Transcriptional Profiles from Paired Normal Samples Offer Complementary Information on Cancer Patient Survival -- Evidence from TCGA Pan-Cancer Data

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Transcriptional Profiles from Paired Normal Samples Offer Complementary Information on Cancer Patient Survival -- Evidence from TCGA Pan-Cancer Data Supplementary Materials Xiu Huang, David Stern, and Hongyu Zhao Fig. S1. Diagram illustrating the analyses performed in this article. Fig. S2. Rand indexes comparing groupings based on clinical or genetic features with those based on gene expression data of each data type. Fig. S3. Boxplot comparing distributions of Out Of Bag Error Rate from 20 random runs for Random Forest survival model using different datasets for six cancer cohorts of the RNASeq data. Fig. S4. Barplot of the similarity levels of the sample expression barcodes versus cell type specific barcodes defined by the gene expression barcode project. Fig. S5. Barplot of the Rand indexes comparing stratifications using different types translational data and using clinical variables. Fig. S6. Boxplot of the similarity levels of the sample expression barcodes versus cell type specific barcodes defined by the gene expression barcode project. Table S1. Backer s Gamma index comparing grouping similarity of hierarchical clustering from each two of the tumor, normal and fold change data types. Table S2. Detailed list of the clinical features explanations and grouping structures. Table S3. Detailed list of the four mutually exclusive gene set modules. Table S4. Detailed list of the sample sizes of each category of patients according to the mutation patterns of the four driving modules in the 60 breast cancer patients data. Table S5. Number of patients bearing somatic mutations on key tumor driving genes in tumor samples, adjacent normal samples and both normal and tumor samples. Table S6. Top 100 gene set signatures being differentially associated with survival.

Fig. S1. Diagram illustrating the analyses performed in this article. 2

Rand 0.8 0.6 0.4 0.2 0.8 0.6 0.4 0.2 0.8 0.6 0.4 0.2 0.8 0.6 0.4 0.2 0.8 0.6 0.4 0.2 0.8 0.6 0.4 0.2 PAM50 TripleNegative er_status_by_ihc pr_status_by_ihc Fig. S2. Rand indexes comparing groupings based on clinical or genetic features with those based on gene expression data of each data type. In each panel, there are three curves representing the Rand index values for comparing clinical features with clusters derived from tumor samples (green), normal samples (blue), and expression level changes between tumor and normal samples (red) using 6,000 most varying genes, respectively. Different points of each curve correspond to clinical features clustered using k-means clustering where k is varied from 2 to 10. The statistical significance level of similarity is calculated from permutation and represented by the size of the filled circle. 2 4 6 8 10 2 4 6 8 10 k her2_status_by_ihc Histology pharmaceutical_therapy_t pharmaceutical_tx_ongoin ajcc_tumor_pathologic_pt ajcc_nodes_pathologic_pn ajcc_pathologic_tumor_st tumor_nuclei_percent tumor_necrosis_percent tumor_weight menopause_status age_at_diagnosis consent_or_death_status mut.module1 mut.module2 mut.module3 mut.module4 Mutation.Modules Data FC Tumor Normal log(p + 1e 04) log(0.1) log(0.05) log(0.01) log(0.001) 3

TCGA Breast Cancer TCGA Head and Neck Cancer TCGA Kidney Clear Cell Carcinoma Normalized OOB error rate 1.0 0.8 0.6 1.0 0.8 0.6 TCGA Liver Cancer TCGA Lung Adenocarcinoma TCGA Lung Squamous Cell Carcinoma Tumor Normal FC T+FC N+FC T+N T+N+FC Tumor Normal FC Fig. S3. Boxplot comparing distributions of Out Of Bag Error Rate from 20 random runs for Random Forest survival model using different datasets for six cancer cohorts of the RNASeq data. T+FC data N+FC T+N T+N+FC Tumor Normal FC T+FC N+FC T+N T+N+FC 4

Fig. S4. Barplot of the similarity levels of the sample expression barcodes versus cell type specific barcodes defined by the gene expression barcode project. 5

Fig. S5. Barplot of the Rand indexes comparing stratifications using different types of translational data and using clinical variables. 6

Fig. S6. Boxplot of the similarity levels of the sample expression barcodes versus cell type specific barcodes defined by the gene expression barcode project. 7

fc vs. tumor fc vs. normal tumor vs. normal Top 1000 Genes 0.13/0.04* 0.71/0* -0.04/0.695 Top 2000 Genes 0.21/0.004* 0.31/0* -0.03/0.644 Top 3000 Genes 0.09/0.105 0.28/0* -0.06/0.79 Top 4000 Genes 0.16/0.021* 0.26/0* -0.07/0.831 Top 5000 Genes 0.18/0.013* 0.26/0* -0.03/0.644 Top 6000 Genes 0.14/0.032* 0.28/0* -0.05/0.748 Top 7000 Genes 0.15/0.024* 0.23/0.002* -0.03/0.644 Top 8000 Genes 0.43/0* 0.49/0* -0.04/0.695 Top 9000 Genes 0.31/0* 0.3/0* -0.03/0.644 Top 10000 Genes 0.43/0* 0.45/0* -0.02/0.572 Top 11000 Genes 0.48/0* 0.47/0* -0.01/0.521 Top 12000 Genes 0.12/0.054 0.69/0* -0.05/0.748 Top 13000 Genes 0.22/0.002* 0.6/0* -0.06/0.79 Top 14000 Genes 0.41/0* 0.47/0* -0.04/0.695 Top 15000 Genes 0.24/0.002* 0.6/0* -0.05/0.748 Top 16000 Genes 0.24/0.002* 0.62/0* -0.05/0.748 Top 17000 Genes 0.24/0.002* 0.62/0* -0.05/0.748 Top 18000 Genes 0.25/0.001* 0.62/0* -0.05/0.748 Table S1. Backer s Gamma index comparing grouping similarity of hierarchical clustering from each two of the tumor, normal and fold change data types. Each entry in the table shows both the index value and the statistical significance of the similarity between the two clusters, i.e. smaller p-values indicating evidence suggesting similarity. 8

Clinical features Explanation Categorical sample size PAM50 A 50-gene-expression signature. 10 Basal; 4 Her2; 31 LumA; 13 LumB, 2 NA. TripleNegative Breast cancer that does not 8 TripleNegative; 50 Nonexpress ER, PR and Her2. TripleNegative; 2 NA. ER status Estrogene receptor status by 49 Positive; 9 Negative; 1 immunohistochemistry. Indeterminate; 1 NA. PR status Progesterone receptor status by 42 Positive; 16 Negative; 1 immunohistochemistry. Indeterminate; 1 NA. HER2 status Human epidermal growth factor 10 Positive; 37 Negative; 8 receptor 2 status by Equivocal; 5 NA. immunohistochemistry. Histology Sample histological type. 48 Infiltrating ductal carcinoma; 4 Infiltrating Lobular Carcinoma; 1 Mucinous Carcinoma; 5 Mixed Pharmaceutical therapy type Pharmaceutical tx ongoing indicator AJCC tumor pathologic type AJCC nodes pathologic type AJCC pathologic tumor stage Indicator of whether the pharmaceutical treatment is still ongoing. Tumor pathologic type classified by the American Joint Committee on Cancer (AJCC) system. Lymph nodes pathologic type classified by the American Joint Committee on Cancer (AJCC) system. Pathologic tumor stage classified by the American Joint Committee on Cancer (AJCC) system. Percentage of tumor cells in the histology; 2 NA. 11 Chemotherapy; 18 Hormone Therapy; 1 Chemotherapy or Hormone Therapy; 30 NA. 18 Yes; 12 No; 30 NA. 4 T1; 1 T1a; 1 T1b; 14 T1c; 30 T2; 1 T2b; 8 T3; 1 T4b. 14 N0; 11 N0(i-); 7 N1; 13 N1a; 4 N1b; 2N1c; 2 N1mi; 1 N2; 3 N2a; 1 N3; 2 N3a. 12 Stage I; 1 Stage IA; 19 Stage IIA; 16 Stage IIB; 8 Stage IIIA; 3 Stage IIIC; 1 Stage IV. Tumor nuclei percent sample. 2 60; 36 70; 3 75; 9 80; 3 85; 4 90; 3 95. Tumor necrosis Percentage of cell death in the 13 0; 1 1; 2 2; 6 5; 4 10; 1 15; 33 percent sample. 30. 11 (, 200); 25 [200,400); 15 Tumor weight [400,600); 3 [600,800); 4 [800,1000); 2 [1000, ). Menopause status 19 Pre; 1 Peri; 28 Post; 1 9

Indeterminate; 11 NA. 6 [0,40); 15 [40,50); 15 [50,60); Age at diagnosis 14 [60,70); 6 [70,80); 4 [80, ). Consent or death 46 Consented; 14 Deceased. status Table S2. Detailed list of the clinical features considered and grouping structures. The clinical features were used to group the 60 breast cancer patients into subgroups and these subgroups were compared with the groupings from hierarchical clustering using transcriptional data of tumor samples, normal samples and fold changes respectively to evaluate the clinical relevance of transcriptional signals from each source. 10

Module Name Module 1 Module 2 Module 3 Module 4 Genes in the module PTEN, AKT1, PIK3CA, PIK3R1, 12p3.33(A), HIF3A TP53, CDH1, GATA3, CTCF, GPRIN2 MAP2K4(D), MAP3K1, PPEF1, WWP2, SMARCA4 CCDN1(A), RB1, MAP2K4, GRID1 Categorical sample size 2 with PTEN mutated; 2 with AKT1 mutated; 25 with PIK3CA mutated; 1 with PIK3R1 mutated; 2 with 12p3.33(A) mutated; 1 with 12p13.33(A) and HIF3A both mutated; 1 with PTEN and PIK3R1 both mutated; 26 with this module not mutated. 16 with TP53 mutated; 2 with CDH1 mutated; 4 with GATA3 mutated; 1 with CTCF mutated; 1 with GPRIN2 mutated; 36 with this module not mutated. 4 with MAP2K4(D) mutated; 6 with MAP3K1 mutated; 1 with WWP2 mutated; 1 with SMARCA4 mutated; 48 with this module not mutated. 9 with CCDN1(A) mutated; 1 with RB1 mutated; 3 with MAP2K4 mutated; 1 with GRID1 mutated; 46 with this module not mutated. Table S3. Detailed list of the four mutually exclusive gene set modules. 11

0000 0001 0010 0011 0101 0110 0111 Number of patients 2 2 2 5 2 7 14 1000 1001 1011 1101 1110 1111 Number of patients 1 2 10 3 2 8 Table S4. Detailed list of the sample size of each category of patients according to the mutation patterns of the four driving modules in the 60 breast cancer patients data. 12

Number of patients bearing tumor only mutations Number of patients bearing adjacent normal only mutations Number of patients bearing mutations in both tissues PIK3CA 12 0 1 TP53 8 3 1 CDH1 4 0 0 MAP3K1 2 0 0 MAP2K4 2 0 2 Table S5. Number of patients bearing somatic mutations on key tumor driving genes in tumor samples, adjacent normal samples and both normal and tumor samples. 13

Immune Signatures Normal Associated Rank GeneSet p_tumor/ p_normal 1 GSE17721_LPS_VS_GARDIQUIMOD_2H_BMDM_UP 360 2 GSE17721_CTRL_VS_LPS_1H_BMDM_DN 291 3 GSE18148_CBFB_KO_VS_WT_TREG_DN 289 4 GSE17721_CTRL_VS_GARDIQUIMOD_4H_BMDM_DN 249 5 GSE1432_CTRL_VS_IFNG_1H_MICROGLIA_DN 248 6 GSE18791_CTRL_VS_NEWCASTLE_VIRUS_DC_2H_DN 217 7 GSE360_L_DONOVANI_VS_L_MAJOR_DC_UP 211 8 GSE22886_TH1_VS_TH2_12H_ACT_DN 165 9 GSE17721_CTRL_VS_LPS_4H_BMDM_DN 161 10 GSE27786_LSK_VS_ERYTHROBLAST_DN 159 11 GSE3982_CTRL_VS_LPS_1H_NEUTROPHIL_UP 150 12 GSE7460_TREG_VS_TCONV_ACT_WITH_TGFB_UP 146 13 GSE7460_TREG_VS_TCONV_ACT_UP 112 14 GSE17721_CTRL_VS_CPG_1H_BMDM_DN 110 15 GSE20715_0H_VS_24H_OZONE_LUNG_DN 108 16 GSE1460_DP_THYMOCYTE_VS_THYMIC_STROMAL_CELL_DN 84 17 GSE29614_DAY3_VS_DAY7_TIV_FLU_VACCINE_PBMC_UP 78 18 GSE29615_CTRL_VS_DAY3_LAIV_IFLU_VACCINE_PBMC_UP 69 19 GSE20366_EX_VIVO_VS_DEC205_CONVERSION_NAIVE_CD4_TCELL _DN 61 20 GSE18791_CTRL_VS_NEWCASTLE_VIRUS_DC_12H_DN 61 21 GSE20366_EX_VIVO_VS_DEC205_CONVERSION_DN 60 22 GSE17721_0.5H_VS_4H_LPS_BMDM_DN 55 23 GSE18791_CTRL_VS_NEWCASTLE_VIRUS_DC_10H_DN 54 24 GSE24081_CONTROLLER_VS_PROGRESSOR_HIV_SPECIFIC_CD8_TC ELL_UP 53 25 GSE2826_WT_VS_XID_BCELL_DN 50 26 GSE13484_UNSTIM_VS_3H_YF17D_VACCINE_STIM_PBMC_DN 47 27 GSE13411_NAIVE_VS_SWITCHED_MEMORY_BCELL_UP 46 28 GSE11924_TH1_VS_TH2_CD4_TCELL_DN 45 29 GSE360_T_GONDII_VS_M_TUBERCULOSIS_MAC_DN 45 30 GSE7460_WT_VS_FOXP3_HET_ACT_WITH_TGFB_TCONV_DN 45 31 GSE37416_CTRL_VS_3H_F_TULARENSIS_LVS_NEUTROPHIL_DN 44 32 GSE9988_LOW_LPS_VS_CTRL_TREATED_MONOCYTE_UP 43 33 GSE29618_PRE_VS_DAY7_POST_LAIV_FLU_VACCINE_PDC_UP 42 34 GSE17974_IL4_AND_ANTI_IL12_VS_UNTREATED_1H_ACT_CD4_TC 41 14

ELL_UP 35 GSE17974_0H_VS_0.5H_IN_VITRO_ACT_CD4_TCELL_DN 39 36 GSE2706_R848_VS_R848_AND_LPS_8H_STIM_DC_DN 39 37 GSE17721_CTRL_VS_PAM3CSK4_6H_BMDM_DN 38 38 GSE17974_IL4_AND_ANTI_IL12_VS_UNTREATED_6H_ACT_CD4_TC ELL_DN 38 39 GSE2706_2H_VS_8H_R848_STIM_DC_DN 38 40 GSE17721_CTRL_VS_POLYIC_1H_BMDM_DN 36 41 GSE17580_UNINFECTED_VS_S_MANSONI_INF_TREG_DN 35 42 GSE39820_CTRL_VS_IL1B_IL6_CD4_TCELL_DN 33 43 GSE17721_LPS_VS_POLYIC_2H_BMDM_UP 33 44 GSE2706_LPS_VS_R848_AND_LPS_8H_STIM_DC_DN 32 45 GSE9037_CTRL_VS_LPS_1H_STIM_IRAK4_KO_BMDM_DN 31 46 GSE20366_CD103_POS_VS_NEG_TREG_KLRG1NEG_DN 31 47 GSE13411_NAIVE_VS_IGM_MEMORY_BCELL_UP 30 48 GSE17721_CTRL_VS_GARDIQUIMOD_1H_BMDM_DN 30 49 GSE20366_TREG_VS_TCONV_UP 28 50 GSE360_L_MAJOR_VS_M_TUBERCULOSIS_MAC_DN 26 51 GSE17974_IL4_AND_ANTI_IL12_VS_UNTREATED_48H_ACT_CD4_T CELL_DN 26 52 GSE17721_PAM3CSK4_VS_GADIQUIMOD_1H_BMDM_UP 26 53 GSE27786_LIN_NEG_VS_ERYTHROBLAST_DN 25 54 GSE22886_CD8_VS_CD4_NAIVE_TCELL_UP 25 55 GSE36392_TYPE_2_MYELOID_VS_MAC_IL25_TREATED_LUNG_UP 25 56 GSE2706_R848_VS_R848_AND_LPS_2H_STIM_DC_DN 25 57 GSE360_CTRL_VS_B_MALAYI_LOW_DOSE_DC_UP 25 58 GSE7460_FOXP3_MUT_VS_WT_ACT_WITH_TGFB_TCONV_UP 25 59 GSE7460_CTRL_VS_FOXP3_OVEREXPR_TCONV_DN 24 60 GSE17721_LPS_VS_CPG_2H_BMDM_UP 24 61 GSE17721_CPG_VS_GARDIQUIMOD_24H_BMDM_DN 23 62 GSE9988_ANTI_TREM1_VS_LPS_MONOCYTE_DN 23 63 GSE1448_CTRL_VS_ANTI_VALPHA2_DP_THYMOCYTE_DN 23 64 GSE9988_LPS_VS_CTRL_TREATED_MONOCYTE_UP 22 65 GSE22886_CD4_TCELL_VS_BCELL_NAIVE_DN 22 66 GSE27786_NKTCELL_VS_ERYTHROBLAST_DN 22 67 GSE29615_CTRL_VS_LAIV_FLU_VACCINE_PBMC_UP 22 68 GSE29617_CTRL_VS_TIV_FLU_VACCINE_PBMC_2008_UP 21 69 GSE13484_12H_UNSTIM_VS_YF17D_VACCINE_STIM_PBMC_DN 21 70 GSE360_L_DONOVANI_VS_L_MAJOR_DC_DN 21 71 GSE22886_NAIVE_CD4_TCELL_VS_NEUTROPHIL_DN 21 72 GSE2706_UNSTIM_VS_8H_LPS_AND_R848_DC_DN 21 15

73 GSE18791_UNSTIM_VS_NEWCATSLE_VIRUS_DC_10H_DN 20 74 GSE9988_LOW_LPS_VS_VEHICLE_TREATED_MONOCYTE_UP 20 75 GSE360_HIGH_DOSE_B_MALAYI_VS_M_TUBERCULOSIS_DC_DN 20 76 GSE22886_NAIVE_CD8_TCELL_VS_NEUTROPHIL_DN 20 77 GSE9988_ANTI_TREM1_VS_ANTI_TREM1_AND_LPS_MONOCYTE_D N 20 78 GSE17721_0.5H_VS_24H_CPG_BMDM_DN 20 79 GSE7460_FOXP3_MUT_VS_WT_ACT_TCONV_UP 20 80 GSE14000_UNSTIM_VS_4H_LPS_DC_UP 19 81 GSE1460_NAIVE_CD4_TCELL_CORD_BLOOD_VS_THYMIC_STROMA L_CELL_DN 19 82 GSE17721_POLYIC_VS_CPG_0.5H_BMDM_DN 19 83 GSE360_L_MAJOR_VS_B_MALAYI_LOW_DOSE_DC_UP 19 84 GSE9650_EFFECTOR_VS_EXHAUSTED_CD8_TCELL_DN 18 85 GSE17580_TREG_VS_TEFF_S_MANSONI_INF_UP 18 86 GSE2706_UNSTIM_VS_8H_R848_DC_DN 18 87 GSE26928_EFF_MEMORY_VS_CXCR5_POS_CD4_TCELL_DN 17 88 GSE13306_RA_VS_UNTREATED_TCONV_DN 17 89 GSE2706_UNSTIM_VS_2H_R848_DC_DN 17 90 GSE17721_CTRL_VS_CPG_4H_BMDM_DN 17 91 GSE17974_CTRL_VS_ACT_IL4_AND_ANTI_IL12_1H_CD4_TCELL_DN 17 92 GSE3982_BASOPHIL_VS_NKCELL_UP 16 93 GSE2706_R848_VS_LPS_2H_STIM_DC_DN 16 94 GSE32423_CTRL_VS_IL7_MEMORY_CD8_TCELL_DN 16 95 GSE13306_TREG_VS_TCONV_LAMINA_PROPRIA_UP 16 96 GSE339_EX_VIVO_VS_IN_CULTURE_CD4POS_DC_DN 16 97 GSE9650_NAIVE_VS_EXHAUSTED_CD8_TCELL_DN 16 98 GSE9988_LPS_VS_VEHICLE_TREATED_MONOCYTE_UP 15 99 GSE11924_TH2_VS_TH17_CD4_TCELL_UP 15 100 GSE360_L_MAJOR_VS_B_MALAYI_HIGH_DOSE_MAC_UP 15 Immunology Signature Tumor Associated Rank GeneSet p_normal/ p_tumor 1 GSE17721_POLYIC_VS_PAM3CSK4_2H_BMDM_UP 422 2 GSE37416_CTRL_VS_6H_F_TULARENSIS_LVS_NEUTROPHIL_UP 111 3 GSE27786_LIN_NEG_VS_ERYTHROBLAST_UP 59 4 GSE27786_CD4_TCELL_VS_NKCELL_DN 56 5 GSE17721_POLYIC_VS_GARDIQUIMOD_4H_BMDM_DN 56 6 GSE17721_CTRL_VS_CPG_0.5H_BMDM_UP 53 7 GSE360_HIGH_DOSE_B_MALAYI_VS_M_TUBERCULOSIS_DC_UP 50 16

8 GSE11864_UNTREATED_VS_CSF1_IFNG_PAM3CYS_IN_MAC_UP 49 9 GSE29617_DAY3_VS_DAY7_TIV_FLU_VACCINE_PBMC_2008_DN 49 10 GSE17721_POLYIC_VS_GARDIQUIMOD_6H_BMDM_DN 48 11 GSE17721_CTRL_VS_PAM3CSK4_4H_BMDM_DN 43 12 GSE17721_POLYIC_VS_CPG_2H_BMDM_UP 39 13 GSE17974_0.5H_VS_72H_UNTREATED_IN_VITRO_CD4_TCELL_UP 36 14 GSE360_CTRL_VS_M_TUBERCULOSIS_DC_UP 35 15 GSE17721_CTRL_VS_PAM3CSK4_12H_BMDM_UP 34 16 GSE17721_POLYIC_VS_PAM3CSK4_16H_BMDM_UP 31 17 GSE17721_POLYIC_VS_PAM3CSK4_6H_BMDM_DN 30 18 GSE1432_1H_VS_6H_IFNG_MICROGLIA_UP 28 19 GSE14769_UNSTIM_VS_240MIN_LPS_BMDM_UP 25 20 GSE17721_CPG_VS_GARDIQUIMOD_4H_BMDM_DN 24 21 GSE360_L_DONOVANI_VS_M_TUBERCULOSIS_DC_UP 24 22 GSE27786_LIN_NEG_VS_NEUTROPHIL_DN 23 23 GSE360_LOW_DOSE_B_MALAYI_VS_M_TUBERCULOSIS_DC_UP 23 24 GSE17721_CTRL_VS_GARDIQUIMOD_1H_BMDM_UP 23 25 GSE36392_TYPE_2_MYELOID_VS_EOSINOPHIL_IL25_TREATED_LU NG_UP 22 26 GSE17721_CTRL_VS_PAM3CSK4_2H_BMDM_UP 21 27 GSE3982_EOSINOPHIL_VS_CENT_MEMORY_CD4_TCELL_DN 20 28 GSE17721_CTRL_VS_PAM3CSK4_8H_BMDM_DN 20 29 GSE13485_CTRL_VS_DAY21_YF17D_VACCINE_PBMC_UP 20 30 GSE2826_XID_VS_BTK_KO_BCELL_UP 20 31 GSE17721_0.5H_VS_12H_CPG_BMDM_UP 19 32 GSE339_CD8POS_VS_CD4CD8DN_DC_IN_CULTURE_DN 18 33 GSE32423_IL7_VS_IL4_MEMORY_CD8_TCELL_UP 17 34 GSE7852_THYMUS_VS_FAT_TCONV_UP 17 35 GSE27786_NKTCELL_VS_MONO_MAC_DN 17 36 GSE20366_EX_VIVO_VS_HOMEOSTATIC_CONVERSION_NAIVE_CD4 _TCELL_UP 16 37 GSE17721_LPS_VS_GARDIQUIMOD_6H_BMDM_DN 16 38 GSE14308_TH17_VS_NAIVE_CD4_TCELL_DN 16 39 GSE17721_CTRL_VS_POLYIC_4H_BMDM_UP 16 40 GSE2826_WT_VS_XID_BCELL_UP 16 41 GSE14308_TH2_VS_NATURAL_TREG_DN 15 42 GSE1460_DP_VS_CD4_THYMOCYTE_UP 15 43 GSE17721_LPS_VS_PAM3CSK4_8H_BMDM_DN 15 44 GSE17721_CTRL_VS_GARDIQUIMOD_6H_BMDM_UP 15 45 GSE17721_LPS_VS_PAM3CSK4_2H_BMDM_DN 14 46 GSE14308_TH2_VS_TH1_DN 14 17

47 GSE29618_PRE_VS_DAY7_POST_TIV_FLU_VACCINE_BCELL_DN 14 48 GSE32423_IL7_VS_IL7_IL4_MEMORY_CD8_TCELL_UP 14 49 GSE12845_IGD_NEG_BLOOD_VS_NAIVE_TONSIL_BCELL_DN 13 50 GSE3982_MAC_VS_BASOPHIL_UP 13 51 GSE8384_CTRL_VS_B_ABORTUS_4H_MAC_CELL_LINE_UP 13 52 GSE32423_MEMORY_VS_NAIVE_CD8_TCELL_IL7_IL4_DN 13 53 GSE29617_CTRL_VS_DAY3_TIV_FLU_VACCINE_PBMC_2008_UP 13 54 GSE17721_PAM3CSK4_VS_GADIQUIMOD_2H_BMDM_DN 12 55 GSE15324_NAIVE_VS_ACTIVATED_ELF4_KO_CD8_TCELL_DN 12 56 GSE11924_TFH_VS_TH1_CD4_TCELL_UP 12 57 GSE17721_0.5H_VS_4H_CPG_BMDM_UP 12 58 GSE10094_LCMV_VS_LISTERIA_IND_EFF_CD4_TCELL_UP 12 59 GSE14308_NAIVE_CD4_TCELL_VS_INDUCED_TREG_DN 12 60 GSE11864_UNTREATED_VS_CSF1_IFNG_PAM3CYS_IN_MAC_DN 11 61 GSE27786_CD4_TCELL_VS_MONO_MAC_UP 11 62 GSE9650_NAIVE_VS_EFF_CD8_TCELL_UP 11 63 GSE17974_IL4_AND_ANTI_IL12_VS_UNTREATED_0.5H_ACT_CD4_T CELL_UP 11 64 GSE37416_0H_VS_3H_F_TULARENSIS_LVS_NEUTROPHIL_DN 11 65 GSE14769_40MIN_VS_360MIN_LPS_BMDM_UP 11 66 GSE29618_PRE_VS_DAY7_POST_LAIV_FLU_VACCINE_PDC_DN 11 67 GSE39820_TGFBETA1_VS_TGFBETA3_IN_IL6_TREATED_CD4_TCEL L_UP 11 68 GSE7764_IL15_NK_CELL_24H_VS_SPLENOCYTE_DN 11 69 GSE17974_0.5H_VS_72H_IL4_AND_ANTI_IL12_ACT_CD4_TCELL_UP 11 70 GSE360_L_DONOVANI_VS_B_MALAYI_HIGH_DOSE_DC_DN 10 71 GSE3982_MEMORY_CD4_TCELL_VS_TH2_DN 10 72 GSE2197_IMMUNOSUPPRESSIVE_DNA VS_UNTREATEDIN_DC_DN 10 73 GSE3982_DC_VS_NEUTROPHIL_UP 10 74 GSE17721_0.5H_VS_24H_GARDIQUIMOD_BMDM_DN 10 75 GSE1460_DP_THYMOCYTE_VS_NAIVE_CD4_TCELL_CORD_BLOOD_ UP 10 76 GSE17974_0H_VS_72H_IN_VITRO_ACT_CD4_TCELL_DN 10 77 GSE12845_NAIVE_VS_DARKZONE_GC_TONSIL_BCELL_DN 10 78 GSE37416_0H_VS_3H_F_TULARENSIS_LVS_NEUTROPHIL_UP 10 79 GSE27786_CD8_TCELL_VS_ERYTHROBLAST_UP 10 80 GSE17721_CTRL_VS_GARDIQUIMOD_2H_BMDM_UP 10 81 GSE12845_IGD_NEG_BLOOD_VS_PRE_GC_TONSIL_BCELL_DN 10 82 GSE9037_CTRL_VS_LPS_1H_STIM_IRAK4_KO_BMDM_UP 10 83 GSE15750_DAY6_VS_DAY10_EFF_CD8_TCELL_UP 10 84 GSE10239_NAIVE_VS_KLRG1HIGH_EFF_CD8_TCELL_DN 9 18

85 GSE360_CTRL_VS_T_GONDII_MAC_UP 9 86 GSE15930_STIM_VS_STIM_AND_IFNAB_72H_CD8_T_CELL_DN 9 87 GSE360_CTRL_VS_L_DONOVANI_DC_UP 9 88 GSE29618_LAIV_VS_TIV_FLU_VACCINE_DAY7_BCELL_DN 9 89 GSE15659_CD45RA_NEG_CD4_TCELL_VS_ACTIVATED_TREG_UP 9 90 GSE3982_CENT_MEMORY_CD4_TCELL_VS_TH2_DN 9 91 GSE31082_DP_VS_CD4_SP_THYMOCYTE_UP 9 92 GSE29618_PRE_VS_DAY7_POST_LAIV_FLU_VACCINE_MONOCYTE_ DN 9 93 GSE1448_ANTI_VALPHA2_VS_VBETA5_DP_THYMOCYTE_DN 9 94 GSE6269_FLU_VS_STREP_AUREUS_INF_PBMC_UP 9 95 GSE339_EX_VIVO_VS_IN_CULTURE_CD4POS_DC_UP 8 96 GSE17580_TREG_VS_TEFF_UP 8 97 GSE37416_CTRL_VS_12H_F_TULARENSIS_LVS_NEUTROPHIL_UP 8 98 GSE17721_LPS_VS_CPG_8H_BMDM_DN 8 99 GSE27786_LSK_VS_CD4_TCELL_UP 8 100 GSE14769_40MIN_VS_360MIN_LPS_BMDM_DN 8 Table S6. Top 100 gene set signatures differentially associated with survival. The gene sets are defined either as normal associated (more associated with survival using normal data) or tumor associated (more associated with survival using tumor data). The gene set signatures are from the oncogenic signatures and immunology signatures defined by MSigDB. 19