Supplementary Figure 1. Somatic mutation spectrum#

Subs

tituti

ons

# Substitutions per Mb

b

c

a#

Subs

tituti

ons

per M

b

Repeats

Pseudogenes

Whole genome

Splice sites

Non-coding RNA

Intron

Promoter5’ U

TR3’ U

TRCDS

Supplementary Figure 2. TP53 mutations associated with chromosomal instability and clinical variables

c.CIN ( p = 3.12e-05)

b.

a.

Tumour Grade ( p = 0.0075)

p53 mutation: n=31

p53 wild type: n=51

20 40 60 80 100 1200.

00.

20.

40.

60.

81.

0

DFS

Months

Sur

viva

l Pro

babi

lity

p = 0.136

Nucleotide-binding ATP-binding

ERBB2: L755P,S ERBB2: G776SV777A,L,M

JAK1:L910P JAK1: Q644H,V645F

JAK1: S703I

ACRG-HCC mutationACRG-HCC mutation (recurrent)Known mutationKnown mutation (recurrent)Known mutation (activating)Known mutation (resistant)

Supplementary Figure 3. Alignment of the mutations in kinase domains of JAK1, JAK2, JAK3 and ERBB2

Supplementary Figure 4. JAK inhibitors inhibit JAK1 S703I mutant-mediated activation of p-STAT3 in Ba/F3 cells

BMS-911543

DMSORuxoliti

nib

Stat3

pStat3

Actin

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

% T

umou

r Sam

ples

Supplementary Figure 6. Selective amplification and deletion of cancer genes

Oncogene

G-s

core

Am

plifi

catio

n

CNV Regions Non-CNV Regions

Tumor SuppressorOther

G-s

core

Del

etion

a

b Oncogene Tumor SuppressorOther

Oncogene Tumor SuppressorOther Oncogene Tumor SuppressorOther

CNV Regions Non-CNV Regions

Supplementary Figure 7. Overview of cancer pathways impacted by genomic alterations

Down RegulationUp RegulationMutation Amplification Deletion No Change

Supplementary Figure 8. Genomic alterations of key genes and pathways across three subclasses

Pathway alterationMutation

Amplification

Not altered

Alteration Status

Deletion

HBV Integration

S1 S2 S3

Map to reference genome hg19

(SOAP2)

Predict mutant alleles in tumors (SOAPsnv)

Predicted somatic mutation

Performed on tumour and normal separately

Read Depth ≥ 10Read SupportBinomial test

p > 0.01

Quality ScoreWilcoxon rank sum

test p > 0.01

Mutant allele frequency difference

≥ 20%

Mutant allele enriched in

repeatedly aligned reads?

Mutant allele enriched within 10 bps of read ends?

QC sequence readsCollect read support

info on all sites

Tumor vs. Normalmutant allele frequency

Fisher’s Exact testp < 0.01

Y

Y

Y

Y

N

N Y

Supplementary Figure 9. Somatic SNV detection work flow

Sequenom validation497