031900 alanine--glyoxylate aminotransferase 2 1,66 0,013 ABCC2 NM_000392 ATP-binding cassette, sub-family C (CFTR/MRP), member 2 1,66 0,045 EPHA1 NM_005232 EPH receptor A1 1,66 0,029 PECR NM_018441 peroxisomal trans-2-enoyl-CoA reductase 1,65 0,017 MAP3K13 NM_004721 mitogen-activated protein kinase kinase kinase 13 1,65 0,014 DUSP19 NM_080876 dual specificity phosphatase 19 1,64 0,010 TNFSF10 NM_003810 tumor necrosis factor (ligand) superfamily, member 10 1,64 0,041 GBE1 NM_000158 glucan (1,4-alpha-), branching enzyme 1 1,64 0,016 PFKFB1 NM_002625 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 1 1,64 0,016 CABYR NM_012189 calcium binding tyrosine-(Y)-phosphorylation regulated 1,64 0,016 SLC23A1 NM_005847 solute carrier family 23 (nucleobase transporters), member 1 1,64 0,010 FAM72D AB096683 family with sequence similarity 72, member D 1,64 0,012 36

excision repair cross-complementing rodent repair deficiency, complementation ERCC6L NM_017669 group 6-like 1,64 0,018 GRB7 NM_001030002 growth factor receptor-bound protein 7 1,64 0,020 serpin peptidase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium SERPINF2 NM_001165920 derived factor), member 2 1,64 0,008 MTMR10 NM_017762 myotubularin related protein 10 1,64 0,006 CCR10 NM_016602 chemokine (C-C motif) receptor 10 1,63 0,007 ARHGAP19 NM_032900 Rho GTPase activating protein 19 1,63 0,023 ASTE1 NM_014065 asteroid homolog 1 (Drosophila) 1,63 0,006 SNX10 NM_013322 sorting nexin 10 1,63 0,050 DGKK NM_001013742 diacylglycerol kinase, kappa 1,62 0,018 AGXT NM_000030 alanine-glyoxylate aminotransferase 1,62 0,023 KRTAP21-1 NM_181619 associated protein 21-1 1,62 0,036 DLGAP5 NM_014750 discs, large (Drosophila) homolog-associated protein 5 1,62 0,010 EFNA3 NM_004952 ephrin-A3 1,62 0,018 PCID2 BC008975 PCI domain containing 2 1,61 0,031 TRIM38 NM_006355 tripartite motif containing 38 1,61 0,042 CD9 NM_001769 CD9 molecule 1,61 0,021 ADK NM_006721 adenosine kinase 1,60 0,008 HMGCR NM_000859 3-hydroxy-3-methylglutaryl-CoA reductase 1,60 0,015 IDI1 NM_004508 isopentenyl-diphosphate delta 1 1,60 0,010 FRMD4B NM_015123 FERM domain containing 4B 1,59 0,010 SLC25A15 NM_014252 solute carrier family 25 (; ornithine transporter) member 15 1,59 0,011 KIF14 NM_014875 kinesin family member 14 1,59 0,020 USP27X NM_001145073 ubiquitin specific peptidase 27, X-linked 1,59 0,011 HAUS4 NM_001166269 HAUS augmin-like complex, subunit 4 1,59 0,007 DPYD NM_000110 dihydropyrimidine dehydrogenase 1,59 0,031 LINC00337 BC030279 long intergenic non-protein coding RNA 337 1,58 0,040 PLCH1 NM_001130960 , eta 1 1,58 0,020 HSD17B12 NM_016142 hydroxysteroid (17-beta) dehydrogenase 12 1,58 0,048 GALM NM_138801 galactose mutarotase (aldose 1-epimerase) 1,58 0,017 HIBADH NM_152740 3-hydroxyisobutyrate dehydrogenase 1,58 0,020 KANK4 NM_181712 KN motif and repeat domains 4 1,58 0,017 ACAT2 NM_005891 acetyl-CoA acetyltransferase 2 1,58 0,032 PPP4R1L NR_003505 protein phosphatase 4, regulatory subunit 1-like 1,58 0,008 solute carrier family 9, subfamily B (NHA1, cation proton antiporter 1), member SLC9B1 NM_139173 1 1,58 0,008 CP NM_000096 (ferroxidase) 1,58 0,009 TNXB NM_032470 tenascin XB 1,57 0,027 AURKA NM_198433 aurora kinase A 1,57 0,010 POT1 NM_015450 protection of telomeres 1 1,57 0,008 IGF1R NM_000875 insulin-like growth factor 1 receptor 1,57 0,009 ZCCHC2 NM_017742 zinc finger, CCHC domain containing 2 1,57 0,018 SNRPA1 NM_003090 small nuclear ribonucleoprotein polypeptide A' 1,57 0,023 MYCN NM_005378 v-myc myelocytomatosis viral related oncogene, neuroblastoma derived (avian) 1,56 0,016 MIR519A2 NR_030222 microRNA 519a-2 1,56 0,037 DARS2 NM_018122 aspartyl-tRNA synthetase 2, mitochondrial 1,56 0,015 37

FAM160A1 NM_001109977 family with sequence similarity 160, member A1 1,56 0,021 ATP10D NM_020453 ATPase, class V, type 10D 1,56 0,025 DZIP1 NM_198968 DAZ interacting protein 1 1,56 0,018 CLCN6 NM_001286 , voltage-sensitive 6 1,56 0,018 PFKFB4 NM_004567 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 1,56 0,043 ATPBD4 NM_080650 ATP binding domain 4 1,56 0,006 FASN NM_004104 fatty acid synthase 1,56 0,029 ZFYVE19 NM_001077268 zinc finger, FYVE domain containing 19 1,55 0,007 TRIM59 NM_173084 tripartite motif containing 59 1,55 0,023 ZNF354A NM_005649 zinc finger protein 354A 1,55 0,011 ZFP82 NM_133466 ZFP82 zinc finger protein 1,55 0,024 RCAN3 NM_013441 RCAN family member 3 1,55 0,024 KCTD6 NM_153331 potassium channel tetramerisation domain containing 6 1,55 0,008 CCNB2 NM_004701 cyclin B2 1,55 0,011 SLC17A3 NM_001098486 solute carrier family 17 (sodium phosphate), member 3 1,55 0,038 CCDC88C NM_001080414 coiled-coil domain containing 88C 1,55 0,009 SQLE NM_003129 squalene epoxidase 1,55 0,010 LSS NM_002340 synthase (2,3-oxidosqualene-lanosterol cyclase) 1,54 0,011 TRPV2 NM_016113 transient receptor potential cation channel, subfamily V, member 2 1,54 0,018 CA5A NM_001739 carbonic anhydrase VA, mitochondrial 1,54 0,008 TKT NM_001135055 transketolase 1,54 0,009 PRC1 NM_003981 protein regulator of cytokinesis 1 1,54 0,024 KIF4A NM_012310 kinesin family member 4A 1,54 0,024 ZNF607 NM_032689 zinc finger protein 607 1,53 0,015 PNP NM_000270 nucleoside 1,53 0,019 DCAF4 NM_015604 DDB1 and CUL4 associated factor 4 1,53 0,008 PARK2 NM_004562 parkinson protein 2, E3 ubiquitin protein ligase (parkin) 1,53 0,036 IGF1R NM_000875 insulin-like growth factor 1 receptor 1,52 0,020 PRUNE NM_021222 prune homolog (Drosophila) 1,52 0,013 FDFT1 NM_004462 farnesyl-diphosphate farnesyltransferase 1 1,52 0,021 PER1 NM_002616 period circadian 1 1,52 0,023 ANXA6 NM_001155 1,52 0,013 TCP10L NM_144659 t-complex 10-like 1,52 0,008 NFAM1 NM_145912 NFAT activating protein with ITAM motif 1 1,51 0,025 CERCAM NM_016174 cerebral endothelial cell adhesion molecule 1,51 0,016 CCNB3 NM_033031 cyclin B3 1,51 0,013 PDZK1 NM_002614 PDZ domain containing 1 1,51 0,019 C6orf123 AB016901 chromosome 6 open reading frame 123 1,50 0,016

Downregulated CIT NM_007174 citron (rho-interacting, serine/threonine kinase 21) 1,50 0,014 SCARNA7 NR_003001 small Cajal body-specific RNA 7 -1,50 0,040 HLA-DQA2 NM_020056 major histocompatibility complex, class II, DQ alpha 2 -1,50 0,027 MMP16 AL136588 matrix metallopeptidase 16 (membrane-inserted) -1,50 0,021 ZNF91 NM_003430 zinc finger protein 91 -1,50 0,016 38

KRT18 NM_199187 -1,51 0,032 WARS NM_004184 tryptophanyl-tRNA synthetase -1,51 0,036 PIEZO2 NM_022068 piezo-type mechanosensitive component 2 -1,51 0,020 SSBP2 NM_012446 single-stranded DNA binding protein 2 -1,51 0,031 GBA NM_000157 glucosidase, beta, acid -1,51 0,015 AP1S3 NM_001039569 adaptor-related protein complex 1, sigma 3 subunit -1,51 0,038 ENC1 NM_003633 ectodermal-neural cortex 1 (with BTB domain) -1,52 0,036 EIF4EBP1 NM_004095 eukaryotic translation initiation factor 4E binding protein 1 -1,52 0,023 NM_005980 S100 calcium binding protein P -1,52 0,049 CYBASC3 NM_001161454 cytochrome b, ascorbate dependent 3 -1,52 0,008 SPATA6 NM_019073 spermatogenesis associated 6 -1,52 0,014 SCN8A NM_014191 , voltage gated, type VIII, alpha subunit -1,53 0,049 ANKS1B NM_152788 ankyrin repeat and sterile alpha motif domain containing 1B -1,54 0,022 IGF2R NM_000876 insulin-like growth factor 2 receptor -1,54 0,026 TRHDE NM_013381 thyrotropin-releasing hormone degrading enzyme -1,54 0,024 MOXD1 NM_015529 monooxygenase, DBH-like 1 -1,54 0,034 BBS1 NM_024649 Bardet-Biedl syndrome 1 -1,55 0,023 USP17L2 NM_201402 ubiquitin specific peptidase 17-like family member 2 -1,55 0,050 OAS1 NM_016816 2'-5'-oligoadenylate synthetase 1, 40/46kDa -1,55 0,017 DSG3 NM_001944 desmoglein 3 -1,55 0,023 NIPAL2 NM_024759 NIPA-like domain containing 2 -1,56 0,039 CYFIP2 NM_001037332 cytoplasmic FMR1 interacting protein 2 -1,56 0,039 SETD7 NM_030648 SET domain containing (lysine methyltransferase) 7 -1,57 0,012 TFPI2 NM_006528 tissue factor pathway inhibitor 2 -1,57 0,023 CSRNP2 NM_030809 cysteine-serine-rich nuclear protein 2 -1,57 0,016 C3orf52 NM_024616 open reading frame 52 -1,57 0,035 PNMA2 NM_007257 paraneoplastic Ma antigen 2 -1,57 0,048 CHST9 NM_031422 carbohydrate (N-acetylgalactosamine 4-0) sulfotransferase 9 -1,57 0,016 PKI55 AK125369 DKFZp434H1419 -1,57 0,017 NBEA NM_015678 neurobeachin -1,58 0,021 AMHR2 NM_020547 anti-Mullerian hormone receptor, type II -1,58 0,047 KRT18 NM_000224 keratin 18 -1,58 0,032 GABRR1 NM_002042 gamma-aminobutyric acid (GABA) A receptor, rho 1 -1,58 0,050 NNMT NM_006169 nicotinamide N-methyltransferase -1,59 0,024 OAS3 NM_006187 2'-5'-oligoadenylate synthetase 3, 100kDa -1,59 0,017 SNORD105 NR_004381 small nucleolar RNA, C/D box 105 -1,60 0,031 GPR98 NM_032119 G protein-coupled receptor 98 -1,60 0,024 PIGQ NM_004204 phosphatidylinositol glycan anchor biosynthesis, class Q -1,60 0,013 IGSF3 NM_001542 immunoglobulin superfamily, member 3 -1,61 0,010 LZTFL1 NM_020347 leucine zipper transcription factor-like 1 -1,61 0,050 CXCL1 NM_001511 chemokine (C-X-C motif) ligand 1 (melanoma growth stimulating activity, alpha) -1,61 0,031 DNAJC10 NM_018981 DnaJ (Hsp40) homolog, subfamily C, member 10 -1,62 0,013 TNFRSF12A NM_016639 tumor necrosis factor receptor superfamily, member 12A -1,62 0,006 USP6NL NM_014688 USP6 N-terminal like -1,62 0,008 NRP2 NM_201266 neuropilin 2 -1,63 0,007 39

GFRA1 NM_005264 GDNF family receptor alpha 1 -1,64 0,040 C7orf53 NM_182597 open reading frame 53 -1,64 0,015 sphingomyelin , neutral membrane (neutral SMPD2 NM_003080 sphingomyelinase) -1,64 0,008 HSPB8 NM_014365 heat shock 22kDa protein 8 -1,64 0,010 SSTR2 NM_001050 2 -1,65 0,010 ANGPTL4 NM_139314 angiopoietin-like 4 -1,66 0,032 FGD6 NM_018351 FYVE, RhoGEF and PH domain containing 6 -1,66 0,037 TBCEL NM_152715 folding cofactor E-like -1,66 0,018 PCDH17 NM_001040429 protocadherin 17 -1,67 0,015 PARP8 NM_001178055 poly (ADP-ribose) polymerase family, member 8 -1,67 0,016 FLRT3 NM_198391 fibronectin leucine rich transmembrane protein 3 -1,67 0,045 PPIC NM_000943 peptidylprolyl isomerase C (cyclophilin C) -1,67 0,008 DUSP4 NM_001394 dual specificity phosphatase 4 -1,68 0,006 ACP5 NM_001111035 5, tartrate resistant -1,68 0,011 CSTA NM_005213 cystatin A (stefin A) -1,69 0,032 NEB NM_001164507 nebulin -1,69 0,035 NRG3 NM_001010848 -1,69 0,024 SESN2 NM_031459 sestrin 2 -1,71 0,011 ITGAV NM_002210 integrin, alpha V -1,73 0,022 SMPD1 NM_000543 sphingomyelin phosphodiesterase 1, acid lysosomal -1,74 0,013 SNORA20 NR_002960 small nucleolar RNA, H/ACA box 20 -1,75 0,036 NT5E NM_002526 5'-, ecto (CD73) -1,75 0,005 SLC6A9 NM_201649 solute carrier family 6 (neurotransmitter transporter, glycine), member 9 -1,75 0,013 GPR137B NM_003272 G protein-coupled receptor 137B -1,76 0,023 LRRN1 NM_020873 leucine rich repeat neuronal 1 -1,76 0,016 TAX1BP3 NM_014604 Tax1 (human T-cell leukemia virus type I) binding protein 3 -1,76 0,021 MATN3 NM_002381 matrilin 3 -1,77 0,022 LARP6 NM_018357 La ribonucleoprotein domain family, member 6 -1,78 0,037 ANO4 NM_178826 anoctamin 4 -1,82 0,043 USP17L6P NR_027279 ubiquitin specific peptidase 17-like family member 6, pseudogene -1,83 0,027 RND3 NM_005168 Rho family GTPase 3 -1,84 0,018 SP100 NM_001080391 SP100 nuclear antigen -1,84 0,016 CCSER1 NM_001145065 coiled-coil serine-rich protein 1 -1,85 0,004 UGT2A3 NM_024743 UDP glucuronosyltransferase 2 family, polypeptide A3 -1,85 0,020 ENSA NM_207046 endosulfine alpha -1,85 0,026 SLC37A1 NM_018964 solute carrier family 37 (glycerol-3-phosphate transporter), member 1 -1,86 0,024 SNORD82 NR_004398 small nucleolar RNA, C/D box 82 -1,87 0,041 NPY NM_000905 neuropeptide Y -1,89 0,038 SH3BGRL2 NM_031469 SH3 domain binding -rich protein like 2 -1,90 0,033 NOSTRIN NM_001039724 trafficker -1,92 0,041 RCN1 NM_002901 reticulocalbin 1, EF-hand calcium binding domain -1,95 0,009 GLIS3 NM_152629 GLIS family zinc finger 3 -1,96 0,024 CHAC1 NM_024111 ChaC, cation transport regulator homolog 1 (E. coli) -1,96 0,017 NRCAM NM_001037132 neuronal cell adhesion molecule -1,96 0,013 40

DSEL NM_032160 epimerase-like -1,97 0,020 GDPD3 NM_024307 glycerophosphodiester phosphodiesterase domain containing 3 -1,98 0,039 PECAM1 NM_000442 platelet/endothelial cell adhesion molecule 1 -1,99 0,018 JAG1 NM_000214 jagged 1 -2,00 0,018 TP53INP1 NM_033285 tumor protein p53 inducible nuclear protein 1 -2,02 0,015 COL12A1 NM_004370 , type XII, alpha 1 -2,04 0,013 GXYLT2 NM_001080393 glucoside xylosyltransferase 2 -2,08 0,010 DPP4 NM_001935 dipeptidyl-peptidase 4 -2,09 0,023 CLGN NM_004362 calmegin -2,15 0,009 BICC1 NM_001080512 bicaudal C homolog 1 (Drosophila) -2,15 0,010 C14orf105 NM_018168 open reading frame 105 -2,17 0,011 CYR61 NM_001554 cysteine-rich, angiogenic inducer, 61 -2,18 0,004 CXCL5 NM_002994 chemokine (C-X-C motif) ligand 5 -2,20 0,015 LTBP1 NM_206943 latent transforming growth factor beta binding protein 1 -2,21 0,016 LRRC49 NM_017691 leucine rich repeat containing 49 -2,22 0,019 FBN1 NM_000138 fibrillin 1 -2,28 0,004 INHBE NM_031479 inhibin, beta E -2,30 0,041 MCOLN3 NM_018298 mucolipin 3 -2,31 0,043 UDP-N-acetyl-alpha-D-galactosamine:polypeptide N- GALNT5 NM_014568 acetylgalactosaminyltransferase 5 (GalNAc-T5) -2,32 0,044 CD24 NM_013230 CD24 molecule -2,32 0,021 SLCO2A1 NM_005630 solute carrier organic anion transporter family, member 2A1 -2,33 0,026 CCL20 NM_004591 chemokine (C-C motif) ligand 20 -2,35 0,030 ECH1 NM_001398 enoyl CoA hydratase 1, peroxisomal -2,35 0,017 AKR1D1 NM_005989 aldo-keto reductase family 1, member D1 -2,38 0,048 EDN1 NM_001955 -2,39 0,025 ALPK2 NM_052947 alpha-kinase 2 -2,41 0,004 FAM129A NM_052966 family with sequence similarity 129, member A -2,41 0,016 SLC12A2 NM_001046 solute carrier family 12 (sodium/potassium/chloride transporters), member 2 -2,43 0,010 AFF3 NM_002285 AF4/FMR2 family, member 3 -2,44 0,023 UNC5B NM_170744 unc-5 homolog B (C. elegans) -2,68 0,018 RASEF NM_152573 RAS and EF-hand domain containing -2,72 0,015 LAMP3 NM_014398 lysosomal-associated membrane protein 3 -2,79 0,004 ANKRD1 NM_014391 ankyrin repeat domain 1 (cardiac muscle) -2,80 0,013 CD3G NM_000073 CD3g molecule, gamma (CD3-TCR complex) -2,84 0,020 KCNH7 NM_033272 potassium voltage-gated channel, subfamily H (eag-related), member 7 -2,84 0,046 TLL1 NM_012464 tolloid-like 1 -2,92 0,018 THBS1 NM_003246 -3,31 0,024 SCGN NM_006998 secretagogin, EF-hand calcium binding protein -3,37 0,027 AREG NM_001657 -3,55 0,004 VCAN NM_004385 versican -4,64 0,008

RELN NM_005045 -5,20 0,044

41

Supplementary Table 8: Representative list of gene sets associated with sorafenib-resistant tumor-derived spheres by GSEA (FDR<0.05). * 40 representative top scored gene sets are shown

NAME SIZE NES FDR q-val Reference LIVER CANCER GENE SETS VILLANUEVA_CK19_SIGNATURE 148 2,03 0,001 Villanueva et al. Gastroenterology. 2011

CHIANG_LIVER_CANCER_SUBCLASS_CTNNB1 129 1,99 0,001 MsigDB v5.0

BOYAULT_LIVER_CANCER_SUBCLASS_G3 128 1,79 0,007 MsigDB v5.0

TOVAR_IGFR1_ACTIVATION 188 1,78 0,006 Tovar et al. J Hepatology. 2010

CHIANG_LIVER_CANCER_SUBCLASS_PROLIFERATION 127 1,74 0,008 MsigDB v5.0

CAIRO_LIVER_CANCER_HEPATOBLAST 7 1,61 0,020 MsigDB v5.0

YE_LIVER_CANCER_INTRAHEPATIC_METS 21 1,56 0,029 MsigDB v5.0

YAMASHITA_LIVER_CANCER_EPCAM 43 1,48 0,046 MsigDB v5.0

FUNCTIONAL GENE SETS (C2 CURATED )* Biological states and cancer-related ROSTY_CERVICAL_CANCER_PROLIFERATION_CLUSTER 127 2,85 0,000 MsigDB v5.0

SOTIRIOU_BREAST_CANCER_GRADE_1_VS_3_UP 135 2,80 0,000 MsigDB v5.0

KONG_E2F3_TARGETS 88 2,76 0,000 MsigDB v5.0

LEE_EARLY_T_LYMPHOCYTE_UP 91 2,65 0,000 MsigDB v5.0

CROONQUIST_IL6_DEPRIVATION_DN 88 2,64 0,000 MsigDB v5.0

CHANG_CYCLING_GENES 129 2,57 0,000 MsigDB v5.0

ODONNELL_TFRC_TARGETS_DN 124 2,55 0,000 MsigDB v5.0

ISHIDA_E2F_TARGETS 49 2,54 0,000 MsigDB v5.0

KANG_DOXORUBICIN_RESISTANCE_UP 48 2,53 0,000 MsigDB v5.0

ZHOU_CELL_CYCLE_GENES_IN_IR_RESPONSE_24HR 112 2,50 0,000 MsigDB v5.0

DUTERTRE_ESTRADIOL_RESPONSE_24HR_UP 290 2,50 0,000 MsigDB v5.0

GRAHAM_NORMAL_QUIESCENT_VS_NORMAL_DIVIDING_DN 77 2,50 0,000 MsigDB v5.0

CROONQUIST_NRAS_SIGNALING_DN 64 2,47 0,000 MsigDB v5.0

WINNEPENNINCKX_MELANOMA_METASTASIS_UP 135 2,46 0,000 MsigDB v5.0

REACTOME_MITOTIC_PROMETAPHASE 78 2,46 0,000 MsigDB v5.0

ZHAN_MULTIPLE_MYELOMA_PR_UP 36 2,45 0,000 MsigDB v5.0

REACTOME_DNA_REPLICATION 170 2,45 0,000 MsigDB v5.0

HOFFMANN_LARGE_TO_SMALL_PRE_BII_LYMPHOCYTE_UP 148 2,44 0,000 MsigDB v5.0

HORIUCHI_WTAP_TARGETS_DN 271 2,44 0,000 MsigDB v5.0

GAVIN_FOXP3_TARGETS_CLUSTER_P6 83 2,43 0,000 MsigDB v5.0

AMUNDSON_GAMMA_RADIATION_RESPONSE 35 2,43 0,000 MsigDB v5.0

WHITEFORD_PEDIATRIC_CANCER_MARKERS 108 2,43 0,000 MsigDB v5.0

REICHERT_MITOSIS_LIN9_TARGETS 25 2,41 0,000 MsigDB v5.0

GOBERT_OLIGODENDROCYTE_DIFFERENTIATION_UP 488 2,41 0,000 MsigDB v5.0

FARMER_BREAST_CANCER_CLUSTER_2 29 2,41 0,000 MsigDB v5.0

MORI_IMMATURE_B_LYMPHOCYTE_DN 83 2,40 0,000 MsigDB v5.0

REACTOME_MITOTIC_M_M_G1_PHASES 151 2,39 0,000 MsigDB v5.0

GRAHAM_CML_DIVIDING_VS_NORMAL_QUIESCENT_UP 161 2,38 0,000 MsigDB v5.0

KOBAYASHI_EGFR_SIGNALING_24HR_DN 220 2,36 0,000 MsigDB v5.0

ZHOU_CELL_CYCLE_GENES_IN_IR_RESPONSE_6HR 75 2,35 0,000 MsigDB v5.0 42

SCHMIDT_POR_TARGETS_IN_LIMB_BUD_UP 24 2,34 0,000 MsigDB v5.0

MISSIAGLIA_REGULATED_BY_METHYLATION_DN 107 2,34 0,000 MsigDB v5.0

MORI_LARGE_PRE_BII_LYMPHOCYTE_UP 81 2,34 0,000 MsigDB v5.0

TANG_SENESCENCE_TP53_TARGETS_DN 51 2,33 0,000 MsigDB v5.0

REACTOME_CELL_CYCLE 352 2,32 0,000 MsigDB v5.0

LINDGREN_BLADDER_CANCER_CLUSTER_3_UP 290 2,32 0,000 MsigDB v5.0

HORTON_SREBF_TARGETS 24 2,32 0,000 MsigDB v5.0

BLUM_RESPONSE_TO_SALIRASIB_DN 303 2,31 0,000 MsigDB v5.0

REACTOME_CELL_CYCLE_MITOTIC 278 2,31 0,000 MsigDB v5.0

ODONNELL_TARGETS_OF_MYC_AND_TFRC_DN 42 2,30 0,000 MsigDB v5.0

HALLMARKS GENE SETS HALLMARK_E2F_TARGETS 181 2,52 0,000 MsigDB v5.0

HALLMARK_G2M_CHECKPOINT 191 2,27 0,000 MsigDB v5.0

HALLMARK_MYC_TARGETS_V1 183 1,67 0,015 MsigDB v5.0

HALLMARK_MITOTIC_SPINDLE 197 1,60 0,023 MsigDB v5.0

HALLMARK_BILE_ACID_METABOLISM 112 1,60 0,019 MsigDB v5.0

HALLMARK_CHOLESTEROL_HOMEOSTASIS 71 1,52 0,032 MsigDB v5.0

HALLMARK_XENOBIOTIC_METABOLISM 187 1,51 0,030 MsigDB v5.0

HALLMARK_PEROXISOME 97 1,50 0,027 MsigDB v5.0

HALLMARK_REACTIVE_OXIGEN_SPECIES_PATHWAY 48 1,50 0,026 MsigDB v5.0

HALLMARK_MYC_TARGETS_V2 53 1,42 0,045 MsigDB v5.0

HALLMARK_MTORC1_SIGNALING 197 1,39 0,056 MsigDB v5.0

ONCOGENIC GENE SETS RPS14_DN.V1_DN 171 1,89 0,005 MsigDB v5.0

GCNP_SHH_UP_EARLY.V1_UP 158 1,77 0,011 MsigDB v5.0

PRC2_EZH2_UP.V1_UP 171 1,69 0,023 MsigDB v5.0

VEGF_A_UP.V1_DN 173 1,67 0,020 MsigDB v5.0

PKCA_DN.V1_UP 149 1,66 0,018 MsigDB v5.0

KRAS.AMP.LUNG_UP.V1_UP 124 1,61 0,023 MsigDB v5.0

MTOR_UP.V1_UP 147 1,58 0,029 MsigDB v5.0

HOXA9_DN.V1_DN 162 1,58 0,025 MsigDB v5.0

CSR_LATE_UP.V1_UP 155 1,56 0,027 MsigDB v5.0

NFE2L2.V2 390 1,55 0,028 MsigDB v5.0

RB_DN.V1_UP 115 1,53 0,030 MsigDB v5.0

E2F1_UP.V1_UP 172 1,49 0,045 MsigDB v5.0

FUNCTIONAL GENE SETS (C2 CURATED )

43

Supplementary Table 9: List of genes differentially expressed in tumors treated with brivanib after development of resistance (≥2-fold, p<0.05).

p Symbol Accession Gene name//Description Fold change value Upregulated

CES1 NM_001025195 carboxylesterase 1 6,26 0,002

GSTA1 NM_145740 glutathione S-transferase alpha 1 4,51 0,000

HRASLS2 NM_017878 HRAS-like suppressor 2 4,25 0,005 UGT1A1 NM_000463 UDP glucuronosyltransferase 1 family, polypeptide A1 3,98 0,009 ABCB11 NM_003742 ATP-binding cassette, sub-family B (MDR/TAP), member 11 3,91 0,003 CYP1A1 NM_000499 cytochrome P450, family 1, subfamily A, polypeptide 1 3,91 0,004 MBL2 NM_000242 mannose-binding lectin (protein C) 2, soluble 3,49 0,000 CD5 NM_014207 CD5 molecule 3,18 0,002 FCER1G NM_004106 Fc fragment of IgE, high affinity I, receptor for; gamma polypeptide 3,06 0,010 GSTA2 NM_000846 glutathione S-transferase alpha 2 2,94 0,003 CYP2B6 NM_000767 cytochrome P450, family 2, subfamily B, polypeptide 6 2,91 0,035 HP NM_005143 haptoglobin 2,87 0,009 FGL1 NM_201553 -like 1 2,87 0,012 MUC12 NM_001164462 mucin 12, cell surface associated 2,87 0,011 PALMD NM_017734 palmdelphin 2,83 0,000 TAPBP NM_003190 TAP binding protein (tapasin) 2,82 0,025 OSTalpha NM_152672 organic solute transporter alpha 2,67 0,008 NUPR1 NM_001042483 nuclear protein, transcriptional regulator, 1 2,67 0,000 HS6ST1 NM_004807 6-O-sulfotransferase 1 2,65 0,013 EFNA1 NM_004428 ephrin-A1 2,65 0,000 MUC12 NM_001164462 mucin 12, cell surface associated 2,64 0,011 sulfotransferase family, cytosolic, 2A, (DHEA)- SULT2A1 NM_003167 2,63 0,009 preferring, member 1 TRIM31 NM_007028 tripartite motif containing 31 2,61 0,007 SLC22A7 NM_006672 solute carrier family 22 (organic anion transporter), member 7 2,60 0,001 SFXN3 NM_030971 sideroflexin 3 2,56 0,000 TRIM31 NM_007028 tripartite motif containing 31 2,49 0,007 HPR NM_020995 haptoglobin-related protein 2,46 0,004 RBP2 NM_004164 retinol binding protein 2, cellular 2,45 0,000 CXCL10 NM_001565 chemokine (C-X-C motif) ligand 10 2,43 0,013 TRIM29 NM_012101 tripartite motif containing 29 2,41 0,000 RARB NM_000965 retinoic acid receptor, beta 2,38 0,004 GPX2 NM_002083 glutathione peroxidase 2 (gastrointestinal) 2,37 0,021 SNORA60 NR_002986 small nucleolar RNA, H/ACA box 60 2,36 0,036 serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), SERPINA3 NM_001085 2,36 0,010 member 3 LEAP2 NM_052971 liver expressed antimicrobial peptide 2 2,35 0,000 SUSD2 NM_019601 sushi domain containing 2 2,30 0,001 solute carrier family 6 (neurotransmitter transporter, betaine/GABA), SLC6A12 NM_003044 2,29 0,000 member 12 SNORA38B NR_003706 small nucleolar RNA, H/ACA box 38B (retrotransposed) 2,29 0,040 AADAC NM_001086 arylacetamide deacetylase (esterase) 2,28 0,001 IP6K3 NM_054111 inositol hexakisphosphate kinase 3 2,28 0,001 DPYS NM_001385 dihydropyrimidinase 2,27 0,000 HPD NM_002150 4-hydroxyphenylpyruvate dioxygenase 2,27 0,000 HAO2 NM_001005783 hydroxyacid oxidase 2 (long chain) 2,25 0,005 HIF3A NM_152794 inducible factor 3, alpha subunit 2,24 0,000 44

FBLN5 NM_006329 fibulin 5 2,23 0,003 SLC2A9 NM_020041 solute carrier family 2 (facilitated glucose transporter), member 9 2,22 0,050 LRMP NM_006152 lymphoid-restricted membrane protein 2,20 0,006 INHBC NM_005538 inhibin, beta C 2,19 0,002 TRIM16L NM_001037330 tripartite motif containing 16-like 2,19 0,012 HMOX1 NM_002133 heme (decycling) 1 2,17 0,008 DHRS3 NM_004753 dehydrogenase/reductase (SDR family) member 3 2,17 0,000 PIM1 NM_002648 pim-1 oncogene 2,17 0,001 SNAI2 NM_003068 snail homolog 2 (Drosophila) 2,17 0,001 SOAT2 NM_003578 sterol O-acyltransferase 2 2,16 0,003 TRIM16 NM_006470 tripartite motif containing 16 2,16 0,003 APOL1 NM_145343 apolipoprotein L, 1 2,14 0,005 EPO NM_000799 2,13 0,000 OR2A1 NM_001005287 olfactory receptor, family 2, subfamily A, member 1 2,12 0,008 CES1P1 NR_003276 carboxylesterase 1 pseudogene 1 2,12 0,002 ABCC2 NM_000392 ATP-binding cassette, sub-family C (CFTR/MRP), member 2 2,11 0,024 PLTP NM_006227 phospholipid transfer protein 2,10 0,044 PRG4 NM_005807 4 2,09 0,001 ACSM2A NM_001010845 acyl-CoA synthetase medium-chain family member 2A 2,09 0,001 CDA NM_001785 cytidine deaminase 2,07 0,048 GPR157 NM_024980 G protein-coupled receptor 157 2,05 0,000 C1S NM_201442 complement component 1, s subcomponent 2,05 0,001 DUSP1 NM_004417 dual specificity phosphatase 1 2,05 0,006 PROZ NM_003891 protein Z, -dependent plasma glycoprotein 2,05 0,002 CYP2S1 NM_030622 cytochrome P450, family 2, subfamily S, polypeptide 1 2,04 0,047 SLC6A13 NM_016615 solute carrier family 6 (neurotransmitter transporter, GABA), member 13 2,03 0,000 CLEC2B NM_005127 C-type lectin domain family 2, member B 2,03 0,004 SCNN1A NM_001038 sodium channel, nonvoltage-gated 1 alpha 2,03 0,005 ARG1 NM_000045 arginase, liver 2,02 0,009 NPIPL3 NM_130464 complex interacting protein-like 3 2,01 0,220 TBX4 NM_018488 T-box 4 2,01 0,000 HHLA2 NM_007072 HERV-H LTR-associating 2 2,01 0,031

Downregulated

SLC6A14 NM_007231 solute carrier family 6 (amino acid transporter), member 14 -4,09 0,003 ITGA2 NM_002203 integrin, alpha 2 (CD49B, alpha 2 subunit of VLA-2 receptor) -3,90 0,000 VCAN NM_004385 versican -3,86 0,000 HIST1H2BM NM_003521 histone cluster 1, H2bm -3,80 0,005 GTSF1 NM_144594 gametocyte specific factor 1 -3,44 0,014 FGF18 NM_003862 fibroblast growth factor 18 -3,31 0,000 ITGB8 NM_002214 integrin, beta 8 -3,13 0,005 HIST2H4A NM_003548 histone cluster 2, H4a -3,09 0,001 SPRY4 NM_030964 sprouty homolog 4 (Drosophila) -3,03 0,006 DUSP6 NM_001946 dual specificity phosphatase 6 -3,01 0,000 ZNF594 NM_032530 zinc finger protein 594 -3,00 0,003 RAPGEF4 NM_007023 Rap guanine nucleotide exchange factor (GEF) 4 -3,00 0,005 CDCA7L NM_018719 cell division cycle associated 7-like -2,99 0,001 FAM111B NM_198947 family with sequence similarity 111, member B -2,95 0,000 MMP16 NM_005941 matrix metallopeptidase 16 (membrane-inserted) -2,81 0,000 PRKD1 NM_002742 protein kinase D1 -2,81 0,001 SLC39A10 NM_001127257 solute carrier family 39 (zinc transporter), member 10 -2,74 0,005 CDC6 NM_001254 cell division cycle 6 homolog (S. cerevisiae) -2,74 0,001 45

CCR6 NM_031409 chemokine (C-C motif) receptor 6 -2,74 0,001 C8orf42 NM_175075 chromosome 8 open reading frame 42 -2,68 0,000 GJA1 NM_000165 protein, alpha 1, 43kDa -2,64 0,000 DNAH14 NM_001145154 dynein, axonemal, heavy chain 14 -2,64 0,027 NTS NM_006183 neurotensin -2,63 0,003 DNAH6 NM_001370 dynein, axonemal, heavy chain 6 -2,56 0,032 HSPH1 NM_006644 heat shock 105kDa/110kDa protein 1 -2,56 0,000 FLRT3 NM_198391 fibronectin leucine rich transmembrane protein 3 -2,55 0,000 LOC375010 AK090412 ankyrin repeat domain 20 family, member A pseudogene -2,52 0,003 STXBP5 NM_001127715 syntaxin binding protein 5 (tomosyn) -2,52 0,010 GPR126 NM_020455 G protein-coupled receptor 126 -2,51 0,000 GJC1 NM_005497 , gamma 1, 45kDa -2,46 0,006 FLRT2 NM_013231 fibronectin leucine rich transmembrane protein 2 -2,42 0,005 PLD1 NM_002662 , phosphatidylcholine-specific -2,40 0,000 ZNF780B NM_001005851 zinc finger protein 780B -2,40 0,005 HIST1H2AB NM_003513 histone cluster 1, H2ab -2,38 0,002 protein-L-isoaspartate (D-aspartate) O-methyltransferase domain PCMTD1 NM_052937 -2,37 0,130 containing 1 LFNG NM_001040167 LFNG O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase -2,34 0,003 FREM1 NM_144966 FRAS1 related extracellular matrix 1 -2,33 0,000 ICAM2 NM_001099786 intercellular adhesion molecule 2 -2,31 0,015 MMS22L NM_198468 MMS22-like, DNA repair protein -2,31 0,001 ADAM28 NM_014265 ADAM metallopeptidase domain 28 -2,31 0,002 LTBP1 NM_206943 latent transforming growth factor beta binding protein 1 -2,29 0,002 SCYL3 NM_181093 SCY1-like 3 (S. cerevisiae) -2,28 0,001 LAMA4 NM_001105206 laminin, alpha 4 -2,28 0,000 HMMR NM_001142556 hyaluronan-mediated motility receptor (RHAMM) -2,28 0,000 sema domain, immunoglobulin domain (Ig), short basic domain, secreted, SEMA3D NM_152754 -2,26 0,001 (semaphorin) 3D MMP16 NM_005941 matrix metallopeptidase 16 (membrane-inserted) -2,24 0,000 SNORD50B NR_003044 small nucleolar RNA, C/D box 50B -2,23 0,004 HERC4 NM_022079 hect domain and RLD 4 -2,23 0,001 SPRY2 NM_005842 sprouty homolog 2 (Drosophila) -2,22 0,001 elongation of very long chain fatty acids (FEN1/Elo2, SUR4/Elo3, yeast)- ELOVL4 NM_022726 -2,22 0,006 like 4 THNSL1 NM_024838 threonine synthase-like 1 (S. cerevisiae) -2,21 0,001 GLS NM_014905 -2,20 0,001 PELO NM_015946 pelota homolog (Drosophila) -2,20 0,000 PUS10 NM_144709 pseudouridylate synthase 10 -2,19 0,000 NOC3L NM_022451 nucleolar complex associated 3 homolog (S. cerevisiae) -2,19 0,000 ARHGAP18 NM_033515 Rho GTPase activating protein 18 -2,18 0,000 ESCO2 NM_001017420 establishment of cohesion 1 homolog 2 (S. cerevisiae) -2,18 0,003 WDR52 NM_001164496 WD repeat domain 52 -2,18 0,004 DNAH14 NM_001145154 dynein, axonemal, heavy chain 14 -2,17 0,027 ATM NM_000051 ataxia telangiectasia mutated -2,17 0,000 ASPM NM_018136 asp (abnormal spindle) homolog, associated (Drosophila) -2,17 0,001 WASF1 NM_003931 WAS protein family, member 1 -2,16 0,004 MAP1B NM_005909 -associated protein 1B -2,16 0,003 IRAK1BP1 NM_001010844 interleukin-1 receptor-associated kinase 1 binding protein 1 -2,14 0,005 SLC22A3 NM_021977 solute carrier family 22 (extraneuronal monoamine transporter), member 3 -2,13 0,017 MCM10 NM_182751 minichromosome maintenance complex component 10 -2,13 0,006 LRRCC1 NM_033402 leucine rich repeat and coiled-coil domain containing 1 -2,12 0,001 ECHDC1 NM_001002030 enoyl CoA hydratase domain containing 1 -2,12 0,008 PKI55 AK125369 DKFZp434H1419 -2,12 0,006 46

EXO1 NM_130398 1 -2,11 0,002 PCDHB14 NM_018934 protocadherin beta 14 -2,11 0,004 FAM72D AB096683 family with sequence similarity 72, member D -2,11 0,000 TNFSF4 NM_003326 tumor necrosis factor (ligand) superfamily, member 4 -2,11 0,002 EFTUD1 NM_024580 elongation factor Tu GTP binding domain containing 1 -2,10 0,013 CP110 NM_014711 CP110 protein -2,10 0,001 FAM36A NM_198076 family with sequence similarity 36, member A -2,09 0,004 NETO2 NM_018092 neuropilin (NRP) and tolloid (TLL)-like 2 -2,08 0,001 AGTR1 NM_031850 angiotensin II receptor, type 1 -2,08 0,015 PBX3 NM_006195 pre-B-cell leukemia homeobox 3 -2,07 0,001 VPS13A NM_033305 vacuolar protein sorting 13 homolog A (S. cerevisiae) -2,07 0,002 DAXX NM_001141969 death-domain associated protein -2,07 0,048 HELLS NM_018063 helicase, lymphoid-specific -2,07 0,002 NAPEPLD NM_001122838 N-acyl phosphatidylethanolamine -2,07 0,012 INPP1 NM_001128928 inositol polyphosphate-1-phosphatase -2,06 0,000 DNA2 NM_001080449 DNA replication helicase 2 homolog (yeast) -2,06 0,001 CD47 NM_001777 CD47 molecule -2,06 0,006 HIST1H2AJ NM_021066 histone cluster 1, H2aj -2,05 0,008 RABL2A NM_013412 RAB, member of RAS oncogene family-like 2A -2,05 0,000 SLC35A1 NM_006416 solute carrier family 35 (CMP-sialic acid transporter), member A1 -2,05 0,005 CHORDC1 NM_012124 cysteine and -rich domain (CHORD) containing 1 -2,04 0,000 LZTFL1 NM_020347 leucine zipper transcription factor-like 1 -2,04 0,003 BRCA2 NM_000059 breast cancer 2, early onset -2,03 0,001 EFTUD1 NM_024580 elongation factor Tu GTP binding domain containing 1 -2,03 0,013 C6orf192 NM_052831 chromosome 6 open reading frame 192 -2,02 0,005 NCAPD3 NM_015261 non-SMC condensin II complex, subunit D3 -2,02 0,000 LPAR1 NM_057159 receptor 1 -2,02 0,014 SKA3 NM_145061 spindle and kinetochore associated complex subunit 3 -2,02 0,001 DNAH6 NM_001370 dynein, axonemal, heavy chain 6 -2,01 0,032 DNAH6 NM_001370 dynein, axonemal, heavy chain 6 -2,01 0,032 PDGFD NM_025208 platelet derived growth factor D -2,00 0,002 ZNF121 NM_001008727 zinc finger protein 121 -2,00 0,015 PCDHA5 NM_031501 protocadherin alpha 5 -2,00 0,000 WDR52 NM_001164496 WD repeat domain 52 -2,00 0,004

47

Supplementary Table 10: List of gene sets enriched in tumors treated with brivanib after development of acquired resistance by GSEA (FDR<0.05). *Forty representative top scored gene sets are shown.

NAME SIZE NES FDR q-val Reference

LIVER CANCER GENE SETS LEE_LIVER_CANCER_SURVIVAL_UP 121 2,73 0,000 MsigDB v5.0 YAMASHITA_LIVER_CANCER_STEM_CELL_DN 67 2,71 0,000 MsigDB v5.0 CHIANG_LIVER_CANCER_SUBCLASS_PROLIFERATION_DN 145 2,65 0,000 MsigDB v5.0 WOO_LIVER_CANCER_RECURRENCE_DN 78 2,59 0,000 MsigDB v5.0 CAIRO_HEPATOBLASTOMA_DN 248 2,37 0,000 MsigDB v5.0 BOYAULT_LIVER_CANCER_SUBCLASS_G123_DN 50 2,31 0,000 MsigDB v5.0 HOSHIDA_S3 241 2,21 0,000 MsigDB v5.0 YAMASHITA_LIVER_CANCER_WITH_EPCAM_DN 11 2,21 0,000 MsigDB v5.0 YE_LIVER_CANCER_INTRAHEPATIC_METS 21 1,93 0,002 MsigDB v5.0 CHIANG_LIVER_CANCER_SUBCLASS_CTNNB1 133 1,81 0,006 MsigDB v5.0

FUNCTIONAL GENE SETS (C CURATED ) 2 Reactome, keggs, cancer-related* HSIAO_LIVER_SPECIFIC_GENES 221 2,74 0,000 MsigDB v5.0 REACTOME_BIOLOGICAL_OXIDATIONS 109 2,72 0,000 MsigDB v5.0 REACTOME_PHASE_1_FUNCTIONALIZATION_OF_COMPOUNDS 64 2,68 0,000 MsigDB v5.0 KEGG_METABOLISM_OF_XENOBIOTICS_BY_CYTOCHROME_P450 54 2,58 0,000 MsigDB v5.0 REACTOME_CYTOCHROME_P450_ARRANGED_BY_SUBSTRATE_TYPE 46 2,430 0,000 MsigDB v5.0 KEGG_DRUG_METABOLISM_CYTOCHROME_P450 53 2,33 0,000 MsigDB v5.0 CHARAFE_BREAST_CANCER_BASAL_VS_MESENCHYMAL_UP 109 2,32 0,000 MsigDB v5.0 REACTOME_METABOLISM_OF_BILE_ACIDS_AND_BILE_SALTS 25 2,31 0,000 MsigDB v5.0 SU_LIVER 54 2,28 0,000 MsigDB v5.0 HOUSTIS_ROS 30 2,24 0,000 MsigDB v5.0 REACTOME_PHASE_II_CONJUGATION 45 2,23 0,000 MsigDB v5.0

REACTOME_SYNTHESIS_OF_BILE_ACIDS_AND_BILE_SALTS_VIA_7ALPHA_ 14 2,21 0,001 MsigDB v5.0 HYDROXYCHOLESTEROL

KEGG_GLYCINE_SERINE_AND_THREONINE_METABOLISM 29 2,19 0,001 MsigDB v5.0 REACTOME_SYNTHESIS_OF_BILE_ACIDS_AND_BILE_SALTS 18 2,14 0,001 MsigDB v5.0 RICKMAN_METASTASIS_DN 224 2,14 0,001 MsigDB v5.0 NAKAYAMA_SOFT_TISSUE_TUMORS_PCA2_DN 77 2,14 0,001 MsigDB v5.0 KEGG_PPAR_SIGNALING_PATHWAY 64 2,14 0,001 MsigDB v5.0 KOBAYASHI_EGFR_SIGNALING_24HR_UP 89 2,12 0,002 MsigDB v5.0 THUM_MIR21_TARGETS_HEART_DISEASE_UP 17 2,12 0,002 MsigDB v5.0 REACTOME_PHASE_1_FUNCTIONALIZATION 14 2,09 0,003 MsigDB v5.0 LEONARD_HYPOXIA 33 2,09 0,003 MsigDB v5.0 SANA_RESPONSE_TO_IFNG_UP 57 2,08 0,003 MsigDB v5.0 KEGG_STEROID_HORMONE_BIOSYNTHESIS 42 2,08 0,003 MsigDB v5.0 REACTOME_GLUTATHIONE_CONJUGATION 16 2,06 0,004 MsigDB v5.0 SENGUPTA_EBNA1_ANTICORRELATED 131 2,04 0,005 MsigDB v5.0 WANG_BARRETTS_ESOPHAGUS_AND_ESOPHAGUS_CANCER_DN 31 2,04 0,005 MsigDB v5.0 HINATA_NFKB_TARGETS_KERATINOCYTE_UP 67 2,03 0,005 MsigDB v5.0 ENGELMANN_CANCER_PROGENITORS_DN 61 2,01 0,007 MsigDB v5.0 KEGG_PHENYLALANINE_METABOLISM 15 2,01 0,007 MsigDB v5.0 HAMAI_APOPTOSIS_VIA_TRAIL_DN 111 2,00 0,007 MsigDB v5.0 KEGG_COMPLEMENT_AND_COAGULATION_CASCADES 65 2,00 0,007 MsigDB v5.0 ONDER_CDH1_TARGETS_1_UP 121 2,00 0,007 MsigDB v5.0 CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN 127 2,00 0,007 MsigDB v5.0 KEGG_PRIMARY_BILE_ACID_BIOSYNTHESIS 16 2,00 0,007 MsigDB v5.0 KEGG_PORPHYRIN_AND_CHLOROPHYLL_METABOLISM 29 1,99 0,008 MsigDB v5.0 48

REACTOME_STEROID_METABOLISM 57 1,98 0,008 MsigDB v5.0 ABE_VEGFA_TARGETS_2HR 17 1,97 0,009 MsigDB v5.0 REACTOME_RECYCLING_OF_BILE_ACIDS_AND_SALTS 10 1,96 0,010 MsigDB v5.0 KEGG_RETINOL_METABOLISM 46 1,95 0,012 MsigDB v5.0 SHEN_SMARCA2_TARGETS_DN 298 1,95 0,012 MsigDB v5.0 MANALO_HYPOXIA_UP 189 1,83 0,032 MsigDB v5.0

GENE ONTOLOGY (GO) GENE SETS MONOOXYGENASE_ACTIVITY 26 2,39 0,000 MsigDB v5.0 OXYGEN_BINDING 20 2,25 0,001 MsigDB v5.0 ALDO_KETO_REDUCTASE_ACTIVITY 11 2,05 0,030 MsigDB v5.0 ACUTE_INFLAMMATORY_RESPONSE 10 1,99 0,047 MsigDB v5.0 OXIDOREDUCTASE_ACTIVITY_GO_0016616 56 1,99 0,039 MsigDB v5.0 OXIDOREDUCTASE_ACTIVITY_ACTING_ON_CH_OH_GROUP_OF_DONORS 62 1,99 0,035 MsigDB v5.0 LIPID_CATABOLIC_PROCESS 35 1,98 0,033 MsigDB v5.0 COLLAGEN 21 1,97 0,031 MsigDB v5.0 OXIDOREDUCTASE_ACTIVITY 269 1,95 0,037 MsigDB v5.0 MONOCARBOXYLIC_ACID_METABOLIC_PROCESS 82 1,94 0,040 MsigDB v5.0 CELLULAR_LIPID_CATABOLIC_PROCESS 32 1,94 0,038 MsigDB v5.0 OXIDOREDUCTASE_ACTIVITY_GO_0016705 32 1,93 0,041 MsigDB v5.0 EXTRACELLULAR_SPACE 221 1,92 0,040 MsigDB v5.0 LIPID_METABOLIC_PROCESS 289 1,92 0,039 MsigDB v5.0 EXTRACELLULAR_REGION 400 1,92 0,039 MsigDB v5.0 ACTIVATION_OF_IMMUNE_RESPONSE 16 1,91 0,038 MsigDB v5.0 SERINE_TYPE_ENDOPEPTIDASE_ACTIVITY 35 1,89 0,045 MsigDB v5.0 STEROID_METABOLIC_PROCESS 64 1,89 0,046 MsigDB v5.0

49

Supplementary Table 11: List of genes included in the 175-gene signature of resistance to sorafenib derived from mouse tumors (FDR<0.2)

Name Cls_0up_1dn fc_res.vs.sen

ZNF257 0 2,37

FGF18 0 2,31

LRP12 0 2,30

SNORD44 0 2,28

SLC16A6 0 2,01

SNORA62 0 2,00

FREM1 0 2,00

DNA2 0 1,99

SNORD78 0 1,96

HELLS 0 1,95

ARHGAP29 0 1,92

FAM60A 0 1,91

MMP16 0 1,90

METTL2B 0 1,90

CDC6 0 1,89

FERMT1 0 1,85

SNORD4A 0 1,83

ZNF322 0 1,82

DRD5 0 1,78

SNORD20 0 1,78

SNORD75 0 1,76

DDX21 0 1,73

DUSP6 0 1,72

GOLGA8F 0 1,72

CHRNA5 0 1,63

FGFR1 0 1,63

ROCK2 0 1,62

PLCXD1 0 1,58

GABRG1 0 1,58

50

SEMA3D 0 1,58

GPR75 0 1,56

PNPT1 0 1,55

GPCPD1 0 1,55

NOC3L 0 1,54

PRKDC 0 1,53

NCAPG2 0 1,52

ZFYVE9 0 1,51

BRCA1 0 1,51

BTAF1 0 1,51

NOP56 0 1,50

STXBP4 0 1,50

HEBP1 1 -1,50

C19orf33 1 -1,51

CKB 1 -1,52

NR5A2 1 -1,53

NCF2 1 -1,53

SOCS3 1 -1,53

GAL3ST1 1 -1,54

DAO 1 -1,54

PEMT 1 -1,55

DTX4 1 -1,55

LEFTY2 1 -1,55

AMHR2 1 -1,55

SERPINA4 1 -1,55

HLA-H 1 -1,56

MGST3 1 -1,56

THRA 1 -1,56

YPEL3 1 -1,56

SLC39A5 1 -1,57

ANO3 1 -1,57

C6orf123 1 -1,57

CD151 1 -1,57

51

EFEMP2 1 -1,57

FETUB 1 -1,58

CFB 1 -1,58

KLHL38 1 -1,58

CDX2 1 -1,59

AHSG 1 -1,59

SERPINF2 1 -1,59

UNC13C 1 -1,60

C1orf210 1 -1,60

HSD17B14 1 -1,60

PLEKHG6 1 -1,61

PPP1R14A 1 -1,61

PID1 1 -1,62

SLC13A5 1 -1,62

AQP3 1 -1,62

DGAT2 1 -1,62

BMP8B 1 -1,62

TRIM29 1 -1,62

FLVCR2 1 -1,63

TMEM140 1 -1,63

MFAP4 1 -1,63

FABP1 1 -1,63

HLA-G 1 -1,63

POLD4 1 -1,64

PFKFB3 1 -1,64

SLC2A14 1 -1,65

TMEM27 1 -1,65

ID2 1 -1,65

SHC2 1 -1,65

LRMP 1 -1,66

PPP1R1A 1 -1,66

ASS1 1 -1,66

MYOM3 1 -1,66

52

TMEM141 1 -1,67

PRF1 1 -1,67

HLA-J 1 -1,67

HEY1 1 -1,67

RBP5 1 -1,68

SMAD7 1 -1,68

TMPRSS6 1 -1,68

HOXC10 1 -1,68

HDHD3 1 -1,70

HLA-A 1 -1,71

GPR157 1 -1,71

CLDN6 1 -1,71

AGPAT2 1 -1,72

MAOB 1 -1,73

A1BG 1 -1,73

GSN 1 -1,75

EPB49 1 -1,75

ADH1A 1 -1,75

REEP6 1 -1,76

LGI4 1 -1,77

ZG16 1 -1,77

RARRES3 1 -1,77

EFNA1 1 -1,78

F7 1 -1,79

UPK3A 1 -1,80

VTN 1 -1,81

UBA7 1 -1,83

ELFN1 1 -1,88

GLYATL1 1 -1,89

CX3CL1 1 -1,91

DLL4 1 -1,91

SPINT1 1 -1,91

OLFML3 1 -1,93

53

CPT1A 1 -1,95

STAP2 1 -1,97

S100A14 1 -1,98

CYP27A1 1 -1,98

LEAP2 1 -1,98

HPN 1 -2,00

APOC3 1 -2,02

AMOT 1 -2,02

OSBP2 1 -2,03

GDPD3 1 -2,03

MPP1 1 -2,04

RASL11A 1 -2,08

SERPINA5 1 -2,09

VIM 1 -2,10

TCN2 1 -2,11

EDNRB 1 -2,12

C19orf21 1 -2,14

PIK3IP1 1 -2,14

HAO2 1 -2,14

SFXN3 1 -2,18

TM4SF18 1 -2,23

KLHDC8B 1 -2,25

UNC5CL 1 -2,26

APOBEC3B 1 -2,29

TNFSF10 1 -2,30

RBP1 1 -2,32

FMO1 1 -2,39

LGALS14 1 -2,42

ADH1C 1 -2,44

AADAC 1 -2,46

SERPINA7 1 -2,51

HPX 1 -2,52

UNC93A 1 -2,57

54

GPR133 1 -2,57

FXYD1 1 -2,60

LCN15 1 -2,64

SPARC 1 -2,65

INHBE 1 -2,70

UBD 1 -2,89

PTGIS 1 -2,91

APOA4 1 -2,94

PPP1R3C 1 -2,99

NPNT 1 -3,82

FXYD3 1 -3,85

TBX4 1 -3,98

DPEP1 1 -4,05

PRR15L 1 -4,25

55

Supplementary Table 12. Association between HCC samples harboring the 175-gene signature of resistance to sorafenib with liver gene signatures* of aggressive tumors and poor prognosis.

Signatures Names Description p

CHIANG_LIVER_CANCER_SUBCLASS_PROLIFERATION Proliferation subclass HCC 0,002

BOYAULT_LIVER_CANCER_SUBCLASS_G3 G3 class < 0.001

HOSHIDA_LIVER_CANCER_META_ANALYSIS_SUBCLASS_S2 Class S2 (AKT-MYC) < 0.001

YAMASHITA_LIVER_CANCER_EpCAM EpCAM signature < 0.001

VILLANUEVA_LIVER_CANCER_KRT19 CK19 human signature 0,001

ANDERSEN_LIVER_CANCER_KRT19 CK19 rat signature 0,001

TOVAR_LIVER_CANCER_IGF1R_ACTIVATION IGF1R activation 0,002 VILLANUEVA_LIVER_CANCER_NOTCH_ACTIVATION Notch1 activation < 0.001 LEE_LIVER_CANCER_POOR_SURVIVAL Cluster A < 0.001 MINGUEZ_LIVER_CANCER_VASCULAR_INVASION Vascular invasion signature 0,002 NOVAK_LIVER_CANCER_MET MET signature 0,017 SIA_INTRAHEPATIC_CHOLANGIOCARCINOMA_SUBCLASS_PROLIFERATION Proliferation subclass ICC < 0.001

*reported in Hoshida Y, Semin Liver Dis 2010;30:35-51