Supplementary Figure 1 Somatic mutation spectrum a Substitutions

Supplementary Figure 1. Somatic mutation spectrum a # Substitutions per Mb b # Substitutions c e es ats NA ron om en pe g R Int en og n i Re g d od le eu ho Ps n-c o W N ter Pr o om S CD TR U 5’ TR U 3’ s ite es lic Sp # Substitutions per Mb

Supplementary Figure 2. TP 53 mutations associated with chromosomal instability and clinical variables CIN ( p = 3. 12 e-05) DFS 0. 8 0. 6 0. 4 p 53 wild type: n=51 p 53 mutation: n=31 0. 2 Survival Probability 1. 0 a. c. Tumour Grade ( p = 0. 0075) p = 0. 136 0. 0 b. 20 40 60 Months 80 100 120

Supplementary Figure 3. Alignment of the mutations in kinase domains of JAK 1, JAK 2, JAK 3 and ERBB 2 Nucleotide-binding ATP-binding JAK 1: L 910 P ERBB 2: L 755 P, S JAK 1: S 703 I ACRG-HCC mutation (recurrent) Known mutation (activating) Known mutation (resistant) JAK 1: Q 644 H, V 645 F ERBB 2: G 776 S V 777 A, L, M

Supplementary Figure 4. JAK inhibitors inhibit JAK 1 S 703 I mutant-mediated activation of p -STAT 3 in Ba/F 3 cells 43 ib SO DM p. Stat 3 Actin R n liti o ux BM S- 15 91

% Tumour Samples Supplementary Figure 5. Frequencies of copy number gain and loss for chromosomal arms

Supplementary Figure 6. Selective amplification and deletion of cancer genes a Non-CNV Regions G-score Amplification CNV Regions b Other Oncogene Tumor Suppressor Other Tumor Suppressor Non-CNV Regions G-score Deletion CNV Regions Oncogene Other Oncogene Tumor Suppressor

Supplementary Figure 7. Overview of cancer pathways impacted by genomic alterations Mutation Amplification Deletion Up Regulation Down Regulation No Change

Supplementary Figure 8. Genomic alterations of key genes and pathways across three subclasses S 1 S 2 S 3 Alteration Status Not altered Pathway alteration Mutation Deletion Amplification HBV Integration

Supplementary Figure 9. Somatic SNV detection work flow Performed on tumour and normal separately QC sequence reads Map to reference genome hg 19 (SOAP 2) Collect read support info on all sites Predict mutant alleles in tumors (SOAPsnv) Tumor vs. Normal mutant allele frequency Fisher’s Exact test p < 0. 01 Y Read Depth ≥ 10 Y Read Support Binomial test p > 0. 01 Y Quality Score Wilcoxon rank sum test p > 0. 01 Y Mutant allele enriched within 10 bps of read ends? N Mutant allele enriched in repeatedly aligned reads? Y Mutant allele frequency difference ≥ 20% N Predicted somatic mutation 497 Sequenom validation