Supplementary file COL1A2 FZD3 1 1 HPRD HPRD Humannet Humannet 0.8 PPIwu 0.8 PPIwu 0.6 0.6 0.4 0.4 Ratio of of indegree Ratio Ratio of Indegree 0.2 0.2 0 0 0 0.05 0.1 0.15 0.2 0 0.05 0.1 0.15 0.2 Frequency Frequency RBL1 SMARCA4 1 1 HPRD HPRD Humannet Humannet 0.8 PPIwu 0.8 PPIwu 0.6 0.6 0.4 0.4 Ratio of Indegree Ratio of Indegree Ratio 0.2 0.2 0 0 0 0.05 0.1 0.15 0.2 0 0.05 0.1 0.15 0.2 Frequency Frequency SRC TP53 1 1 HPRD Humannet 0.95 0.8 PPIwu 0.9 e 0.6 0.85 0.8 0.4 Ratio of Indegree of Ratio Ratio of Indegre 0.75 0.2 HPRD 0.7 Humannet PPIwu 0 0.65 0 0.05 0.1 0.15 0.2 0 0.05 0.1 0.15 0.2 Frequency Frequency VCAN 1 HPRD Humannet 0.8 PPIwu 0.6 0.4 Ratio of Indegree 0.2 0 0 0.05 0.1 0.15 0.2 Frequency Figure S1. Variation of indegree ratio with frequency cutoffs from 0 to 0.2 with a step 0.002 for driver genes common by three fitness cores in COAD. The indegree ratio is set to NULL if total degree of this genes is less than 5. BRAF CASR 1 1 0.8 0.8 0.6 0.6 0.4 0.4 Ratio of Indegree Ratio of Indegree of Ratio HPRD HPRD 0.2 0.2 Humannet Humannet PPIwu PPIwu 0 0 0 0.05 0.1 0.15 0.2 0 0.05 0.1 0.15 0.2 Frequency Frequency HDAC9 NRAS 1 1 0.8 0.8 0.6 0.6 0.4 0.4 HPRD HPRD Ratio of Indegree Ratio of Indegree 0.2 0.2 Humannet Humannet PPIwu PPIwu 0 0 0 0.05 0.1 0.15 0.2 0 0.05 0.1 0.15 0.2 Frequency Frequency NF1 CNTNAP2 1 1 0.9 0.8 0.8 0.6 0.7 0.4 HPRD HPRD Ratio of Indegree Ratio of Indegree 0.6 Humannet 0.2 Humannet PPIwu PPIwu 0.5 0 0 0.05 0.1 0.15 0.2 0 0.05 0.1 0.15 0.2 Frequency Frequency Figure S2. Variation of indegree ratio with frequency cutoffs from 0 to 0.2 with a step 0.002 for driver genes common by three fitness cores in primary melanoma. The indegree ratio is set to NULL if total degree of this genes is less than 5. (A) 1 1 1 0.9 0.9 0.9 0.8 0.8 0.8 0.7 0.7 0.7 0.6 0.6 0.6 0.5 0.5 Mean coverage ratio Mean ratioMean coverge Mean coverage ratio 0.4 0.5 0.4 0.3 0.4 0.3 0.2 0.1 0.2 0 100 200 300 400 500 600 700 800 900 1000 0 200 400 600 800 1000 0 100 200 300 400 500 600 700 800 900 1000 Sampling time Sampling time Sampling time (B) 1 1 1 0.9 0.9 0.9 0.8 0.8 0.8 0.7 0.7 0.7 0.6 0.6 0.6 0.5 0.5 0.5 0.4 0.4 Mean coverage rate Mean coverage ratio 0.4 Mean coverage ratio 0.3 0.3 0.3 0.2 0.2 0.1 0.2 0.1 0 0.1 0 0 100 200 300 400 500 600 700 800 900 1000 0 100 200 300 400 500 600 700 800 900 1000 0 100 200 300 400 500 600 700 800 900 1000 Sampling time Sampling time Sampling time Figure S3. The convergence of sampling strategy in combinations of cases and background networks. (A) Mean coverage of driver genes in COAD with sampling times under HPRD (left), Humannet (middle) and PPIwu (right); (B) Mean coverage of driver genes in primary with sampling times under HPRD (left), Humannet (middle) and PPIwu (right). For a given driver gene and a case-background network combination, a universal set of driver genes covered by DIMs are generated by a 5000 times sampling procedure and DIM filtering procedure, and also subsets of DIM covered driver genes are generate by the same procedures with sampling time from 50 to 5000. Mean coverage is calculated for each sampling time by 100 repeats. The mean coverage is larger than 0.98 for almost all driver genes in each combination when sampling time get up to 1000, which implies the convergence of the sampling strategy employed in the flowchart. COAD COAD 4 5 HPRD HPRD Humannet Humannet 4 3 PPIwu PPIwu 3 2 2 1 Probability Density Probability Probability Density 1 0 0 0 0.2 0.4 0.6 0.8 1 0 0.2 0.4 0.6 0.8 1 Frequency Frequency Primary Melanoma Primary Melanoma 30 25 HPRD HPRD Humannet 25 Humannet PPIwu 20 PPIwu y 20 15 15 10 10 Probability Densit Probability Density Probability 5 5 0 0 0 0.2 0.4 0.6 0.8 1 0 0.2 0.4 0.6 0.8 1 Frequency Frequency Figure S4. Frequency distribution of fitness (left) and co-occurred (right) edges modeled by the kernel probability distribution with normal smoothing function. Results show significant differences of frequency distribution in different fitness networks. A COAD 1 1 P value (fitness) 0.9 P value (co-occur) 0.9 Overlap percent (fitness) Overlap percent (co-occur) 0.8 0.8 0.7 0.7 0.6 0.6 0.5 0.5 P value P 0.4 0.4 0.3 0.3 Percentage of overlapped edges 0.2 0.2 0.1 0.1 0 0 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 Percentage of edges with cutoff vs. all edges B Primary Melanoma 1 0.5 P value (Fitness) 0.9 P value (Co-occur) Overlap percent (Fitness) Overlap (Co-occur) 0.8 0.4 es 0.7 g 0.6 0.3 ed ed pp 0.5 P value P 0.4 0.2 overla of e g 0.3 Percenta 0.2 0.1 0.1 0 0 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 Percentage of edges with cutoff vs. all edges Figure S5. Percentage of the number of fitness and co-occurred edges common by fitness networks with frequency cutoffs and corresponding significance. Results indicate that consistent significances of fitness edges are obtained when percentage of edges in fitness networks larger than 0.23 and 0.28 for COAD and primary melanoma respectively, as well as 0.47 and 0.25 for co-occurred edges for COAD and primary melanoma respectively. Figure S6. Overlap of fitness cores identified under different background networks (HPRD, Humannet, PPIwu) in COAD (Figure A) and primary melanoma (Figure B). Significant overlaps are obtained in both of cases with p-value < 2.2E-16. Figure S7. A concise exhibition of functional relationships among top mutated driver genes for SKCM. Table S1. Fitness core obtained by combinations of cases and background networks cancer type Fitness core in FNs Fitness core in common BMP7, COL1A2, VCAN, LRP2, RBL1, SMARCA4, COAD (HPRD) SRC, TP53, USH2A, FZD3, TOMM34, NCOA6, PCDH17 BMP7, COL1A2, COL5A1, VCAN, DNAH5, PFDN4, COL1A2, VCAN, RBL1, COAD (Huannet) RBL1, SMARCA4, SRC, TP53, UBE2V1, FZD3, RAE1, SMARCA4, SRC, TP53, TCFL5, MXRA5 FZD3 COL1A2, COL5A1, VCAN, PFDN4, RBL1, SMARCA4, COAD (PPIwu) SRC, TP53, UBE2V1, FZD3, RAE1, TOMM34, MAPRE1, NEURL2, ASPM ACTN2, ZFHX3, BRAF, CASR, CDKN2A, CHGB, BRAF, CASR, NF1, NRAS, SKCM (HPRD) LYST, COL4A1, COL5A2, DSCAM, FLT1, GRM8, HDAC9, CNTNAP2 KDR, KEL, NF1, NID1, NRAS, ATXN1, SELE, CD163, MDC1, HDAC9, ADAM28, CNTNAP2, KCNQ5 ACTN2, ANK1, APOB, ZFHX3, BRAF, CASR, LYST, DSCAM, BPTF, GRIN2A, NF1, NRAS, PPP6C, PTEN, SKCM (Humannet) ATXN1, TTN, KMT2D, MDC1, HDAC9, CNTNAP2, CHD6 BRAF, CASR, CDKN2A, CLCN1, NF1, NRAS, HDAC9, SKCM (PPIwu) BCLAF1, CNTNAP2, PCDH18 Table S2 Absolute coverage of fitness cores FN num.all coverage.all num.core coverage.core num.core3 coverage.core3 COAD.hp 16 (440,271,0.8432) 13 (440,342,0.7773) 7 (440,307,0.6977) COAD.hu 25 (439,404,0.9203) 15 (439,337,0.7677) 7 (439,307,0.6993) COAD.wu 17 (439,334,0.7608) 15 (439,319,0.7267) 7 (439,307,0.6993) SKCM.hp 27 (350,315,0.9000) 25 (350,310,0.8857) 6 (350,298,0.8514) SKCM.hu 28 (357,334,0.9076) 21 (357,323,0.9048) 6 (357,298,0.8347) SKCM.wu 17 (348,316,0.9080) 10 (348,304,0.8736) 6 (348,298,0.8563) Table S3 Relative coverage of fitness cores FN num.all coverage.all num.core coverage.core num.core3 coverage.core3 COAD.hp 16 (440,371,0.8432) 13 (440,342,0.7773) 7 (440,307,0.6977) COAD.hu 25 (439,404,0.9203) 15 (439,337,0.7677) 7 (439,307,0.6993) COAD.wu 17 (438,333,0.7603) 15 (439,319,0.7267) 7 (439,307,0.6993) SKCM.hp 27 (150,115,0.7667) 25 (156,116,0.7436) 6 (167,123,0.7365) SKCM.hu 28 (169,136,0.8047) 21 (172,138,0.8023) 6 (195,144,0.7385) SKCM.wu 17 (128,99,0.7734) 10 (143,102,0.7133) 6 (138,99,0.7174) * FN: Fitness network.