Supplementary Information

Hoshida, et al., Integrative Transcriptome Analysis Reveals Common Molecular Subclasses of Human Hepatocellular Carcinoma

Data analysis Preprocess of microarray datasets: Non-HCC and replicated samples were removed based on the sample annotation attached to each dataset. To integrate the datasets generated by different microarray platforms, each probe ID was converted and collapsed into symbols (http://www.genenames.org/) by averaging the signal intensities. For Affymetrix GeneChip datasets, only probe sets with a minimal 3-fold differential expression and absolute difference >100 units across the samples were included (after applying floor and ceiling values of 20 and 16000 units, respectively). Gene filtering for two-channel cDNA array datasets was based on a minimal 2-fold differential expression across the samples and an absolute fold change >2. In addition, only having missing values in less than 20% of the samples were included. Missing values were imputated using a k-nearest neighbor algorithm (1) (ImuputeMissingValues module, GenePattern).

Identification of common HCC subclasses: i) Subclass Mapping (SubMap) Subclass Mapping (SubMap) was used to identify corresponding subclasses between the training datasets (2). The subclasses to be mapped (candidate subclasses) were defined in each dataset before collapsing into gene symbols using three unsupervised clustering methods: hierarchical clustering (HC, http://biosun1.harvard.edu/complab/dchip/), non- negative matrix factorization (3) (NMF, http://www.broad.mit.edu/cgi- bin/cancer/publications/pub_paper.cgi?mode=view&paper_id=89) and k-means clustering (kmeans function of Matlab software, Mathworks).

For the dendrogram generated by HC, the subclass splitting was traced from its root and splitting was allowed if each resulting subclass contained at least 10% of the samples in the dataset. For NMF and k-means clustering, the number of clusters tested (k) was 2 to 7, and the size threshold for candidate subclass was set at 5% of the cases in a given dataset, because these methods tend to call small distinct subclasses at smaller k.

For each clustering algorithm, candidate subclasses were mapped between datasets using Subclass Mapping algorithm (SubMap module, GenePattern). First, over-expressed marker genes of a candidate subclass in the first dataset (A) were chosen using the signal- to-noise ratio (SNR) (4). Similarly, genes in a second dataset (B) were -ordered according to the extent of over-expression in a candidate subclass in B using SNR. Enrichment of the marker genes in A in the rank-ordered gene list in B was measured using the gene set enrichment score (ES) (5), and a nominal p-value was computed by the random permutation test (n=1,000). The procedure was repeated by switching the roles for A and B, allowing the generation of an enrichment p-value. The two bi-directional p- values for each pair of the candidate subclasses were summarized using Fisher’s inverse

chi-square statistic, F (6). The significance of F was estimated based on a null distribution for F generated by randomly picking a pair of nominal p-values from the null for ES corresponding to the pair of candidate subclasses. The nominal p-values for F were adjusted by Bonferroni correction. A candidate subclass connection with Bonferroni-corrected p < 0.05 was regarded as significant (Supplementary Fig. S5). ii) HCC subclass signatures For the common subclasses defined by each clustering algorithms, meta-analysis marker genes were selected from the intersection of the three training datasets including 1950 genes. Over-expression of a gene in a subclass was measured using SNR in each dataset, and its significance was computed as a nominal p-value based on the random permutation test (n=1000). The three nominal p-values for the gene computed in the three training datasets were summarized using Fisher’s inverse chi-square statistic (6). Significance of the statistic was evaluated using a null distribution generated by picking three nominal p- values for the SNR computed in the random permutation tests and subsequently corrected using the false discovery rate (FDR) (7). An FDR of 0.005 was used as a significance threshold. The significant genes selected in all three clustering methods were regarded as the marker genes of common HCC subclasses (HCC subclass signature). iii) Prediction of HCC subclasses The property of the signal widely varies across the datasets due to platform difference, lab-to-lab/day-to-day variation, etc. This makes it practically infeasible to build a model of gene expression signal trained on one particular dataset and apply it to the rest as seen in standard machine learning prediction procedures. In addition, the meta-analysis signature is associated only by the summary statistic, F, instead of gene expression signal. To accommodate these problems, we designed a nearest neighbor- based method simply assessing the direction of change of the signature, i.e., if either of the subclass signatures is ON or OFF (NearestTemplatePrediction module, GenePattern). Briefly, a hypothetical expression pattern of each subclass (template) was defined as a vector having the same length with all subclass signature genes. In a template for a subclass, values for corresponding signature genes were set as 1 and the rest were set to 0. For each sample, a prediction was made based on the closest “template” by the cosine distance. The confidence of the prediction was evaluated as a nominal p-value based on a null distribution generated by randomly picking the same number of genes 1,000 times from the same sample’s microarray data, and corrected for multiple hypothesis testing using FDR. An FDR < 0.05 was regarded as significant.

To ensure the significance of the prediction, we evaluated if the confident predictions occur by chance. First, for each cohort, we generated 100 datasets by randomly picking the same number of genes with the subclass signature 100 times. The prediction was performed on each randomly generated dataset, and we counted how many samples received prediction with statistically significant confidence (i.e., FDR<0.05). As a summary of the results, we computed an average of the proportion of samples received high confident prediction. The randomly generated datasets yielded high confidence predictions in less than 1% of the samples, indicating no sample received a high confident prediction by chance.

Microarrays for fixed tissues A panel of 6,000-gene DASL probes was designed by prioritizing the most variable genes in previously generated microarray datasets including 24 studies, 2,149 samples, and 15 tissue types. The top 6,000 transcriptionally informative genes in this set cover 70~90% of the genes in published microarray signatures and a panel of biological pathways (8).

Hybridized array was scanned by BeadArray Reader (Illumina). Poor quality scans defined as having %P-call smaller than 65% were eliminated as described elsewhere (8), and the scanned raw data were normalized using the cubic spline algorithm (9) (IlluminaDASL pipeline, GenePattern).

Immuno-staining Immunohistochemical staining: Immunohistochemical staining was performed on 5 micron FFPE sections after antigen retrieval in a pressure cooker with NaCitrate buffer. Antibodies used were beta-catenin (1:2,000 dilution; BD), pAKT (1:100 dilution; ), and p53 (1:1,200 dilution; Immunotech) followed by detection using the Envision+ DAB system (Dako).

Immunohistochemical stains for beta-catenin, pAKT, and p53 and were evaluated by a pathologist blinded to the results of the gene expression profiling. Staining was visually assessed in at least 1,000 tumor cells in the areas of greatest immunopositivity, and the results were scored in a binary system as follows. For beta-catenin, a semi-quantititative quick multiplicative method (10) was first used assign a score to reflect both the distribution and intensity staining. Briefly, a numerical score for the percentage of cells showing membranous staining was assigned: score 0 = no positive cells, 1 = 1-4% of cells positive, 2 = 5-19%, 3 = 20-39%, 4 = 40-59%, 5 = 60-79%, 6 = 80-100% of cells positive. Intensity of staining was also assigned a score: 0 = no detectable staining, 1 = weak intensity, 2 = moderate intensity, 3 = strong intensity. The scores reflecting percentage cells positive was multiplied by the scores for the intensity of staining to yield an overall score. Cases with multiplicative scores of 12 or greater were classified as positive for strong beta-catenin staining. For pAKT, cases showing definite nuclear and/or cytoplasmic positivity in any cells were considered positive and those with no staining were considered negative. For p53, cases showing nuclear positivity in ≥ 10% of cells were considered to be positive whereas those with less than 10% of nuclei positive were considered to be negative.

Immunofluorescence staining: Cells grown on multiwell chamber slides were fixed for 20 minutes in 4% paraformaldehyde in PBS. After PBS wash, non-specific antibody binding was blocked by incubating in 1% bovine serum albumin, 3% normal goat serum, and 0.1% Triton X-100 in PBS for one hour at room temperature. Primary antibody for beta-catenin in block solution was applied at 1:2,000 dilution for 1 hour at room temperature overnight at 4˚C. After PBS washes, goat anti-mouse Alexa Fluor-546 conjugated IgG secondary antibodies (Invitrogen/Molecular Probes) was applied at 1:1000 dilution in block for one hour at room temperature. After PBS washes, slides were coverslipped with Vectashield Mounting Medium with DAPI (Vector Labs).

HCC subclass signature in HCC mouse models To search for dysregulated molecular pathways involved in the HCC subclasses, we tested whether the subclass signatures were induced in in vivo experimental models of HCC. For this purpose, we used a publicly available HCC transgenic mice dataset (11) (NCBI Gene Expression Omnibus, GSE1897). The mouse gene identifiers were converted into those of human orthologous genes using a mapping table (Jackson Laboratory, http://www.jax.org/). A total of 4,036 orthologs were identified.

We tested for over- or under-expression of the subclass signature in each of the HCC mouse models induced by E2f1, Myc, E2f1 + Myc, or Myc + Tgfa transgenes using Gene Set Enrichment Analysis (5). The S1, S2, and S3 signatures were separately mapped on the gene list rank-ordered by the expression level in each mouse model, and their deviation to either of over- or under-expression side was evaluated by Gene Set Enrichment Analysis. The p-value for the enrichment was adjusted by Bonferroni correction.

S1 signature was most strongly enriched in E2f1 transgenic mice, while S2 signature was most strongly enriched in Myc transgenic mice (Supplementary Fig. S3). In Myc + E2f1 mice, both S1 and S2 signatures were similarly showed strong enrichment. These results suggest that E2f1 activation is a common feature shared by S1 and S2, while Myc activation is a characteristic of S2 tumors. This is in agreement with the result of GSEA performed on the subclass signatures defined by a meta-analysis of clinical datasets, where E2F1 target genes are similarly enriched in S1 and S2, while MYC target genes were enriched only in S2 (Supplementary Table S7).

HCC subclass signature in human hepatoma cell lines Two transcriptome profiling studies showed that human hepatoma cell lines are classified into 2 major subclasses according to expression of AFP (12, 13). We speculated that the AFP-expressing subclass belongs to the S2 subclass. To test the hypothesis, we used a gene expression dataset profiling a panel of 17 hepatoma cell lines (12) (kindly provided by Drs. J.S. Lee and S. Thorgeirsson). Genes were rank-ordered based on differential gene expression between AFP-expressing cell lines (huh-1, Huh-6, Huh-7, HepG2, Hep3B, Hep3B-TR, Hep40, and PLC/PRF/5) and the rest (SNU-387, SNU-423, SNU- 449, SNU-475, SNU-182, SK-Hep1, HLE, HLF, and Focus), and enrichment of the S2 signature was evaluated by Gene Set Enrichment Analysis. As expected, we observed

statistically significant over-expression of the S2 signature in the AFP-expressing cell lines (FDR=0.002).

Next, we asked whether the rest of the cell lines expressed any of the subclass signatures. Interestingly, the S1 signature showed statistically significant enrichment in the AFP negative cell lines (FDR=0.002). In summary, the major 2 transcriptome-based subclasses of human HCC cell lines correspond to the S1 and S2 subclasses determined in human HCC tissues.

TGF-beta induced S1 signature in Huh7 cells To eliminate the possibility that the statistically significant S1 signature induction by TGF-beta (Fig. 3B) was solely driven by TGF-beta target genes, we removed genes belonging to the TGF-beta activation signature (TGFBETA_ALL_UP) from the S1 signature, and re-ran GSEA. We observed still significant enrichment (FDR=0.02).

References

1. Troyanskaya O, Cantor M, Sherlock G, et al. Missing value estimation methods for DNA microarrays. Bioinformatics 2001; 17: 520-5. 2. Hoshida Y, Brunet JP, Tamayo P, Golub TR, Mesirov JP. Subclass mapping: identifying common subtypes in independent disease data sets. PLoS ONE 2007; 2: e1195. 3. Brunet JP, Tamayo P, Golub TR, Mesirov JP. Metagenes and molecular pattern discovery using matrix factorization. Proc Natl Acad Sci U S A 2004; 101: 4164-9. 4. Golub TR, Slonim DK, Tamayo P, et al. Molecular classification of : class discovery and class prediction by gene expression monitoring. Science 1999; 286: 531-7. 5. Subramanian A, Tamayo P, Mootha VK, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 2005; 102: 15545-50. 6. Fisher RA. Statistical Methods for Research Workers. London: Oliver and Boyd; 1932. 7. Benjamini Y, Drai D, Elmer G, Kafkafi N, Golani I. Controlling the false discovery rate in behavior genetics research. Behav Brain Res 2001; 125: 279-84. 8. Hoshida Y, Villanueva A, Kobayashi M, et al. Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N Engl J Med 2008; 359: 1995-2004. 9. Workman C, Jensen LJ, Jarmer H, et al. A new non-linear normalization method for reducing variability in DNA microarray experiments. Genome Biol 2002; 3: research0048. 10. Detre S, Saclani Jotti G, Dowsett M. A "quickscore" method for immunohistochemical semiquantitation: validation for oestrogen in breast carcinomas. J Clin Pathol 1995; 48: 876-8. 11. Lee JS, Chu IS, Mikaelyan A, et al. Application of comparative functional genomics to identify best-fit mouse models to study human cancer. Nat Genet 2004; 36: 1306- 11. 12. Lee JS, Thorgeirsson SS. Functional and genomic implications of global gene expression profiles in cell lines from human hepatocellular cancer. Hepatology 2002; 35: 1134-43. 13. Kawai HF, Kaneko S, Honda M, Shirota Y, Kobayashi K. alpha-fetoprotein- producing hepatoma cell lines share common expression profiles of genes in various categories demonstrated by cDNA microarray analysis. Hepatology 2001; 33: 676- 91. 14. Lee JS, Chu IS, Heo J, et al. Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling. Hepatology 2004; 40: 667- 76. 15. Boyault S, Rickman DS, de Reynies A, et al. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology 2007; 45: 42- 52. 16. Chiang DY, Villanueva A, Hoshida Y, et al. Focal gains of VEGFA and molecular classification of hepatocellular carcinoma. Cancer Res 2008; 68: 6779-88. Supplementary Table S1 Datasets used for subclass definition and validation No. of Type of GEO platform Dataset Platform description Data source Reference samples microarray ID HCC-A 90 cDNA NCI/ATC Hs-OperonV2 GPL1528 GSE1898 Nat Genet 36,1306(2004) HCC-B 82 cDNA Stanford GPL2094 a) Mol Biol Cell 13,1929(2002) HCC-C 60 Oligo Affymetrix (HuGeneFL) GPL80 b) Lancet 361,923(2003) HCC-D 43 cDNA Custom N/A c) Cancer Res 64,6058(2004) HCC-E 33 cDNA NCI UniGEM2 GPL257 GSE364 Nat Med 9,416(2003) HCC-F 31 Oligo Affymetrix (U95A) GPL91 d) Cancer Res 64,7263(2004) HCC-G 57 Oligo Affymetrix (U133A) GPL96 E-TABM-36 Hepatology 45,42(2007) HCC-H 89 Oligo Affymetrix (U133 plus2) GPL570 GSE9843 Cancer Res 68,6779(2008) HCC-I 118 DASL 6k Transcriptionally Informative Gene panel GPL5474 GSE10186 GEO: National Center for Biotechnology Information's Gene Expression Omnibus (www.ncbi.nlm.nih.gov/geo/), GSE: data set accession ID in GEO, E-: data set accession ID in European Bioinformatics Institute's ArrayExpress database (http://www.ebi.ac.uk/arrayexpress/?#ae-main[0]), Oligo: one-channel oligonucleotide microarray, cDNA: two-channel cDNA microarray, DASL: DNA-mediated, Annealing, Selection, extension and Ligation (Illumina) a) http://smd.stanford.edu/cgi-bin/publication/viewPublication.pl?pub_no=107 b) http://surgery2.med.yamaguchi-u.ac.jp/research/DNAchip/hcc-recurrence/index.html c) http://www.medizin.uni-koeln.de/kliniken/pathologie/supplementaldata.html d) http://www2.genome.rcast.u-tokyo.ac.jp/HCC/ Supplementary Table S2 Summary of clinical demographics in 9 HCC datasets HCC-A HCC-B HCC-C HCC-D HCC-E HCC-F HCC-G HCC-H HCC-I No. of samples 90 82 60 43 33 31 57 89 118 Sex (male %) 79% na 73% na 97% 68% 82% 58% 81% Age 53 (12) na 63 na 51 (10) 64 (8) 62 (14) 65 (9) 58 (9) Etiology HBV 59% 83% 18% 14% 97% 32% 30% - 23% HCV 9% 5% 67% 26% - 68% 19% 100% 69% HBV+HCV 3% ------1% Alcohol 6% - - 12% - - 32% - 3% Others 4% 11% 15% 2% 3% - 5% - - Cirrhosis 50% na 60 na 82% na 63% na 70% I / II / IIIA* 0/A/B/C† I /II / III / IV* Tumor stage na na na na na na 22/28/10 9/57/5/8 35/55/12/4

G2/3/4‡ G1/2/3‡ G1/2/3/4‡ M/M+P/P† W/M/P§ G1/2/3/4‡ W/M/P§ W/M/P§ Histology na 8/31/1 4/45/10 10/22/10/1 11/19/2 10/13/8 7/51/35/7 20/41/17 24/65/16 Tumor size (cm) na na 4.0 na 7.0 [3.0.5,9] 3.1 [2.2,4.3] 7.9 (5.1) 3.5 [2.5,5.6] 2.2 [1.8,3.0] alpha-fetoprotein (ng/ml) >300, 51% na na na 113 [12,4051] na •100, 33% 18 [7,182] 38 [10,171] HBV: hepatitis B virus, HCV: hepatitis C virus, *: Cancer Study Group of Japan, †: Bercelona Clinic Liver Cancer staging system, ‡: Edmondson-Steiner grade, §: UICC tumor differentiation (Well / Moderate /Poor), Mean (SD, if available), Median [25%, 75%] na: not available Supplementary Table S3 HCC subclass signature genes Subtype GeneID Symbol Description False discovery rate HC NMF k-means S1 8826 IQGAP1 IQ motif containing GTPase activatingprotein 1 0.001 0.002 0.002 S1 6282 S100A11 S100 calcium bindingprotein A11 (calgizzarin) 0.001 0.002 0.002 S1 11031 RAB31 RAB31, member RAS oncogene family 0.001 0.002 0.002 S1 951 CD37 CD37 molecule 0.001 0.002 0.002 S1 10631 POSTN periostin, osteoblast specific factor 0.001 0.002 0.002 S1 397 ARHGDIB Rho GDP dissociation inhibitor (GDI) beta 0.001 0.002 0.002 S1 241 ALOX5AP arachidonate 5-lipoxygenase-activatingprotein 0.001 0.002 0.002 S1 7805 LAPTM5 lysosomal associated multispanning membrane 5 0.001 0.002 0.002 S1 1462 CSPG2 chondroitin sulfate 2 () 0.001 0.002 0.002 S1 10109 ARPC2 actin related protein 2/3 complex, subunit 2, 34kDa 0.001 0.002 0.002 S1 10437 IFI30 interferon, gamma-inducible protein 30 0.001 0.002 0.002 S1 1278 COL1A2 collagen, type I, alpha 2 0.001 0.002 0.002 S1 10457 GPNMB glycoprotein (transmembrane) nmb 0.001 0.002 0.002 S1 7114 TMSB4X thymosin, beta 4, X-linked 0.001 0.002 0.002 S1 301 ANXA1 A1 0.001 0.002 0.002 S1 4060 LUM lumican 0.001 0.002 0.002 S1 8099 CDK2AP1 CDK2-associated protein 1 0.001 0.002 0.002 S1 10184 LHFPL2 lipoma HMGIC fusion partner-like 2 0.001 0.002 0.002 S1 4046 LSP1 -specific protein 1 0.001 0.002 0.002 S1 10659 CUGBP2 CUG triplet repeat, RNA bindingprotein 2 0.001 0.002 0.002 S1 1075 CTSC 0.001 0.002 0.002 S1 3936 LCP1 lymphocyte cytosolic protein 1 (L-plastin) 0.001 0.002 0.002 S1 8870 IER3 immediate early response 3 0.001 0.002 0.002 S1 5788 PTPRC protein tyrosine , receptor type, C 0.001 0.002 0.002 collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, S1 1281 COL3A1 0.001 0.002 0.002 autosomal dominant) S1 4478 MSN moesin 0.001 0.002 0.002 S1 6503 SLA Src-like-adaptor 0.001 0.002 0.002 S1 3561 IL2RG interleukin 2 receptor, gamma (severe combined ) 0.001 0.002 0.002 S1 1284 COL4A2 collagen, type IV, alpha 2 0.001 0.002 0.002 S1 2669 GEM GTP bindingprotein overexpressed in skeletal muscle 0.001 0.002 0.002 S1 5355 PLP2 proteolipid protein 2 (colonic -enriched) 0.001 0.002 0.002 S1 10095 ARPC1B actin related protein 2/3 complex, subunit 1B, 41kDa 0.001 0.002 0.002 S1 1545 CYP1B1 cytochrome P450, family 1, subfamily B, polypeptide 1 0.001 0.002 0.002 S1 4256 MGP 0.001 0.002 0.002 S1 308 ANXA5 0.001 0.002 0.002 S1 1601 DAB2 disabled homolog 2, -responsive phosphoprotein 0.001 0.002 0.002 S1 30851 TAX1BP3 Tax1 (human T-cell virus type I) bindingprotein 3 0.001 0.002 0.002 S1 5552 PRG1 proteoglycan 1, secretorygranule 0.001 0.002 0.002 S1 719 C3AR1 complement component 3a receptor 1 0.001 0.002 0.002 S1 6352 CCL5 chemokine (C-C motif) ligand 5 0.001 0.002 0.002 S1 5834 PYGB , glycogen; brain 0.001 0.002 0.002 S1 7169 TPM2 tropomyosin 2 (beta) 0.001 0.002 0.002 S1 1282 COL4A1 collagen, type IV, alpha 1 0.001 0.002 0.002 S1 865 CBFB core-binding factor, beta subunit 0.001 0.002 0.002 S1 7070 THY1 Thy-1 cell surface antigen 0.001 0.002 0.002 S1 226 ALDOA aldolase A, fructose-bisphosphate 0.001 0.002 0.002 S1 3710 ITPR3 inositol 1,4,5-triphosphate receptor, type 3 0.001 0.002 0.002 S1 644 BLVRA reductase A 0.001 0.002 0.002 S1 3098 HK1 hexokinase 1 0.001 0.002 0.002 S1 963 CD53 CD53 molecule 0.001 0.002 0.002 S1 3119 HLA-DQB1 major histocompatibility complex, class II, DQ beta 1 0.001 0.002 0.002 S1 11151 CORO1A coronin, actin bindingprotein, 1A 0.001 0.002 0.002 S1 5329 PLAUR plasminogen activator, 0.001 0.002 0.002 S1 7077 TIMP2 TIMP metallopeptidase inhibitor 2 0.001 0.002 0.002 S1 4946 OAZ1 ornithine decarboxylase antizyme 1 0.001 0.002 0.002 S1 3115 HLA-DPB1 major histocompatibility complex, class II, DP beta 1 0.001 0.002 0.002 S1 3575 IL7R interleukin 7 receptor 0.001 0.002 0.002 S1 597 BCL2A1 BCL2-related protein A1 0.001 0.002 0.002 S1 7187 TRAF3 TNF receptor-associated factor 3 0.001 0.002 0.002 S1 3912 LAMB1 , beta 1 0.001 0.002 0.002 cytosolic factor 1, (chronic granulomatous disease, S1 4687 NCF1 0.001 0.002 0.002 autosomal 1) S1 4053 LTBP2 latent transforminggrowth factor beta bindingprotein 2 0.001 0.002 0.002 S1 1009 CDH11 11, type 2, OB-cadherin (osteoblast) 0.001 0.002 0.002 S1 6510 SLC1A5 solute carrier family 1 (neutral transporter), member 5 0.001 0.002 0.002 S1 688 KLF5 Kruppel-like factor 5 (intestinal) 0.001 0.002 0.002 S1 3945 LDHB B 0.001 0.002 0.002 S1 1306 COL15A1 collagen, type XV, alpha 1 0.001 0.002 0.002 S1 6925 TCF4 factor 4 0.001 0.002 0.002 S1 961 CD47 CD47 molecule 0.001 0.002 0.002 S1 1490 CTGF connective tissue growth factor 0.001 0.002 0.002 S1 4860 NP nucleoside phosphorylase 0.001 0.002 0.002 S1 3399 ID3 inhibitor of DNA binding 3, dominant negative helix-loop-helix protein 0.001 0.002 0.002 S1 3543 IGLL1 immunoglobulin lambda-like polypeptide 1 0.001 0.002 0.002 S1 9768 KIAA0101 KIAA0101 0.001 0.002 0.002 S1 2200 FBN1 fibrillin 1 0.001 0.002 0.002 S1 101 ADAM8 ADAM metallopeptidase domain 8 0.001 0.002 0.002 hypoxia-inducible factor 1, alpha subunit (basic helix-loop-helix S1 3091 HIF1A 0.001 0.002 0.002 ) S1 7188 TRAF5 TNF receptor-associated factor 5 0.001 0.002 0.002 S1 1291 COL6A1 collagen, type VI, alpha 1 0.001 0.002 0.002 S1 59 ACTA2 actin, alpha 2, smooth muscle, aorta 0.001 0.002 0.002 S1 3956 LGALS1 , galactoside-binding, soluble, 1 ( 1) 0.001 0.002 0.002 S1 10099 TSPAN3 tetraspanin 3 0.001 0.002 0.002 S1 5216 PFN1 profilin 1 0.001 0.002 0.002 S1 8439 NSMAF neutral sphingomyelinase (N-SMase) activation associated factor 0.001 0.002 0.002 S1 9296 ATP6V1F ATPase, H+ transporting, lysosomal 14kDa, V1 subunit F 0.001 0.002 0.002 S1 4054 LTBP3 latent transforminggrowth factor beta bindingprotein 3 0.001 0.002 0.002 S1 1536 CYBB cytochrome b-245, beta polypeptide (chronic granulomatous disease 0.001 0.002 0.002 S1 3118 HLA-DQA2 major histocompatibility complex, class II, DQ alpha 2 0.001 0.002 0.002 S1 3959 LGALS3BP lectin, galactoside-binding, soluble, 3 bindingprotein 0.001 0.002 0.002 S1 10577 NPC2 Niemann-Pick disease, type C2 0.001 0.002 0.002 S1 2202 EFEMP1 EGF-containing -like protein 1 0.001 0.002 0.002 S1 4131 MAP1B microtubule-associated protein 1B 0.001 0.002 0.002 S1 6876 TAGLN transgelin 0.001 0.002 0.002 S1 526 ATP6V1B2 ATPase, H+ transporting, lysosomal 56/58kDa, V1 subunit B2 0.001 0.002 0.002 S1 10540 DCTN2 dynactin 2 (p50) 0.001 0.002 0.002 S1 7852 CXCR4 chemokine (C-X-C motif) receptor 4 0.001 0.002 0.002 S1 3108 HLA-DMA major histocompatibility complex, class II, DM alpha 0.001 0.002 0.002 S1 2316 FLNA filamin A, alpha (actin bindingprotein 280) 0.001 0.002 0.002 S1 8857 FCGBP Fc fragment of IgG bindingprotein 0.001 0.002 0.002 S1 23077 MYCBP2 MYC bindingprotein 2 0.001 0.002 0.002 S1 5480 PPIC peptidylprolyl C (cyclophilin C) 0.001 0.002 0.002 S1 165 AEBP1 AE bindingprotein 1 0.001 0.002 0.002 S1 3059 HCLS1 hematopoietic cell-specific Lyn 1 0.001 0.002 0.002 S1 5066 PAM peptidylglycine alpha-amidating monooxygenase 0.001 0.002 0.002 S100 calcium binding protein A10 (annexin II ligand, calpactin I, S1 6281 S100A10 0.001 0.002 0.002 polypeptide (p11)) S1 2162 F13A1 factor XIII, A1 polypeptide 0.001 0.002 0.002 S1 713 C1QB complement component 1, q subcomponent, B chain 0.001 0.002 0.002 S1 2982 GUCY1A3 guanylate cyclase 1, soluble, alpha 3 0.001 0.002 0.002 S1 8543 LMO4 LIM domain only4 0.001 0.002 0.002 S1 6809 STX3 syntaxin 3 0.001 0.002 0.002 S1 11329 STK38 serine/threonine 38 0.001 0.002 0.002 S1 1947 EFNB1 ephrin-B1 0.001 0.002 0.002 S1 829 CAPZA1 cappingprotein (actin filament) muscle Z-line, alpha 1 0.001 0.002 0.002 S1 10200 MPHOSPH6 M-phase phosphoprotein 6 0.001 0.002 0.002 S1 171017 ZNF384 zinc finger protein 384 0.001 0.002 0.002 S1 972 CD74 CD74 molecule, major histocompatibility complex, class II invariant 0.001 0.002 0.002 S1 4681 NBL1 neuroblastoma, suppression of tumorigenicity 1 0.001 0.002 0.002 S1 977 CD151 CD151 molecule (Raph group) 0.001 0.002 0.002 methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 2, S1 10797 MTHFD2 0.001 0.002 0.002 methenyltetrahydrofolate cyclohydrolase S1 2896 GRN granulin 0.001 0.002 0.002 S1 6039 RNASE6 , RNase A family, k6 0.001 0.002 0.002 S1 1382 CRABP2 cellular retinoic acid bindingprotein 2 0.001 0.002 0.002 S1 994 CDC25B cell division cycle 25B 0.001 0.002 0.002 S1 780 DDR1 discoidin domain receptor family, member 1 0.001 0.002 0.002 S1 5585 PKN1 protein kinase N1 0.001 0.002 0.002 S1 3428 IFI16 interferon, gamma-inducible protein 16 0.001 0.002 0.002 S1 25800 SLC39A6 solute carrier family 39 (zinc transporter), member 6 0.001 0.002 0.002 S1 9088 PKMYT1 protein kinase, membrane associated tyrosine/threonine 1 0.001 0.002 0.002 inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase S1 9641 IKBKE 0.001 0.002 0.002 epsilon S1 1292 COL6A2 collagen, type VI, alpha 2 0.001 0.002 0.003 S1 2995 GYPC (Gerbich blood group) 0.001 0.002 0.002 S1 3491 CYR61 cysteine-rich, angiogenic inducer, 61 0.001 0.002 0.002 S1 8754 ADAM9 ADAM metallopeptidase domain 9 (meltrin gamma) 0.001 0.002 0.002 S1 427 ASAH1 N-acylsphingosine (acid )1 0.001 0.002 0.002 S1 2950 GSTP1 glutathione S- pi 0.001 0.002 0.002 S1 1397 CRIP2 cysteine-rich protein 2 0.001 0.002 0.002 S1 6955 TRA@ receptor alpha 0.001 0.002 0.002 S1 1290 COL5A2 collagen, type V, alpha 2 0.001 0.002 0.002 S1 11040 PIM2 pim-2 oncogene 0.001 0.002 0.002 S1 1301 COL11A1 collagen, type XI, alpha 1 0.001 0.002 0.002 S1 3492 IGH@ immunoglobulin heavy locus 0.001 0.002 0.002 S1 1808 DPYSL2 -like 2 0.001 0.002 0.002 S1 5768 QSCN6 quiescin Q6 0.001 0.002 0.002 S1 8048 CSRP3 cysteine and glycine-rich protein 3 (cardiac LIM protein) 0.001 0.002 0.002 S1 2212 FCGR2A Fc fragment of IgG, low affinity IIa, receptor (CD32) 0.001 0.002 0.002 guanine nucleotide binding protein (G protein), alpha inhibiting S1 2771 GNAI2 0.001 0.002 0.002 activitypolypeptide 2 S1 5900 RALGDS ral guanine nucleotide dissociation stimulator 0.001 0.002 0.002 S1 54 ACP5 5, tartrate resistant 0.001 0.002 0.002 S1 2533 FYB FYN bindingprotein (FYB-120/130) 0.001 0.002 0.002 S1 3514 IGKC immunoglobulin kappa constant 0.002 0.002 0.002 S1 9516 LITAF lipopolysaccharide-induced TNF factor 0.001 0.002 0.002 S1 10714 POLD3 polymerase (DNA-directed), delta 3, accessory subunit 0.001 0.002 0.002 S1 6251 RSU1 Ras suppressor protein 1 0.001 0.002 0.002 S1 8682 PEA15 phosphoprotein enriched in astrocytes 15 0.001 0.002 0.002 S1 2275 FHL3 four and a half LIM domains 3 0.001 0.002 0.002 S1 307 ANXA4 0.001 0.002 0.002 S1 915 CD3D CD3d molecule, delta (CD3-TCR complex) 0.001 0.002 0.002 S1 4074 M6PR mannose-6-phosphate receptor (cation dependent) 0.001 0.002 0.002 S1 6035 RNASE1 ribonuclease, RNase A family, 1 (pancreatic) 0.001 0.002 0.002 S1 3831 KNS2 kinesin 2 0.001 0.002 0.002 S1 3488 IGFBP5 insulin-like growth factor bindingprotein 5 0.001 0.002 0.002 S1 5311 PKD2 polycystic kidney disease 2 (autosomal dominant) 0.001 0.002 0.002 S1 1520 CTSS cathepsin S 0.002 0.002 0.002 S1 64319 FBS1 fibrosin 1 0.001 0.002 0.002 S1 1606 DGKA diacylglycerol kinase, alpha 80kDa 0.001 0.002 0.002 solute carrier family 2 (facilitated glucose/fructose transporter), S1 6518 SLC2A5 0.001 0.002 0.002 member 5 solute carrier family 7 (cationic amino acid transporter, y+ system), S1 8140 SLC7A5 0.001 0.002 0.002 member 5 S1 2526 FUT4 4 (alpha (1,3) fucosyltransferase, myeloid- 0.001 0.002 0.002 S1 991 CDC20 CDC20 cell division cycle 20 homolog(S. cerevisiae) 0.001 0.002 0.002 S1 1535 CYBA cytochrome b-245, alpha polypeptide 0.001 0.002 0.002 S1 25865 PRKD2 protein kinase D2 0.001 0.002 0.002 S1 7158 TP53BP1 tumor protein p53 bindingprotein, 1 0.001 0.002 0.002 S1 6284 S100A13 S100 calcium bindingprotein A13 0.001 0.002 0.002 S1 1854 DUT dUTP pyrophosphatase 0.001 0.002 0.002 S1 3659 IRF1 interferon regulatory factor 1 0.001 0.002 0.002 SWI/SNF related, matrix associated, actin dependent regulator of S1 6602 SMARCD1 0.001 0.002 0.002 chromatin, subfamily d, member 1 S1 358 AQP1 1 (Colton blood group) 0.001 0.002 0.002 S1 5058 PAK1 p21/Cdc42/Rac1-activated kinase 1 (STE20 homolog, yeast) 0.001 0.002 0.002 S1 1236 CCR7 chemokine (C-C motif) receptor 7 0.001 0.002 0.002 S1 9322 TRIP10 thyroid receptor interactor 10 0.001 0.002 0.002 S1 4067 LYN v-yes-1 Yamaguchi sarcoma viral related oncogene homolog 0.002 0.002 0.002 S1 381 ARF5 ADP-ribosylation factor 5 0.001 0.002 0.002 S1 10875 FGL2 -like 2 0.001 0.004 0.002 chemokine (C-X-C motif) ligand 1 ( growth stimulating S1 2919 CXCL1 0.002 0.002 0.002 activity, alpha) S1 11010 GLIPR1 GLI pathogenesis-related 1 (glioma) 0.001 0.002 0.002 S1 5708 PSMD2 proteasome (prosome, macropain) 26S subunit, non-ATPase, 2 0.001 0.002 0.002 S1 894 CCND2 cyclin D2 0.001 0.002 0.002 S1 199 AIF1 allograft inflammatory factor 1 0.001 0.002 0.002 S1 9061 PAPSS1 3'-phosphoadenosine 5'-phosphosulfate synthase 1 0.001 0.002 0.002 S1 6717 SRI sorcin 0.001 0.002 0.002 S1 4199 ME1 malic 1, NADP(+)-dependent, cytosolic 0.001 0.002 0.002 S1 23646 PLD3 D family, member 3 0.001 0.004 0.002 S1 1847 DUSP5 dual specificityphosphatase 5 0.001 0.002 0.003 S1 1785 DNM2 dynamin 2 0.001 0.002 0.002 S1 8751 ADAM15 ADAM metallopeptidase domain 15 (metargidin) 0.001 0.002 0.003 S1 3111 HLA-DOA major histocompatibility complex, class II, DO alpha 0.002 0.002 0.002 S1 2799 GNS glucosamine (N-acetyl)-6- (Sanfilippo disease IIID) 0.001 0.003 0.002 S1 1104 RCC1 regulator of condensation 1 0.001 0.002 0.002 S1 6016 RIT1 Ras-like without CAAX 1 0.001 0.004 0.002 S1 9989 PPP4R1 4, regulatory subunit 1 0.001 0.004 0.004 S1 387 RHOA ras homologgene family, member A 0.001 0.005 0.002 S1 4236 MFAP1 microfibrillar-associated protein 1 0.001 0.002 0.002 S1 483 ATP1B3 ATPase, Na+/K+ transporting, beta 3 polypeptide 0.001 0.002 0.004 S1 10544 PROCR protein C receptor, endothelial (EPCR) 0.001 0.002 0.004 S1 537 ATP6AP1 ATPase, H+ transporting, lysosomal accessoryprotein 1 0.001 0.002 0.002 DEAD/H (Asp-Glu-Ala-Asp/His) box polypeptide 11 (CHL1-like S1 1663 DDX11 0.002 0.002 0.002 helicase homolog, S. cerevisiae) S1 4015 LOX lysyl oxidase 0.001 0.004 0.002 S1 5641 LGMN legumain 0.001 0.002 0.002 S1 962 CD48 CD48 molecule 0.001 0.002 0.002 S1 3689 ITGB2 integrin, beta 2 ( receptor 3 and 4 subunit) 0.002 0.002 0.002 S1 7033 TFF3 trefoil factor 3 (intestinal) 0.002 0.002 0.002 S1 8525 DGKZ diacylglycerol kinase, zeta 104kDa 0.001 0.003 0.004 S1 54453 RIN2 Ras and Rab interactor 2 0.001 0.004 0.003 S1 7884 SLBP stem-loop(histone) bindingprotein 0.001 0.002 0.003 S1 925 CD8A CD8a molecule 0.001 0.002 0.003 S1 6118 RPA2 replication protein A2, 32kDa 0.001 0.004 0.003 S1 26206 SPAG8 sperm associated antigen 8 0.001 0.005 0.004 S1 23191 CYFIP1 cytoplasmic FMR1 interactingprotein 1 0.002 0.002 0.003 S1 7133 TNFRSF1B tumor necrosis factor receptor superfamily, member 1B 0.002 0.005 0.002 v-ral simian leukemia viral oncogene homolog B (ras related; GTP S1 5899 RALB 0.001 0.004 0.003 bindingprotein) S1 3560 IL2RB interleukin 2 receptor, beta 0.003 0.004 0.002 S1 5230 PGK1 phosphoglycerate kinase 1 0.001 0.004 0.002 S1 6348 CCL3 chemokine (C-C motif) ligand 3 0.003 0.003 0.002 S1 5500 PPP1CB , catalytic subunit, beta isoform 0.001 0.005 0.003 S1 3601 IL15RA interleukin 15 receptor, alpha 0.001 0.004 0.004 S1 6513 SLC2A1 solute carrier family 2 (facilitated glucose transporter), member 1 0.002 0.005 0.002 S1 1175 AP2S1 adaptor-related protein complex 2, sigma 1 subunit 0.002 0.002 0.004 S1 4057 LTF lactotransferrin 0.002 0.005 0.002 S1 7277 TUBA1 tubulin, alpha 1 (testis specific) 0.001 0.005 0.003 v-akt murine thymoma viral oncogene homolog 3 (protein kinase B, S1 10000 AKT3 0.004 0.002 0.002 gamma) S1 10419 PRMT5 protein methyltransferase 5 0.002 0.003 0.002 S1 3965 LGALS9 lectin, galactoside-binding, soluble, 9 (galectin 9) 0.002 0.003 0.003 S1 533 ATP6V0B ATPase, H+ transporting, lysosomal 21kDa, V0 subunit b 0.002 0.004 0.003 S1 3073 HEXA hexosaminidase A (alpha polypeptide) 0.003 0.004 0.002 S1 4087 SMAD2 SMAD, mothers against DPP homolog 2 (Drosophila) 0.001 0.004 0.004 S1 1123 CHN1 chimerin (chimaerin) 1 0.002 0.004 0.004 S1 4921 DDR2 discoidin domain receptor family, member 2 0.002 0.004 0.004 S1 5531 PPP4C protein phosphatase 4 (formerly X), catalytic subunit 0.002 0.004 0.004 collagen, type II, alpha 1 (primary osteoarthritis, spondyloepiphyseal S2 1280 COL2A1 0.003 0.002 0.001 dysplasia, congenital) S2 2719 GPC3 glypican 3 0.003 0.002 0.001 S2 174 AFP alpha-fetoprotein 0.003 0.002 0.001 S2 191 AHCY S-adenosylhomocysteine 0.003 0.002 0.001 S2 6894 TARBP1 Tar (HIV-1) RNA bindingprotein 1 0.003 0.002 0.001 S2 1820 ARID3A AT rich interactive domain 3A (BRIGHT- like) 0.003 0.002 0.001 fibroblast growth factor receptor 3 (achondroplasia, thanatophoric S2 2261 FGFR3 0.003 0.002 0.001 dwarfism) SWI/SNF related, matrix associated, actin dependent regulator of S2 6599 SMARCC1 0.003 0.002 0.001 chromatin, subfamily c, member 1 S2 6193 RPS5 ribosomal protein S5 0.003 0.002 0.001 S2 1974 EIF4A2 eukaryotic translation initiation factor 4A, isoform 2 0.003 0.002 0.001 S2 7726 TRIM26 tripartite motif-containing 26 0.003 0.002 0.001 S2 23469 PHF3 PHD finger protein 3 0.003 0.002 0.001 S2 2091 FBL fibrillarin 0.003 0.002 0.001 S2 6741 SSB Sjogren syndrome antigen B (autoantigen La) 0.003 0.002 0.001 S2 7267 TTC3 tetratricopeptide repeat domain 3 0.003 0.002 0.001 S2 3930 LBR lamin B receptor 0.003 0.002 0.001 heterogeneous nuclear ribonucleoprotein U (scaffold attachment S2 3192 HNRPU 0.003 0.002 0.001 factor A) S2 6635 SNRPE small nuclear ribonucleoprotein polypeptide E 0.003 0.002 0.001 S2 2746 GLUD1 glutamate dehydrogenase 1 0.003 0.002 0.001 S2 3481 IGF2 insulin-like growth factor 2 (somatomedin A) 0.003 0.002 0.001 S2 5597 MAPK6 mitogen-activated protein kinase 6 0.003 0.002 0.001 S2 25814 ATXN10 ataxin 10 0.003 0.002 0.001 S2 6229 RPS24 ribosomal protein S24 0.003 0.002 0.001 S2 9315 C5orf13 chromosome 5 open reading frame 13 0.003 0.002 0.001 S2 8886 DDX18 DEAD (Asp-Glu-Ala-Asp) box polypeptide 18 0.003 0.002 0.001 S2 8031 NCOA4 nuclear receptor coactivator 4 0.003 0.002 0.001 S2 1459 CSNK2A2 casein kinase 2, alpha prime polypeptide 0.003 0.002 0.001 S2 1975 EIF4B eukaryotic translation initiation factor 4B 0.005 0.002 0.001 S2 7175 TPR translocated promoter region (to activated MET oncogene) 0.003 0.002 0.001 S2 1434 CSE1L CSE1 chromosome segregation 1-like (yeast) 0.003 0.002 0.001 SWI/SNF related, matrix associated, actin dependent regulator of S2 6594 SMARCA1 0.003 0.002 0.001 chromatin, subfamily a, member 1 solute carrier family 6 ( transporter, noradrenalin), S2 6530 SLC6A2 0.003 0.002 0.001 member 2 S2 6223 RPS19 ribosomal protein S19 0.003 0.002 0.001 S2 9777 TM9SF4 transmembrane 9 superfamilyprotein member 4 0.003 0.002 0.001 S2 23076 KIAA0179 KIAA0179 0.003 0.002 0.001 S2 10276 NET1 neuroepithelial cell transforminggene 1 0.003 0.002 0.001 S2 9152 SLC6A5 solute carrier family 6 (neurotransmitter transporter, glycine), 0.003 0.002 0.001 S2 7073 TIAL1 TIA1 cytotoxic granule-associated RNA bindingprotein-like 1 0.003 0.002 0.001 S2 1119 CHKA choline kinase alpha 0.003 0.002 0.001 S2 3156 HMGCR 3-hydroxy-3-methylglutaryl- reductase 0.003 0.002 0.001 S2 120 ADD3 adducin 3 (gamma) 0.003 0.002 0.001 S2 8019 BRD3 bromodomain containing3 0.003 0.002 0.001 S2 5178 PEG3 paternally expressed 3 0.003 0.002 0.001 S2 2065 ERBB3 v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (avian) 0.003 0.002 0.001 S2 2909 GRLF1 receptor DNA binding factor 1 0.003 0.002 0.001 S2 10950 BTG3 BTG family, member 3 0.003 0.002 0.001 S2 491 ATP2B2 ATPase, Ca++ transporting, plasma membrane 2 0.003 0.002 0.001 S2 5867 RAB4A RAB4A, member RAS oncogene family 0.003 0.002 0.001 S2 3422 IDI1 isopentenyl-diphosphate delta isomerase 1 0.003 0.002 0.001 S2 23456 ABCB10 ATP-binding cassette, sub-family B (MDR/TAP), member 10 0.003 0.002 0.001 S2 3093 HIP2 huntingtin interactingprotein 2 0.003 0.002 0.001 S2 5468 PPARG peroxisome proliferative activated receptor, gamma 0.005 0.002 0.001 S2 7159 TP53BP2 tumor protein p53 bindingprotein, 2 0.003 0.002 0.001 S2 1525 CXADR coxsackie virus and adenovirus receptor 0.003 0.002 0.001 S2 5364 PLXNB1 plexin B1 0.003 0.002 0.001 S2 22794 CASC3 cancer susceptibility candidate 3 0.003 0.002 0.001 S2 1362 CPD D 0.003 0.002 0.001 S2 1386 ATF2 activating transcription factor 2 0.003 0.002 0.001 S2 490 ATP2B1 ATPase, Ca++ transporting, plasma membrane 1 0.003 0.002 0.001 S2 2317 FLNB filamin B, beta (actin bindingprotein 278) 0.003 0.002 0.001 S2 6152 RPL24 ribosomal protein L24 0.003 0.002 0.001 S2 3181 HNRPA2B1 heterogeneous nuclear ribonucleoprotein A2/B1 0.003 0.002 0.001 S2 7913 DEK DEK oncogene (DNA binding) 0.003 0.002 0.001 S2 1653 DDX1 DEAD (Asp-Glu-Ala-Asp) box polypeptide 1 0.003 0.002 0.001 S2 4059 BCAM basal molecule (Lutheran blood group) 0.003 0.002 0.001 S2 1457 CSNK2A1 casein kinase 2, alpha 1 polypeptide 0.005 0.002 0.001 S2 6160 RPL31 ribosomal protein L31 0.003 0.002 0.001 S2 9584 RBM39 RNA binding motif protein 39 0.003 0.002 0.001 S2 9774 BCLAF1 BCL2-associated transcription factor 1 0.003 0.002 0.001 S2 4232 MEST mesoderm specific transcript homolog(mouse) 0.003 0.002 0.001 S2 7072 TIA1 TIA1 cytotoxic granule-associated RNA bindingprotein 0.003 0.002 0.001 S2 2976 GTF3C2 general transcription factor IIIC, polypeptide 2, beta 110kDa 0.003 0.002 0.001 S2 6905 TBCE tubulin-specific e 0.003 0.002 0.001 S2 51274 KLF3 Kruppel-like factor 3 (basic) 0.003 0.002 0.001 S2 3005 H1F0 H1 histone family, member 0 0.003 0.002 0.001 S2 22929 SEPHS1 selenophosphate synthetase 1 0.003 0.002 0.001 S2 4179 CD46 CD46 molecule, complement regulatoryprotein 0.003 0.002 0.001 S2 9972 NUP153 nucleoporin 153kDa 0.003 0.002 0.001 S2 23509 POFUT1 protein O-fucosyltransferase 1 0.003 0.002 0.001 S2 6155 RPL27 ribosomal protein L27 0.003 0.002 0.001 S2 1021 CDK6 cyclin-dependent kinase 6 0.003 0.005 0.001 S2 6230 RPS25 ribosomal protein S25 0.003 0.002 0.001 S2 7181 NR2C1 nuclear receptor subfamily 2, group C, member 1 0.005 0.002 0.001 S2 1196 CLK2 CDC-like kinase 2 0.003 0.002 0.001 S2 3698 ITIH2 inter-alpha (globulin) inhibitor H2 0.003 0.002 0.001 (formerly 2A), regulatory subunit A (PR 65), S2 5518 PPP2R1A 0.005 0.002 0.001 alpha isoform S2 2264 FGFR4 fibroblast growth factor receptor 4 0.003 0.002 0.001 S2 2033 EP300 E1A bindingprotein p300 0.003 0.002 0.001 S2 5256 PHKA2 phosphorylase kinase, alpha 2 (liver) 0.003 0.002 0.001 S2 6232 RPS27 ribosomal protein S27 (metallopanstimulin 1) 0.003 0.002 0.001 S2 53635 PTOV1 prostate tumor overexpressed gene 1 0.003 0.002 0.001 S2 5279 PIGC phosphatidylinositol glycan anchor , class C 0.003 0.002 0.001 S2 6721 SREBF2 sterol regulatory element binding transcription factor 2 0.003 0.002 0.001 S2 8729 GBF1 golgi-specific brefeldin A resistance factor 1 0.003 0.002 0.001 S2 52 ACP1 acid phosphatase 1, soluble 0.003 0.002 0.001 syntrophin, beta 1 (dystrophin-associated protein A1, 59kDa, basic S2 6641 SNTB1 0.003 0.002 0.001 component 1) S2 4907 NT5E 5'-, ecto (CD73) 0.003 0.002 0.001 S2 3482 IGF2R insulin-like growth factor 2 receptor 0.003 0.002 0.001 S2 5411 PNN pinin, desmosome associated protein 0.003 0.002 0.001 S2 9931 HELZ helicase with zinc finger 0.003 0.002 0.001 S2 7341 SUMO1 SMT3 suppressor of mif two 3 homolog 1 (S. cerevisiae) 0.003 0.002 0.001 S2 10935 PRDX3 peroxiredoxin 3 0.003 0.002 0.001 S2 23512 SUZ12 suppressor of zeste 12 homolog(Drosophila) 0.005 0.002 0.001 ataxia telangiectasia mutated (includes complementation groups A, S2 472 ATM 0.003 0.002 0.001 C and D) S2 1499 CTNNB1 catenin (cadherin-associated protein), beta 1, 88kDa 0.003 0.002 0.002 S2 5167 ENPP1 ectonucleotide pyrophosphatase/ 1 0.003 0.002 0.001 S2 2969 GTF2I general transcription factor II, i 0.003 0.002 0.001 S2 8451 CUL4A cullin 4A 0.003 0.002 0.003 S2 5825 ABCD3 ATP-binding cassette, sub-family D (ALD), member 3 0.003 0.005 0.001 S2 2494 NR5A2 nuclear receptor subfamily 5, group A, member 2 0.003 0.002 0.001 S2 515 ATP5F1 ATP synthase, H+ transporting, mitochondrial F0 complex, subunit 0.003 0.005 0.001 guanine nucleotide binding protein (G protein), alpha inhibiting S2 2770 GNAI1 0.005 0.004 0.001 activitypolypeptide 1 S2 10985 GCN1L1 GCN1 general control of amino-acid synthesis 1-like 1 (yeast) 0.003 0.002 0.001 S2 24144 TFIP11 tuftelin interactingprotein 11 0.005 0.002 0.002 S2 3183 HNRPC heterogeneous nuclear ribonucleoprotein C (C1/C2) 0.003 0.002 0.001 S3 10249 GLYAT glycine-N-acyltransferase 0.002 0.001 0.001 S3 462 SERPINC1 serpin peptidase inhibitor, clade C (antithrombin), member 1 0.002 0.001 0.001 S3 346 APOC4 apolipoprotein C-IV 0.002 0.001 0.001 methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1, S3 4522 MTHFD1 methenyltetrahydrofolate cyclohydrolase, formyltetrahydrofolate 0.002 0.001 0.001 synthetase S3 2875 GPT glutamic-pyruvate transaminase (alanine aminotransferase) 0.002 0.001 0.001 S3 3242 HPD 4-hydroxyphenylpyruvate dioxygenase 0.002 0.001 0.001 serpin peptidase inhibitor, clade G (C1 inhibitor), member 1, S3 710 SERPING1 0.002 0.001 0.001 (angioedema, hereditary) dolichyl-phosphate (UDP-N-acetylglucosamine) N- S3 1798 DPAGT1 0.002 0.001 0.001 acetylglucosaminephosphotransferase 1 (GlcNAc-1-P transferase) S3 5105 PCK1 phosphoenolpyruvate carboxykinase 1 (soluble) 0.002 0.001 0.001 S3 3081 HGD homogentisate 1,2-dioxygenase (homogentisate oxidase 0.002 0.001 0.001 S3 1559 CYP2C9 cytochrome P450, family 2, subfamily C, polypeptide 9 0.002 0.001 0.001 S3 1666 DECR1 2,4-dienoyl CoA reductase 1, mitochondria 0.002 0.001 0.001 S3 4329 ALDH6A1 aldehyde dehydrogenase 6 family, member A1 0.002 0.001 0.001 S3 1528 CYB5A cytochrome b5 type A (microsomal) 0.002 0.001 0.001 S3 563 AZGP1 alpha-2-glycoprotein 1, zinc 0.002 0.001 0.001 S3 716 C1S complement component 1, s subcomponent 0.002 0.001 0.001 S3 6647 SOD1 superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 0.002 0.001 0.001 S3 1066 CES1 1 (/ serine 1) 0.002 0.001 0.001 S3 2160 F11 coagulation factor XI (plasma thromboplastin antecedent) 0.002 0.001 0.001 S3 3033 HADHSC L-3-hydroxyacyl-Coenzyme A dehydrogenase, short chain 0.002 0.001 0.001 S3 1361 CPB2 carboxypeptidase B2 (plasma, carboxypeptidase U) 0.002 0.001 0.001 S3 5106 PCK2 phosphoenolpyruvate carboxykinase 2 (mitochondrial) 0.002 0.001 0.001 S3 5446 PON3 3 0.002 0.001 0.001 S3 325 APCS amyloid P component, serum 0.002 0.001 0.001 S3 5096 PCCB propionyl Coenzyme A carboxylase, beta polypeptide 0.002 0.001 0.001 inter-alpha (globulin) inhibitor H4 (plasma Kallikrein-sensitive S3 3700 ITIH4 0.002 0.001 0.001 glycoprotein) isovaleryl Coenzyme A dehydrogenase S3 229 ALDOB aldolase B, fructose-bisphosphate 0.002 0.001 0.001 acetyl-Coenzyme A acyltransferase 2 (mitochondrial 3-oxoacyl- S3 10449 ACAA2 0.002 0.001 0.001 Coenzyme A thiolase) S3 722 C4BPA complement component 4 bindingprotein, alpha 0.002 0.001 0.001 sulfotransferase family, cytosolic, 2A, dehydroepiandrosterone S3 6822 SULT2A1 0.002 0.001 0.001 (DHEA)-preferring, member 1 S3 1593 CYP27A1 cytochrome P450, family 27, subfamily A, polypeptide 1 0.002 0.001 0.001 S3 2180 ACSL1 acyl-CoA synthetase long-chain family member 1 0.002 0.001 0.001 S3 1491 CTH cystathionase (cystathionine gamma-) 0.002 0.001 0.001 S3 23584 VSIG2 V-set and immunoglobulin domain containing2 0.002 0.001 0.001 S3 732 C8B complement component 8, beta polypeptide 0.002 0.001 0.001 S3 8991 SELENBP1 selenium bindingprotein 1 0.002 0.001 0.001 S3 5244 ABCB4 ATP-binding cassette, sub-family B (MDR/TAP), member 4 0.002 0.001 0.001 S3 847 CAT catalase 0.002 0.001 0.001 S3 90338 ZNF160 zinc finger protein 160 0.002 0.001 0.001 S3 715 C1R complement component 1, r subcomponent 0.002 0.001 0.001 dodecenoyl-Coenzyme A delta isomerase (3,2 trans-enoyl- S3 1632 DCI 0.002 0.001 0.001 Coenzyme A isomerase) S3 48 ACO1 aconitase 1, soluble 0.002 0.001 0.001 S3 5095 PCCA propionyl Coenzyme A carboxylase, alpha polypeptide 0.002 0.001 0.001 S3 211 ALAS1 aminolevulinate, delta-, synthase 1 0.002 0.001 0.001 S3 9963 SLC23A1 solute carrier family 23 (nucleobase transporters), member 1 0.002 0.001 0.001 S3 9962 SLC23A2 solute carrier family 23 (nucleobase transporters), member 2 0.002 0.001 0.001 S3 2329 FMO4 flavin containing monooxygenase 4 0.002 0.001 0.001 S3 3295 HSD17B4 hydroxysteroid (17-beta) dehydrogenase 4 0.002 0.001 0.001 S3 873 CBR1 carbonyl reductase 1 0.002 0.001 0.001 S3 4258 MGST2 microsomal glutathione S-transferase 2 0.002 0.001 0.001 S3 622 BDH1 3-hydroxybutyrate dehydrogenase, type 1 0.002 0.001 0.001 S3 51119 SBDS Shwachman-Bodian-Diamond syndrome 0.002 0.001 0.001 S3 95 ACY1 1 0.002 0.001 0.001 S3 6470 SHMT1 serine hydroxymethyltransferase 1 (soluble) 0.002 0.001 0.001 S3 7263 TST thiosulfate sulfurtransferase (rhodanese) 0.002 0.001 0.001 S3 2184 FAH fumarylacetoacetate hydrolase (fumarylacetoacetase) 0.002 0.001 0.001 S3 9104 RGN (senescence marker protein-30) 0.002 0.001 0.001 serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, S3 866 SERPINA6 0.002 0.001 0.001 antitrypsin), member 6 S3 127 ADH4 4 (class II), pi polypeptide 0.002 0.001 0.001 S3 3028 HADH2 hydroxyacyl-Coenzyme A dehydrogenase, type I 0.002 0.001 0.001 alanine-glyoxylate aminotransferase (oxalosis I; hyperoxaluria I; S3 189 AGXT 0.002 0.001 0.001 glycolicaciduria; serine-pyruvate aminotransferase) S3 10993 SDS serine dehydratase 0.002 0.001 0.001 S3 2175 FANCA Fanconi anemia, complementation groupA 0.002 0.001 0.001 S3 2052 EPHX1 epoxide hydrolase 1, microsomal (xenobiotic) 0.002 0.001 0.001 S3 635 BHMT betaine-homocysteine methyltransferase 0.002 0.001 0.001 S3 686 BTD 0.002 0.001 0.001 glutamic-oxaloacetic transaminase 2, mitochondrial (aspartate S3 2806 GOT2 0.002 0.001 0.001 aminotransferase 2) S3 1610 DAO D-amino-acid oxidase 0.002 0.001 0.001 S3 4594 MUT methylmalonyl Coenzyme A mutase 0.002 0.001 0.001 S3 217 ALDH2 aldehyde dehydrogenase 2 family(mitochondrial) 0.002 0.001 0.001 S3 26 ABP1 amiloride bindingprotein 1 (amine oxidase (copper-containing)) 0.002 0.001 0.001 S3 1573 CYP2J2 cytochrome P450, family 2, subfamily J, polypeptide 2 0.002 0.001 0.001 S3 1892 ECHS1 enoyl Coenzyme A hydratase, short chain, 1, mitochondria 0.002 0.001 0.001 S3 2266 FGG 0.002 0.001 0.001 S3 1428 CRYM crystallin, mu 0.002 0.001 0.001 S3 501 ALDH7A1 aldehyde dehydrogenase 7 family, member A1 0.002 0.001 0.001 S3 130 ADH6 alcohol dehydrogenase 6 (class V) 0.002 0.001 0.001 S3 6382 SDC1 syndecan 1 0.004 0.001 0.001 enoyl-Coenzyme A, hydratase/3-hydroxyacyl Coenzyme A S3 1962 EHHADH 0.002 0.001 0.001 dehydrogenase S3 975 CD81 CD81 molecule 0.002 0.001 0.001 S3 5053 PAH phenylalanine hydroxylase 0.002 0.001 0.001 solute carrier family 10 (sodium/bile acid cotransporter family), S3 6554 SLC10A1 0.002 0.001 0.001 member 1 S3 51 ACOX1 acyl-Coenzyme A oxidase 1, palmitoy 0.002 0.001 0.001 S3 6038 RNASE4 ribonuclease, RNase A family, 4 0.002 0.001 0.001 S3 383 ARG1 , liver 0.002 0.001 0.001 ubiquinol-cytochrome c reductase binding protein bile acid Coenzyme A: amino acid N-acyltransferase (glycine N- S3 570 BAAT 0.002 0.001 0.001 choloyltransferase) S3 10788 IQGAP2 IQ motif containing GTPase activatingprotein 2 0.002 0.001 0.001 S3 6653 SORL1 sortilin-related receptor, L(DLR class) A repeats-containing 0.002 0.001 0.001 S3 9235 IL32 interleukin 32 0.002 0.001 0.001 S3 4837 NNMT nicotinamide N-methyltransferase 0.002 0.001 0.001 S3 64129 TINAGL1 tubulointerstitial nephritis antigen-like 1 0.002 0.001 0.001 S3 23498 HAAO 3-hydroxyanthranilate 3,4-dioxygenase 0.002 0.001 0.001 sperm adhesion molecule 1 (PH-20 hyaluronidase, zona pellucida S3 6677 SPAM1 0.002 0.001 0.001 binding) S3 3084 NRG1 neuregulin 1 0.002 0.001 0.001 S3 364 AQP7 aquaporin 7 0.002 0.001 0.001 protein, beta 1, 32kDa ( 32, Charcot-Marie- S3 2705 GJB1 0.002 0.001 0.001 Tooth neuropathy, X-linked) S3 3697 ITIH1 inter-alpha (globulin) inhibitor H1 0.002 0.001 0.001 S3 6414 SEPP1 selenoprotein P, plasma, 1 0.002 0.001 0.001 S3 5342 PLGLB2 plasminogen-like B2 0.002 0.001 0.001 S3 2690 GHR growth hormone receptor 0.002 0.001 0.001 S3 9446 GSTO1 glutathione S-transferase omega 1 0.002 0.001 0.001 S3 1589 CYP21A2 cytochrome P450, family 21, subfamily A, polypeptide 2 0.002 0.001 0.001 S3 3479 IGF1 insulin-like growth factor 1 (somatomedin C) 0.002 0.001 0.001 S3 6567 SLC16A2 solute carrier family 16, member 2 (monocarboxylic acid transporter 0.002 0.001 0.001 S3 475 ATOX1 ATX1 protein 1 homolog(yeast) 0.002 0.001 0.001 S3 445 ASS argininosuccinate synthetase 0.002 0.001 0.001 S3 3273 HRG histidine-rich glycoprotein 0.002 0.001 0.001 S3 2244 FGB fibrinogen beta chain 0.002 0.001 0.001 S3 8659 ALDH4A1 aldehyde dehydrogenase 4 family, member A1 0.002 0.001 0.001 S3 2153 F5 coagulation factor V (proaccelerin, labile factor) 0.002 0.001 0.001 solute carrier family 9 (sodium/hydrogen exchanger), member 3 S3 9351 SLC9A3R2 0.002 0.001 0.001 regulator 2 S3 80781 COL18A1 collagen, type XVIII, alpha 1 0.002 0.001 0.001 S3 5340 PLG plasminogen 0.002 0.001 0.001 S3 5919 RARRES2 retinoic acid receptor responder (tazarotene induced)2 0.002 0.001 0.001 S3 9663 LPIN2 lipin 2 0.002 0.001 0.001 S3 10247 HRSP12 heat-responsive protein 12 0.002 0.001 0.001 S3 1373 CPS1 carbamoyl-phosphate synthetase 1, mitochondria 0.002 0.001 0.001 S3 388 RHOB ras homologgene family, member B 0.002 0.001 0.001 S3 5860 QDPR quinoid dihydropteridine reductase 0.002 0.001 0.001 S3 5166 PDK4 pyruvate dehydrogenase kinase, 4 0.002 0.001 0.001 S3 7009 TEGT testis enhanced gene transcript (BAX inhibitor 1) 0.002 0.001 0.001 S3 216 ALDH1A1 aldehyde dehydrogenase 1 family, member A1 0.004 0.001 0.001 S3 6514 SLC2A2 solute carrier family 2 (facilitated glucose transporter), member 2 0.002 0.001 0.001 S3 3597 IL13RA1 interleukin 13 receptor, alpha 1 0.002 0.001 0.001 S3 10140 TOB1 transducer of ERBB2, 1 0.003 0.001 0.001 S3 5295 PIK3R1 phosphoinositide-3-kinase, regulatory subunit 1 (p85 alpha) 0.002 0.001 0.001 S3 4128 MAOA monoamine oxidase A 0.002 0.001 0.001 S3 3699 ITIH3 inter-alpha (globulin) inhibitor H3 0.002 0.001 0.001 S3 1776 DNASE1L3 I-like 3 0.002 0.001 0.001 S3 10857 PGRMC1 progesterone receptor membrane component 1 0.002 0.001 0.001 S3 1381 CRABP1 cellular retinoic acid bindingprotein 1 0.002 0.001 0.001 S3 83758 RBP5 retinol bindingprotein 5, cellular 0.002 0.001 0.001 S3 4129 MAOB monoamine oxidase B 0.002 0.001 0.001 S3 629 CFB 0.002 0.001 0.001 S3 1551 CYP3A7 cytochrome P450, family 3, subfamily A, polypeptide 7 0.002 0.001 0.001 amylo-1, 6-glucosidase, 4-alpha-glucanotransferase (glycogen S3 178 AGL 0.002 0.001 0.001 debranching enzyme, glycogen storage disease type III S3 9936 CD302 CD302 molecule 0.002 0.001 0.001 S3 344 APOC2 apolipoprotein C-II 0.002 0.001 0.001 S3 1409 CRYAA crystallin, alpha A 0.002 0.001 0.001 S3 6461 SHB Src homology 2 domain containing adaptor protein B 0.003 0.001 0.001 S3 433 ASGR2 asialoglycoprotein receptor 2 0.002 0.001 0.001 S3 2646 GCKR glucokinase (hexokinase 4) regulator 0.002 0.001 0.001 S3 2939 GSTA2 glutathione S-transferase A2 0.002 0.001 0.001 S3 3931 LCAT lecithin-cholesterol acyltransferase 0.002 0.001 0.001 S3 2878 GPX3 glutathione peroxidase 3 (plasma) 0.002 0.001 0.001 S3 6919 TCEA2 transcription elongation factor A (SII), 2 0.002 0.001 0.001 S3 34 ACADM acyl-Coenzyme A dehydrogenase, C-4 to C-12 straight chain 0.002 0.001 0.001 S3 645 BLVRB B (flavin reductase (NADPH)) 0.002 0.001 0.001 metallothionein 2A S3 6999 TDO2 tryptophan 2,3-dioxygenase 0.002 0.001 0.001 S3 4729 NDUFV2 NADH dehydrogenase (ubiquinone) flavoprotein 2, 24kDa 0.002 0.001 0.001 S3 3827 KNG1 kininogen 1 0.002 0.001 0.001 S3 3764 KCNJ8 potassium inwardly-rectifying channel, subfamily J, member 8 0.002 0.001 0.001 S3 760 CA2 carbonic anhydrase II 0.002 0.001 0.001 S3 4782 NFIC nuclear factor I/C (CCAAT-binding transcription factor) 0.002 0.001 0.001 S3 51816 CECR1 cat eye syndrome chromosome region, candidate 1 0.003 0.001 0.001 S3 2954 GSTZ1 glutathione transferase zeta 1 (maleylacetoacetate isomerase) 0.002 0.001 0.001 S3 1359 CPA3 carboxypeptidase A3 (mast cell) 0.002 0.001 0.001 S3 3709 ITPR2 inositol 1,4,5-triphosphate receptor, type 2 0.002 0.001 0.001 S3 219 ALDH1B1 aldehyde dehydrogenase 1 family, member B1 0.002 0.001 0.001 S3 6390 SDHB complex, subunit B, iron sulfur (Ip) 0.002 0.001 0.001 S3 2647 BLOC1S1 biogenesis of lysosome-related organelles complex-1, subunit 1 0.002 0.001 0.001 biphenyl hydrolase-like (; breast epithelial mucin- S3 670 BPHL 0.002 0.001 0.001 associated antigen) S3 720 complement component 4A (Rodgers blood group) 0.002 0.001 0.001 S3 368 ABCC6 ATP-binding cassette, sub-family C (CFTR/MRP), member 6 0.002 0.001 0.001 S3 132 ADK kinase 0.002 0.001 0.001 S3 50717 WDR42A WD repeat domain 42A 0.002 0.001 0.001 S3 6529 SLC6A1 solute carrier family 6 (neurotransmitter transporter, GABA), member 0.002 0.001 0.001 S3 267 AMFR autocrine motility factor receptor 0.002 0.001 0.001 S3 9361 PRSS15 , serine, 15 0.002 0.001 0.001 S3 249 ALPL , liver/bone/kidney 0.002 0.001 0.001 S3 5627 PROS1 protein S (alpha) 0.002 0.001 0.001 5,10-methenyltetrahydrofolate synthetase (5-formyltetrahydrofolate S3 10588 MTHFS 0.002 0.001 0.001 cyclo-) S3 11057 ABHD2 abhydrolase domain containing2 0.002 0.001 0.001 S3 429 ASCL1 achaete-scute complex-like 1 (Drosophila) 0.002 0.001 0.001 S3 36 ACADSB acyl-Coenzyme A dehydrogenase, short/branched chain 0.002 0.001 0.001 S3 2643 GCH1 GTP cyclohydrolase 1 (dopa-responsive ) 0.002 0.001 0.001 S3 410 ARSA A 0.002 0.001 0.001 S3 3385 ICAM3 intercellular adhesion molecule 3 0.002 0.001 0.001 S3 7111 TMOD1 tropomodulin 1 0.002 0.001 0.001 S3 3570 IL6R interleukin 6 receptor 0.003 0.001 0.001 S3 3163 HMOX2 oxygenase (decycling) 2 0.002 0.001 0.001 S3 1356 CP ceruloplasmin (ferroxidase) 0.002 0.001 0.001 S3 2034 EPAS1 endothelial PAS domain protein 1 0.002 0.001 0.001 S3 350 APOH apolipoprotein H (beta-2-glycoprotein I) 0.002 0.001 0.001 S3 22924 MAPRE3 microtubule-associated protein, RP/EB family, member 3 0.002 0.001 0.001 S3 2114 ETS2 v-ets erythroblastosis virus E26 oncogene homolog 2 (avian) 0.002 0.001 0.001 solute carrier family 35 (UDP-/UDP-N- S3 23169 SLC35D1 0.002 0.001 0.001 acetylgalactosamine dual transporter), member D1 S3 5336 PLCG2 , gamma 2 (phosphatidylinositol-specific) 0.002 0.001 0.001 S3 224 ALDH3A2 aldehyde dehydrogenase 3 family, member A2 0.002 0.001 0.001 S3 275 AMT aminomethyltransferase 0.002 0.001 0.001 S3 26999 CYFIP2 cytoplasmic FMR1 interactingprotein 2 0.002 0.001 0.001 S3 2013 EMP2 epithelial 2 0.002 0.001 0.001 S3 3643 INSR 0.002 0.001 0.001 S3 7172 TPMT thiopurine S-methyltransferase 0.002 0.001 0.001 epidermal growth factor receptor (erythroblastic leukemia viral (v-erb- S3 1956 EGFR 0.002 0.001 0.001 b) oncogene homolog, avian) S3 2271 FH fumarate hydratase 0.003 0.001 0.001 S3 432 ASGR1 asialoglycoprotein receptor 1 0.002 0.001 0.001 S3 2920 CXCL2 chemokine (C-X-C motif) ligand 2 0.002 0.001 0.001 S3 5805 PTS 6-pyruvoyltetrahydropterin synthase 0.002 0.001 0.001 S3 51200 CPA4 carboxypeptidase A4 0.002 0.001 0.001 S3 435 ASL argininosuccinate lyase 0.002 0.001 0.001 S3 6307 SC4MOL sterol-C4-methyl oxidase-like 0.002 0.001 0.001 S3 2286 FKBP2 FK506 bindingprotein 2, 13kDa 0.002 0.001 0.001 S3 5236 PGM1 phosphoglucomutase 1 0.002 0.001 0.001 membrane metallo- (neutral endopeptidase, S3 4311 MME 0.002 0.001 0.001 enkephalinase, CALLA, CD10) SWI/SNF related, matrix associated, actin dependent regulator of S3 6595 SMARCA2 0.002 0.001 0.001 chromatin, subfamily a, member 2 S3 2147 F2 coagulation factor II () 0.002 0.001 0.001 S3 929 CD14 CD14 molecule 0.002 0.001 0.001 S3 4638 MYLK myosin, light polypeptide kinase 0.002 0.001 0.001 3'-phosphoadenosine 5'-phosphosulfate synthase 2 sterol O-acyltransferase (acyl-Coenzyme A: cholesterol S3 6646 SOAT1 0.002 0.001 0.001 acyltransferase) 1 S3 4781 NFIB nuclear factor I/B 0.004 0.001 0.001 S3 5320 PLA2G2A , group IIA (, synovial fluid) 0.002 0.002 0.001 aldo-keto reductase family 1, member C1 (dihydrodiol S3 1645 AKR1C1 0.004 0.001 0.001 dehydrogenase 1; 20-alpha (3-alpha)-hydroxysteroid solute carrier family 6 (neurotransmitter transporter, betaine/GABA), S3 6539 SLC6A12 0.002 0.001 0.001 member 12 S3 35 ACADS acyl-Coenzyme A dehydrogenase, C-2 to C-3 short chain 0.002 0.001 0.001 S3 57804 POLD4 polymerase (DNA-directed), delta 4 0.003 0.001 0.001 S3 8309 ACOX2 acyl-Coenzyme A oxidase 2, branched chain 0.002 0.001 0.001 solute carrier family 7 (cationic amino acid transporter, y+ system), S3 6542 SLC7A2 0.002 0.001 0.002 member 2 S3 1329 COX5B cytochrome c oxidase subunit Vb 0.004 0.001 0.001 S3 335 APOA1 apolipoprotein A-I 0.002 0.001 0.001 S3 1910 EDNRB endothelin receptor type B 0.002 0.001 0.001 S3 6648 SOD2 superoxide dismutase 2, mitochondrial 0.002 0.001 0.002 S3 7049 TGFBR3 transforminggrowth factor, beta receptor III (betaglycan, 300kDa) 0.002 0.001 0.001 S3 22949 LTB4DH B4 12-hydroxydehydrogenase 0.003 0.001 0.001 S3 6720 SREBF1 sterol regulatory element binding transcription factor 1 0.002 0.001 0.002 S3 37 ACADVL acyl-Coenzyme A dehydrogenase, very long chain 0.002 0.001 0.001 protein phosphatase 2 (formerly 2A), regulatory subunit A (PR 65), S3 5519 PPP2R1B 0.002 0.001 0.001 beta isoform S3 6578 SLCO2A1 solute carrier organic anion transporter family, member 2A1 0.002 0.001 0.001 S3 8228 PNPLA4 patatin-like phospholipase domain containing4 0.002 0.001 0.001 S3 10669 CGREF1 cell growth regulator with EF-hand domain 1 0.002 0.001 0.003 S3 2324 FLT4 fms-related tyrosine kinase 4 0.003 0.001 0.001 S3 3075 CFH complement 0.003 0.001 0.001 S3 2644 GCHFR GTP cyclohydrolase I feedback regulator 0.002 0.001 0.001 S3 3434 IFIT1 interferon-induced protein with tetratricopeptide repeats 1 0.002 0.001 0.002 S3 23365 ARHGEF12 Rho guanine nucleotide exchange factor (GEF) 12 0.003 0.001 0.001 S3 3418 IDH2 2 (NADP+), mitochondria 0.002 0.001 0.001 S3 2308 FOXO1A forkhead box O1A (rhabdomyosarcoma) 0.002 0.001 0.002 S3 1476 CSTB cystatin B (stefin B) 0.002 0.001 0.001 S3 1259 CNGA1 cyclic nucleotide gated channel alpha 1 0.002 0.001 0.001 S3 8404 SPARCL1 SPARC-like 1 (mast9, hevin) 0.002 0.001 0.001 gamma-glutamyl hydrolase (conjugase, folylpolygammaglutamyl S3 8836 GGH 0.002 0.001 0.002 hydrolase) S3 6590 SLPI secretory leukocyte peptidase inhibitor 0.003 0.001 0.001 S3 3818 KLKB1 kallikrein B, plasma (Fletcher factor) 1 0.003 0.001 0.001 S3 3612 IMPA1 inositol(myo)-1(or 4)-monophosphatase 1 0.002 0.004 0.001 S3 522 ATP5J ATP synthase, H+ transporting, mitochondrial F0 complex, subunit 0.002 0.004 0.001 S3 9513 FXR2 fragile X mental retardation, autosomal homolog2 0.002 0.001 0.001 S3 3158 HMGCS2 3-hydroxy-3-methylglutaryl-Coenzyme A synthase 2 (mitochondrial 0.002 0.001 0.002 nuclear factor of kappa light polypeptide gene enhancer in B-cells S3 4792 NFKBIA 0.003 0.001 0.001 inhibitor, alpha S3 4643 MYO1E myosin IE 0.004 0.001 0.001 S3 8564 KMO kynurenine 3-monooxygenase (kynurenine 3-hydroxylase 0.002 0.001 0.002 S3 9414 TJP2 tight junction protein 2 (zona occludens 2) 0.003 0.001 0.003 S3 1819 DRG2 developmentally regulated GTP bindingprotein 2 0.002 0.001 0.002 S3 5313 PKLR pyruvate kinase, liver and RBC 0.002 0.001 0.002 steroid-5-alpha-reductase, alpha polypeptide 1 (3-oxo-5 alpha- S3 6715 SRD5A1 0.003 0.001 0.002 steroid delta 4-dehydrogenase alpha 1) S3 1519 CTSO cathepsin O 0.002 0.002 0.001 serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, S3 12 SERPINA3 0.002 0.002 0.001 antitrypsin), member 3 S3 309 ANXA6 0.002 0.001 0.002 S3 513 ATP5D ATP synthase, H+ transporting, mitochondrial F1 complex, delta 0.003 0.004 0.001 S3 3419 IDH3A isocitrate dehydrogenase 3 (NAD+) alpha 0.003 0.004 0.001 S3 2877 GPX2 glutathione peroxidase 2 (gastrointestinal) 0.003 0.003 0.002 S3 23175 LPIN1 lipin 1 0.003 0.001 0.003 S3 9636 ISG15 ISG15 ubiquitin-like modifier 0.002 0.001 0.004 HC: hierarchycal clustering, NMF: non-negative matrix factorization Supplementary Table S4 Cox regression modeling for tumor recurrence within 1 year

Variable Hazard ratio 95% CI p-value S1 subclass 4.68 1.45 - 15.11 0.01 Tumor size > 5cm 6.34 1.83 - 22.03 0.004 Supplementary Table S5 Clinical phenotypes associated with HCC subclasses in each dataset (A) HCC-F Variable S1 (n=7) S2 (n=7) S3 (n=13) p-value Tumor size (cm) 6.0 [5.3,7.0] 6.3 [5.8, 7.0] 4.4 [3.2, 6.9] 0.10 Tumor differentiation Well 1 (14%) 0 (0%) 8 (62%) Moderate 3 (43%) 4 (57%) 5 (38%) 0.007 Poor 3 (43%) 3 (43%) 0 (0%)

(B) HCC-H Variable S1 (n=19) S2 (n=17) S3 (n=36) p-value alpha-fetoprotein (ng/ml) 43 [12,612] 132 [22,1291] 9 [4,15] 0.002 Tumor size (cm) 3.5 [2.2,5.0] 6.5 [3.0, 9.0] 3.1 [2.2, 5.1] 0.02 Tumor differentiation Well 2 (12%) 2 (14%) 14 (45%) Moderate 9 (53%) 7 (50%) 15 (48%) 0.01 Poor 6 (35%) 5 (36%) 2 (7%) Vascular invasion 13 (77%) 9 (64%) 11 (36%) 0.02

(C) HCC-I Variable S1 (n=29) S2 (n=22) S3 (n=47) p-value alpha-fetoprotein (ng/ml) 55 [15,317] 190 [42,1210] 24 [8,49] 0.001 Tumor size (cm) 2.4 [1.6,3.0] 2.4 [2.2, 3.3] 2.0 [1.7, 2.8] 0.15 Tumor differentiation Well 5 (19%) 2 (11%) 15 (37%) Moderate 15 (56%) 12 (67%) 25 (61%) 0.012 Poor 7 (26%) 4 (22%) 1 (2%) Satellite lesions 7 (26%) 3 (17%) 6 (14%) 0.40 Angiographic hypervascular stain 22 (81%) 17 (94%) 30 (71%) 0.47 Hepatitis B virus infection 7 (25%) 7 (32%) 10 (21%) 0.65 Hepatitis C virus infection 20 (71%) 13 (59%) 36 (80%) 0.33 median [25%, 75%] Wilcoxon rank sum test for continuous data, Fisher's exact test for categorical data Supplementary Table S6 Gene Set Enrichment Analysis for published HCC subclass signatures on our HCC subclasses Subtype Gene set name NES FDR Reference S1 Chiang's "Proliferation" 4.25 <0.001 a) Lee's "Poor survival" 4.13 <0.001 b) Boyault's "G1+G2+G3" 2.21 <0.001 c) Boyault's "G2+G3" 2.59 <0.001 c) Boyault's "G3" 3.49 <0.001 c) Coulouam's "Late TGF-beta" 2.27 0.003 d)

S2 Chiang's "Proliferation" 2.88 <0.001 a) Lee's "Poor survival" 4.59 <0.001 b) Boyault's "G1+G2+G3" 3.67 <0.001 c) Boyault's "G1+G2" 2.57 <0.001 c) Boyault's "G2+G3" 2.45 <0.001 c) Boyault's "G1" 3.34 <0.001 c) Boyault's "G3" 3.55 <0.001 c) Yamashita's "EpCAM positive" 3.29 <0.001 e)

S3 Lee's "Good survival" 4.50 <0.001 b) Chiang's "CTNNB1" 1.96 0.02 a) NES: normalized enrichment score, FDR: false discovery rate a) Cancer Res 68;6779,2008, b) Hepatology 40;667,2004 c) Hepatology 45;42,2007, d) Hepatology 47;2059,2008 e) Cancer Res 68,1451,2008 Novak's "Met-positive" (J Clin Invest 116;1582, FDR=0.06) and Lee's "Progenitor cell" (Nature Med 12;410, FDR=0.06) signatures showed marginal enrichment in S1. Chiang's "polysomy of " signature showed marginal enrichment in S3 (FDR=0.16) Supplementary Table S7 Gene Set Enrichment Analysis of target gene sets regulated by experimental perturbations for each HCC subclass

S1 S2 Possitive enrichment Possitive enrichment Category Gene set NES FDR Category Gene set NES FDR TGF-beta TGFBETA_ALL_UP 2.91 0.000 E2F1 CMV_IE86_UP 2.46 0.004 TGF-beta TGFBETA_EARLY_UP 3.01 0.000 E2F1 E2F1_TARGETS_CHIP 2.07 0.019 WNT KENNY_WNT_UP 2.03 0.034 Chemotherapy CHAUHAN_2ME2 2.14 0.013 EMT JECHLINGER_EMT_UP 2.38 0.005 Hematopoietic TARTE_PLASMA_BLASTIC 2.72 0.000 IL6 CROONQUIST_IL6_STROMA_UP 2.34 0.007 Hypoxia RCC_NL_UP 2.85 0.000 IL6 IL6_FIBRO_UP 2.04 0.032 Immune response GOLDRATH_CELLCYCLE 2.01 0.026 E2F1 CMV_IE86_UP 2.95 0.000 MYC MYC_HUVEC_SAGE_ARRAY_UP 1.92 0.038 E2F1 E2F1_TARGETS_CHIP 2.29 0.009 H2O2_CSBDIFF_C2 1.96 0.033 RAS CORDERO_KRAS_KNOCK_DOWN 1.98 0.041 UV UVB_NHEK1_C6 2.21 0.010 Telomerase SMITH_HTERT_UP 1.94 0.049 UV UVB_NHEK3_C2 2.02 0.024 HDAC TSA_HEPATOMA_CANCER_UP 2.16 0.016 Wound healing SERUM_FIBROBLAST_CELLCYCLE 3.41 0.000 Chemotherapy BLEO_HUMAN_LYMPH_HIGH_24HRS_UP 3.08 0.000 Chemotherapy TPA_SENS_LATE_UP 1.94 0.048 BRCA1 BRCA1_OVEREXP_DN 2.77 0.000 Chemotherapy TPA_SENS_MIDDLE_UP 2.31 0.008 Chemotherapy ET743_SARCOMA_DN 2.50 0.003 Chromatin BAF57_BT549_UP 2.07 0.028 Chemotherapy ET743_SARCOMA_72HRS_DN 2.35 0.008 Hematopoietic HADDAD_HIVSINT 2.25 0.010 Chemotherapy ET743_SARCOMA_48HRS_DN 2.28 0.009 Hematopoietic ROSS_CBF_MYH 2.29 0.008 Chemotherapy ET743_SARCOMA_24HRS_DN 2.09 0.017 Hematopoietic SASAKI_TSLC1 2.69 0.001 Hypoxia MANALO_HYPOXIA_DOWN 2.93 0.000 Hematopoietic TARTE_PLASMA_BLASTIC 2.91 0.000 IFN IFNG_5ENDOTHELIAL_DOWN 2.16 0.013 Hypoxia RCC_NL_UP 2.12 0.022 p53 P21_P53_ALL_DN 1.86 0.050 Immune response GOLDRATH_CELLCYCLE 2.27 0.009 Starvation PENG_GLUTAMINE_DOWN 3.16 0.000 Invasion, metastasis ZUCCHI_EPITHELIAL_UP 1.93 0.049 Starvation PENG_LEUCINE_DOWN 2.26 0.009 Stress response STRESS_GENOTOXIC_SPECIFIC_UP 1.93 0.049 UV UVC_XPCS_ALL_DN 2.28 0.010 Stress response STRESS_TPA_SPECIFIC_UP 1.99 0.041 UV UVB_NHEK1_DN 2.25 0.009 Wound healing SERUM_FIBROBLAST_CELLCYCLE 3.74 0.000 UV UVC_HIGH_ALL_DN 2.21 0.011 Wound healing SERUM_FIBROBLAST_CORE_UP 2.36 0.006 UV UVC_XPCS_8HR_DN 2.17 0.012 Wound healing SERUM_RESPONSE_ACTIVATED 2.46 0.003 UV UVC_TTD_4HR_DN 1.94 0.035 p53 P21_ALL_DN 2.49 0.002 Negative enrichment p53 P21_P53_ALL_DN 1.95 0.049 Category Gene set NES FDR Telomerase HTERT_DN 2.50 0.003 Chemotherapy TPA_SENS_MIDDLE_DN -2.00 0.025 TNF-alpha TNFA_5ENDOTHELIAL_DOWN 2.27 0.010 CMV CMV_24HRS_DN -3.39 0.000 Chemotherapy ET743_SARCOMA_48HRS_DN 2.07 0.028 CMV CMV_ALL_DN -3.02 0.000 CMV CMV_24HRS_DN 3.40 0.000 CMV CMV_HCMV_TIMECOURSE_24HRS_DN -1.87 0.046 CMV CMV_ALL_DN 3.61 0.000 Telomerase HTERT_DN -2.65 0.001 Hematopoietic KLEIN_PEL_DOWN 2.38 0.005 RAS CROONQUIST_RAS_STROMA_DOWN -2.18 0.010 Hypoxia MANALO_HYPOXIA_DOWN 2.27 0.009 BAF57 BAF57_BT549_UP -2.72 0.000 Negative enrichment Chemotherapy BLEO_HUMAN_LYMPH_HIGH_24HRS_UP -2.15 0.012 Category Gene set NES FDR Chemotherapy ET743_HELA_UP -2.11 0.013 Heart VENTRICLES_UP -2.65 0.002 Chromatin BRG1_SW13_UP -2.79 0.000 CMV CMV_HCMV_TIMECOURSE_12HRS_UP -2.96 0.000 CMV CMV.UV_HCMV_6HRS_UP -2.66 0.001 CMV CMV_8HRS_UP -2.52 0.001 CMV CMV_ALL_UP -2.28 0.006 dsRNA DSRNA_UP -2.05 0.018 S3 EMT JECHLINGER_EMT_UP -1.85 0.048 Negative enrichment HDAC HDACI_COLON_BUT2HRS_UP -2.29 0.006 Category Gene set NES FDR HDAC TSA_HEPATOMA_CANCER_UP -2.22 0.008 Chemotherapy TPA_SENS_LATE_UP -2.45 0.035 HDAC DAC_PANC_UP -2.13 0.012 Hematopoietic TARTE_MATURE_PC -2.59 0.001 Hematopoietic CHIARETTI_T_ALL -1.86 0.047 IFN IFNA_HCMV_6HRS_UP -3.02 0.000 IFN IFNG_5ENDOTHELIAL_UP -2.98 0.000 NES : Normalized enrichment score IFN IFNA_UV.CMV_COMMON_HCMV_6HRS_UP -2.65 0.001 FDR : False discovery rate IFN RADAEVA_IFNA_HEPATO_UP -2.49 0.001 IFN DER_IFNA_HT1080_UP -2.36 0.003 CMV : Cytomegalovirus IFN DER_IFNG_HT1080_UP -2.15 0.012 EMT : Epithelial–mesenchymal transition IFN DER_IFNB_HT1080_UP -1.92 0.036 HDAC : IL1 IL1_CORNEA_UP -1.97 0.028 IFN : Interferon IL6 CROONQUIST_IL6_STROMA_UP -2.84 0.000 IL : Interleukin IL6 IL6_FIBRO_UP -1.85 0.047 NF-kB : Nuclear factor kappa B NF-kB HINATA_NFKB_UP -2.29 0.006 TGF : Transforming growth factor TNF-alpha TNFA_5ENDOTHELIAL_UP -3.72 0.000 TNF : Tumor necrosis factor TNF-alpha TNFALPHA_4HRS_UP -2.22 0.009 UV : Ultraviolet TNF-alpha TNFALPHA_ALL_UP -1.98 0.026 dsRNA : Double-stranded RNA UV UV.CMV_UNIQUE_HCMV_6HRS_UP -2.47 0.002 UV UVB_NHEK2_UP -2.18 0.010 VEGF VEGF_MMMEC_ALL_UP -2.74 0.000 VEGF VEGF_MMMEC_3HRS_UP -2.55 0.001 VEGF VEGF_MMMEC_6HRS_UP -2.08 0.015 Supplementary Table S8 Gene Set Enrichment Analysis of manually-curated pathway gene sets for each HCC subclass Subclass Gene set NES FDR S1 Cell_cycle_KEGG 2.62 0.000 Integrin-mediated_cell_adhesion_KEGG 1.96 0.030 G1_to_S_cell_cycle_Reactome 2.00 0.045 DNA_replication_Reactome 1.86 0.049 mRNA_processing_Reactome 1.78 0.057

S2 Ribosomal_proteins 3.91 0.000 mRNA_processing_Reactome 3.69 0.000 Cell_cycle_KEGG 2.76 0.000 DNA_replication_Reactome 1.80 0.049 RNA_transcription_reactome 1.63 0.081 G1_to_S_cell_cycle_Reactome 1.67 0.084

S3 Fatty_acid_metabolism 3.34 0.000 Valine_leucine_isoleucine_degradation 2.65 0.000 Tryptophan_metabolism 2.45 0.001 Arginine_and_proline_metabolism 2.40 0.002 Propanoate_metabolism 2.03 0.014 Electron_transport_chain 1.93 0.021 Glycolysis 1.63 0.057 Gluconeogenesis 1.65 0.058 Glycine_serine_and_threonine_metabolism 1.65 0.064 Pyruvate_metabolism 1.66 0.072 NES: normalized enrichment score, FDR: false discovery rate Figure legends

Supplementary Fig. S1 (A) HCC subclass prediction in nine independent datasets using Lee’s “survival signature” defined in HCC-A (“Poor” and “Good” survival groups) (14). The proportion of the cases with confident prediction (FDR<0.05) in HCC-A, B, C, D, E, F, G, H, and I were 96%, 68%, 73%, 67%, 61%, 71%, 84%, 73% and 66%, respectively. (B) HCC subclass prediction using Boyault’s subclass signatures defined in HCC-G (G1- 6 subclasses) (15). When five subclasses (G1, 2, 3, 5, and 6) were assumed, the proportion of the cases with confident prediction (FDR<0.05) in HCC-A, B, C, D, E, F, G, H, and I were 63%, 56%, 47%, 37%, 52%, 74%, 65%, 59%, and 54%, respectively. (C) When three subclasses (G1+2, 3, 5+6) were assumed, the proportion of the cases with confident prediction (FDR<0.05) in HCC-A, B, C, D, E, F, G, H, and I were 60%, 46%, 33%, 9%, 33%, 42%, 67%, 56%, and 40%, respectively. (D) When two subclasses (G1+2+3, 5+6) were assumed, the proportion of the cases with confident prediction (FDR<0.05) in HCC-A, B, C, D, E, F, G, H, and I were 46%, 17%, 27%, 0%, 9%, 42%, 61%, 45%, and 20%, respectively. (E) HCC subclass prediction using Chiang’s subclass signatures defined in HCC-H (16). The proportion of the cases with confident prediction (FDR<0.05) in HCC-A, B, C, D, E, F, G, H, and I were 91%, 84%, 82%, 47%, 55%, 77%, 91%, 95%, and 83%, respectively. We note that very high prediction rates in the training datasets, in contrast to inconsistent prediction rate in the rest of datasets, clearly indicates over-fitting of the signature to the training datasets. FDR: false discovery rate.

Supplementary Fig. S2 (A) Overall smoothed hazard function for tumor recurrence over time for entire cases (left) and each subclass (right) in HCC-H. (B) Kaplan-Meier curve for tumor recurrence in each subclass.

Supplementary Fig. S3 HCC subclass signatures in HCC mouse models (11). Heatmap shows Bonferroni- corrected p-values for over- or under-expression of the subclass signatures computed by Gene Set Enrichment Analysis.

Supplementary Fig. S4 Estimated genomic copy number at TGFB1 locus (Affymetrix, Mapping250K Sty array, probe ID SNP_A-1959879) extracted from our previous report (16) (NCBI, Gene Expression Omnibus accession ID: GSE9845).

Supplementary Fig. S5 Subclass Mapping (SubMap) to reveal common subclasses of HCC. (A) The three training datasets were clustered independently yielding the candidate subclasses. Results of hierarchical clustering (HC) were shown. (B) Correspondence of the subclasses was determined using SubMap. Red (S1), blue (S2) and yellow (S3) indicate the three common subclasses. Thickness of the edges indicates significance of the association of candidate subclasses between datasets (Bonferroni- corrected p-value). (C) Consistency of subclassification across different clustering methods. There was no biased accumulation of the dataset in particular subclass. (D) Cophenetic correlation coefficient in NMF clustering was surveyed up to 5 subclasses to evaluate if further subclass splitting shows more robust classification. In all of the training datasets, HCC-A, B, and C, the number of 3 showed the largest coefficient, indicating the most robust classification. NMF: non-negative matrix factorization. Supplementary Fig.S1A

HCC-A HCC-B HCC-C HCC-D HCC-E

HCC-F HCC-G HCC-H HCC-I

“Good” “Poor” -3 Normalized 3 expression Supplementary Fig. S1B

HCC-A HCC-B HCC-C HCC-D HCC-E

HCC-F HCC-G HCC-H HCC-I

G1 G2 G3 G5 G6 -3 Normalized 3 expression Supplementary Fig. S1C

HCC-A HCC-B HCC-C HCC-D HCC-E

HCC-F HCC-G HCC-H HCC-I

G1,2 G3 G5,6 -3 Normalized 3 expression Supplementary Fig. S1D

HCC-A HCC-B HCC-C HCC-D HCC-E

HCC-F HCC-G HCC-H HCC-I

G1,2,3 G5,6 -3 Normalized 3 FDR 㻠 0.05 expression Supplementary Fig.S1E

HCC-A HCC-B HCC-C HCC-D HCC-E

HCC-F HCC-G HCC-H HCC-FFPE

CTNNB1 Proliferation -3 Normalized 3 Polysomy 7 Unknown FDR 㻠 0.05 expression Supplementary Fig.S2

A 0.8 0.8 0.4 rate 0.4

Recurrence 0 0 0 2 4 (yr) 0 2 4 (yr)

B 0.5 S1 S2 S3 recurrence Cumulative 0 0 2 4 (yr) Supplementary Fig. S3 E2f1 Myc Myc + E2f1 Myc + Tgfa S1 S2 S3

0.01 0.1 1.0 0.1 0.01

Negative p-value Positive association association Supplementary Fig. S4

S1 S2 S3

SNP_A-1959879

Estimated copy number > 2.7 Estimated copy number d 2.7 Supplementary Fig. S5

A Datasets A B C HCC-A HCC-B HCC-C Clustering

A A A B B B C C C A1 A3 A2 A4 B2 B1 B3 C4 C1 C2 C3 Candidate subclasses B Bonferroni- A1 A3 A2 A4 Subclass Mapping corrected B2 B1 B3 p-value 0.001 A B C A B C A B C C1 C4 C2 C3 0.01 0.1 Common subclasses Supplementary Fig. S5 (continued)

C HC S1 HCC-A NMF S2 HCC-B k-means Dataset S3 HCC-C

D 1.00

0.98 0.96 HCC-A 0.94 HCC-B 0.92 HCC-C 0.90 Cophenetic correlation 345 Number of subclasses