343-53678-9-4:78;

�

�

�

��

�

�

�

��

��

��

��

�

��

�

��

��

�

��0

250

500

750

1000

1250

MSI-H MSI-L MSS

# M

SI e

vent

s

CRC (COAD & READ)STADUCEC

Supplementary Figure 1: Distribution of MSI events in MSI-H, MSI-L and MSS cases in MSI-prone tumor types.

0

20

40

60#

MSI

eve

nts

Supplementary Figure 2: (a) Landscape of MSI in MSI-L and MSS tumors. (b) Distribution of MSI events across 22 tumor types. Blue points indicate the median and the interquartile range (25th through 75th percentile), whereas red points indicate the mean value.

0.0

2.5

5.0

7.5

10.0

12.5

ACVR2A

SLC35F5

TGFBR2

SLAMF1

CASP5

RPL22

PHACTR4

BAX

RNF43

FGFBP1

AIM2

CYHR1

TMEM60

SLC22A9

LMAN1

OR52N5

MNS1

TMEM22

OR6C75

C9orf114

OR6C76

UBR5

JPH4

MARCKS

MSH3

TCEB3

SEC63

TRIM59

PRDM2

MYO1A

MBD6

EIF2B3

FETUB

PPP1R12B

SEC31A

CLOCK

COIL

ARID1A

CRYGA

SLC3A2

0.0

2.5

5.0

7.5

10.0

12.5

ASTE1

OR7E24

SLC22A9

CASP5

SLC35F5

C18orf34

UPF3A

JAK1

TFAM

FAM111B

SEC31A

RNF43

SMAP1

CTCF

PCDHGA10

MCHR2

ACVR2A

C15orf40

PTEN

TMEM97

TBC1D23

PDS5B

XPOT

TAF1B

MNS1

CCDC28A

KIAA2018

RBM27

CD3G

SRPR

AP1S1

SEC63

TTK

FAM18A

TMEM60

ADD3

CCDC150

RAD50

ATR

FAHD2B

0.0

2.5

5.0

7.5

10.0

12.5

ACVR2AINO80EAIM2

SLC22A9OR6C75FGFBP1SLAMF1TGFBR2SEC31ACCDC43

BAXOR7E24

ARV1C4orf6

KIAA1919TCERG1

CCDC150MNS1SYCP1

TMEM97GBP3RPL22

PHACTR4RNF43

PCDHGA10UPF3ACD3G

GOT1L1TEAD2OR7C1SEC63TRIM59

CCDC28APRR11SRPR

SLC35F5BMPR2

SLC23A2EIF2B3SLC3A2ANO10VEGFBOR6C76

EBPLTTK

RARRES3TMBIM4AASDHLMAN1PRRT2

STAD UCEC COAD

a b c-log10 Q value -log10 Q value -log10 Q value

Supplementary Figure 3: Top-ranked genes with significantly recurrent MSI in STAD (a), UCEC (b) and COAD (c) tumors (Q value, FDR < 0.05; MutSigCV).

0

20

40

MSH

3RAD

50ATR

PRKD

CMSH

6BLM

RBB

P8MLH

3ATM

FANCM

BRCA1

REV

3LNBN

BRCA2

MLH

1PALB2

POLM

POLQ

REC

QL

SHPR

HTO

PBP1

TP53BP

1ATRIP

TOP2A

DCLR

E1C

LIG3

POLE

USP

1BR

IP1

DCLR

E1A

FANCB

PARP1

PMS1

TP53

WRN

XRCC2

ALKB

H2

CLSPN

DDB1

ERCC2

FANCA

FANCI

LIG4

MBD

4MNAT1

NEIL1

NEIL3

PER1

PMS2

RAD

18REC

QL5

REV

1TD

G

# fra

mes

hift

MSI

eve

nts

0

25

50

75

100

ACVR

2ATG

FBR2

RNF43

RPL22

MLL3

PRDM2

JAK1

ATR

ARID1A

PTEN

CTC

FLR

RK2

MEC

OM

ATM

MLL2

BRCA1

FBXW

7NSD

1USP

9XAP

CATRX

MLL4

SETD

2TB

L1XR

1AX

IN2

BRCA2

POLQ

ARID5B

BRAF NF1

SETB

P1AR

HGAP

35AS

XL1

TAF1

TSHZ3

EPHB6

ERBB

4MAP

3K1

NCOR1

TET2

TP53

ACVR

1BCDH1

DNMT3A

EGR3

EP300

ERCC2

FGFR

3GATA3

IDH1

IDH2

NAV3

NFE

2L2

PBRM1

RB1

SIN3A

SMAD

4SM

C3

TSHZ2

# fra

mes

hift

MSI

eve

nts

COAD

ESCA

READ

STAD

UCEC

190 MSI-H tumors

a

b

Supplementary Figure 4: Abundance of frameshift MSI events in genes implicated in DNA repair (a) and tumorigenesis (b) across 5 MSI-prone cancer types.

0

1

2

3

4

MLH

1: m

si�h

MLH

1: m

si�l

MLH

1: m

ssMLH

3: m

si�h

MLH

3: m

si�l

MLH

3: m

ssMSH

2: m

si�h

MSH

2: m

si�l

MSH

2: m

ssMSH

3: m

si�h

MSH

3: m

si�l

MSH

3: m

ssMSH

6: m

si�h

MSH

6: m

si�l

MSH

6: m

ssPM

S1: m

si�h

PMS1

: msi�l

PMS1

: mss

PMS2

: msi�h

PMS2

: msi�l

PMS2

: mss

POLD

1: m

si�h

POLD

1: m

si�l

POLD

1: m

ssPO

LE: m

si�h

POLE

: msi�l

POLE

: mss

% o

f pat

ient

s

0.0

2.5

5.0

7.5

MLH

1: m

si�h

MLH

1: m

si�l

MLH

1: m

ssMLH

3: m

si�h

MLH

3: m

si�l

MLH

3: m

ssMSH

2: m

si�h

MSH

2: m

si�l

MSH

2: m

ssMSH

3: m

si�h

MSH

3: m

si�l

MSH

3: m

ssMSH

6: m

si�h

MSH

6: m

si�l

MSH

6: m

ssPM

S1: m

si�h

PMS1

: msi�l

PMS1

: mss

PMS2

: msi�h

PMS2

: msi�l

PMS2

: mss

POLD

1: m

si�h

POLD

1: m

si�l

POLD

1: m

ssPO

LE: m

si�h

POLE

: msi�l

POLE

: mss

% o

f pat

ient

s

0.0

0.5

1.0

1.5

2.0

MLH

1: m

si�h

MLH

1: m

si�l

MLH

1: m

ssMLH

3: m

si�h

MLH

3: m

si�l

MLH

3: m

ssMSH

2: m

si�h

MSH

2: m

si�l

MSH

2: m

ssMSH

3: m

si�h

MSH

3: m

si�l

MSH

3: m

ssMSH

6: m

si�h

MSH

6: m

si�l

MSH

6: m

ssPM

S1: m

si�h

PMS1

: msi�l

PMS1

: mss

PMS2

: msi�h

PMS2

: msi�l

PMS2

: mss

POLD

1: m

si�h

POLD

1: m

si�l

POLD

1: m

ssPO

LE: m

si�h

POLE

: msi�l

POLE

: mss

% o

f pat

ient

s

0

10

20

30

40

MLH

1: m

si�h

MLH

1: m

si�l

MLH

1: m

ssMLH

3: m

si�h

MLH

3: m

si�l

MLH

3: m

ssMSH

2: m

si�h

MSH

2: m

si�l

MSH

2: m

ssMSH

3: m

si�h

MSH

3: m

si�l

MSH

3: m

ssMSH

6: m

si�h

MSH

6: m

si�l

MSH

6: m

ssPM

S1: m

si�h

PMS1

: msi�l

PMS1

: mss

PMS2

: msi�h

PMS2

: msi�l

PMS2

: mss

POLD

1: m

si�h

POLD

1: m

si�l

POLD

1: m

ssPO

LE: m

si�h

POLE

: msi�l

POLE

: mss

0

20

40

60

MLH

1: m

si�h

MLH

1: m

si�l

MLH

1: m

ssMLH

3: m

si�h

MLH

3: m

si�l

MLH

3: m

ssMSH

2: m

si�h

MSH

2: m

si�l

MSH

2: m

ssMSH

3: m

si�h

MSH

3: m

si�l

MSH

3: m

ssMSH

6: m

si�h

MSH

6: m

si�l

MSH

6: m

ssPM

S1: m

si�h

PMS1

: msi�l

PMS1

: mss

PMS2

: msi�h

PMS2

: msi�l

PMS2

: mss

POLD

1: m

si�h

POLD

1: m

si�l

POLD

1: m

ssPO

LE: m

si�h

POLE

: msi�l

POLE

: mss

0

10

20

30

MLH

1: m

si�h

MLH

1: m

si�l

MLH

1: m

ssMLH

3: m

si�h

MLH

3: m

si�l

MLH

3: m

ssMSH

2: m

si�h

MSH

2: m

si�l

MSH

2: m

ssMSH

3: m

si�h

MSH

3: m

si�l

MSH

3: m

ssMSH

6: m

si�h

MSH

6: m

si�l

MSH

6: m

ssPM

S1: m

si�h

PMS1

: msi�l

PMS1

: mss

PMS2

: msi�h

PMS2

: msi�l

PMS2

: mss

POLD

1: m

si�h

POLD

1: m

si�l

POLD

1: m

ssPO

LE: m

si�h

POLE

: msi�l

POLE

: mss

a b

c d

e f

Frameshift Missense Nonsense Splice site

Supplementary Figure 5: Frequency of SNVs and indels in MMR genes, POLE and POLD1 in COAD (a,b), UCEC (c,d) and STAD (e,f).

MLH1 MLH3 MSH2 MSH3

Exp

Met

CN

Mut

MS

I

Exp

Met

CN

Mut

MS

I

Exp

Met

CN

Mut

MS

I

Exp

Met

CN

Mut

MS

I

Exp

Met

CN

Mut

MS

I

MSH6

PMS1 PMS2 POLD1 POLE

Exp

Met

CN

Mut

MS

I

Exp

Met

CN

Mut

MS

I

Exp

Met

CN

Mut

MS

I

Exp

Met

Mut

MS

I

Exp (Gene expression)

Met (Methylation)

CN (DNA copy numbers)

-1.5 +1.5

1 0

-1 +1

Missense SNV

Truncating mutations (nonsense/splicing SNVs, frameshift indel) and MSI

* *

*

* * * * * * *

* * *

Pearson correlation < -0.5 (Met), > 0.2 (CN), P < 0.05 (Mann-Whitney test; Mut and MSI)

Supplementary Figure 6: Gene expression, promoter methylation and DNA copy number profiles for MMR genes (MLH1, MLH3, MSH2, MSH3, MSH6, PMS1 and PMS2) and two proofreading DNA polymerase (POLD1 and POLE) corresponding to186 MSI-H cases.

Supplementary Figure 6: Gene expression, promoter methylation and DNA copy number profiles for MMR genes and two proofreading DNA polymerase corresponding to186 MSI-H cases.

0

100

200

300

BRCACESC

ESOGBM

HNSCKIRPLIHC

LUSCPHPGPRADSKCMTHCA

LGGPACOV

LUADSTADACC

KIRCBLCAUCECCOADREAD

DPY

SL2

(chr

8:26

5107

91)

ALPK

2 (c

hr18

:562

4644

2)CAR

D9

(chr

9:13

9266

396)

FAM129A

(chr

1:18

4764

498)

OR5K4

(chr

3:98

0735

91)

OR11G2

(chr

14:2

0666

175)

GMIP

(chr

19:1

9741

076)

SULT1A2

(chr

16:2

8603

654)

PRAM

EF4

(chr

1:12

9395

46)

PCDHB5

(chr

5:14

0517

173)

SDC3

(chr

1:31

3515

04)

SLC22A9

(chr

11:6

3149

670)

C4orf43

(chr

4:16

4435

264)

ACVR

2A (c

hr2:

1486

8368

5)KIAA

2018

(chr

3:11

3377

481)

OR1B1

(chr

9:12

5391

770)

ASTE

1 (c

hr3:

1307

3304

6)TG

FBR2

(chr

3:30

6918

71)

OR6C

68 (c

hr12

:558

8648

8)OR13G1

(chr

1:24

7836

000)

MET

TL17

(chr

14:2

1464

874)

NEK

3 (c

hr13

:527

1805

0)LTN1

(chr

21:3

0339

205)

SEC31A

(chr

4:83

7855

64)

AIM2

(chr

1:15

9032

486)

NDUFC

2 (c

hr11

:777

8414

6)MEG

F10

(chr

5:12

6769

145)

C18orf34

(chr

18:3

0913

142)

ABT1

(chr

6:26

5981

87)

OR7E24

(chr

19:9

3617

40)

ATE1

(chr

10:1

2359

6252

)NIPA2

(chr

15:2

3021

238)

RPL22

(chr

1:62

5778

4)OR1J2

(chr

9:12

5273

385)

CCDC150

(chr

2:19

7531

518)

RNF43

(chr

17:5

6435

160)

MLL3

(chr

7:15

1874

147)

SLC35G5

(chr

8:11

1887

57)

RNAS

E8 (c

hr14

:215

2608

1)MSH

3 (c

hr5:

7997

0914

)MIS18BP

1 (c

hr14

:457

1601

8)SLC35F5

(chr

2:11

4500

276)

PTCHD3

(chr

10:2

7702

256)

CAS

P5 (c

hr11

:104

8780

40)

SRPR

(chr

11:1

2613

7086

)PH

ACTR

4 (c

hr1:

2878

5729

)CNTN

5 (c

hr11

:100

2268

81)

CAS

P5 (c

hr11

:104

8796

86)

LMAN

1 (c

hr18

:570

1319

3)OR5K3

(chr

3:98

1104

06)

LRRIQ1

(chr

12:8

5638

645)

Sample count

0 25 50 75 100

0 5 1 0 1 5

Sample percentageb

a

BRCACESC

ESOGBM

HNSCKIRPLIHC

LUSCPHPGPRADSKCMTHCA

LGGPACOV

LUADSTADACC

KIRCBLCAUCECCOADREAD

DPY

SL2

(chr

8:26

5107

91)

ALPK

2 (c

hr18

:562

4644

2)CAR

D9

(chr

9:13

9266

396)

OR5K4

(chr

3:98

0735

91)

OR11G2

(chr

14:2

0666

175)

PRAM

EF4

(chr

1:12

9395

46)

FAM

129A

(chr

1:18

4764

498)

SDC3

(chr

1:31

3515

04)

KIAA

2018

(chr

3:11

3377

481)

SLC22A9

(chr

11:6

3149

670)

ACVR

2A (c

hr2:

1486

8368

5)SU

LT1A2

(chr

16:2

8603

654)

ASTE

1 (c

hr3:

1307

3304

6)AB

T1 (c

hr6:

2659

8187

)PC

DHB5

(chr

5:14

0517

173)

TGFB

R2

(chr

3:30

6918

71)

OR1B1

(chr

9:12

5391

770)

SEC31A

(chr

4:83

7855

64)

OR7E24

(chr

19:9

3617

40)

OR13G1

(chr

1:24

7836

000)

LTN1

(chr

21:3

0339

205)

NDUFC

2 (c

hr11

:777

8414

6)AIM2

(chr

1:15

9032

486)

C18orf34

(chr

18:3

0913

142)

C4orf43

(chr

4:16

4435

264)

GMIP

(chr

19:1

9741

076)

CCDC150

(chr

2:19

7531

518)

PTCHD3

(chr

10:2

7702

256)

RPL22

(chr

1:62

5778

4)RNF43

(chr

17:5

6435

160)

OR6C

68 (c

hr12

:558

8648

8)MEG

F10

(chr

5:12

6769

145)

MSH

3 (c

hr5:

7997

0914

)SR

PR (c

hr11

:126

1370

86)

MLL3

(chr

7:15

1874

147)

SLC22A24

(chr

11:6

2863

517)

SLC35F5

(chr

2:11

4500

276)

PHAC

TR4

(chr

1:28

7857

29)

MIS18BP

1 (c

hr14

:457

1601

8)ATE1

(chr

10:1

2359

6252

)LM

AN1

(chr

18:5

7013

193)

CAS

P5 (c

hr11

:104

8780

40)

SLC35G5

(chr

8:11

1887

57)

RBM

27 (c

hr5:

1456

4731

9)OR1J2

(chr

9:12

5273

385)

CAS

P5 (c

hr11

:104

8796

86)

CNTN

5 (c

hr11

:100

2268

81)

SMAP

1 (c

hr6:

7150

8369

)NIPA2

(chr

15:2

3021

238)

OSB

PL5

(chr

11:3

1417

42)

SLAM

F1 (c

hr1:

1605

8960

0)TM

EM22

(chr

3:13

6573

485)

CLO

CK

(chr

4:56

3369

53)

NEK

3 (c

hr13

:527

1805

0)LG

ALS8

(chr

1:23

6702

201)

OR52N5

(chr

11:5

7996

51)

XPOT

(chr

12:6

4812

754)

OR5K3

(chr

3:98

1104

06)

LRRIQ1

(chr

12:8

5638

645)

MNS1

(chr

15:5

6736

722)

AASD

H (c

hr4:

5722

0268

)UBR

5 (c

hr8:

1032

8934

8)UPF

3A (c

hr13

:115

0572

10)

TMEM

60 (c

hr7:

7742

3459

)TE

AD2

(chr

19:4

9850

472)

RNAS

E8 (c

hr14

:215

2608

1)MET

TL17

(chr

14:2

1464

874)

C4orf6

(chr

4:55

2711

5)SE

C63

(chr

6:10

8214

754)

PSMD9

(chr

12:1

2235

3789

)C15orf40

(chr

15:8

3677

270)

DOCK3

(chr

3:51

4176

03)

PRDM2

(chr

1:14

1087

48)

CCDC168

(chr

13:1

0338

1995

)CELA3B

(chr

1:22

3107

24)

FAM111B

(chr

11:5

8892

376)

BAX

(chr

19:4

9458

970)

SPINK5

(chr

5:14

7499

874)

TMIGD2

(chr

19:4

2928

40)

PCDHGA10

(chr

5:14

0795

208)

KIAA

1919

(chr

6:11

1587

360)

GBP

3 (c

hr1:

8947

3441

)KC

NMA1

(chr

10:7

8729

785)

FGFB

P1 (c

hr4:

1593

8177

)JPH4

(chr

14:2

4040

435)

COBLL1

(chr

2:16

5551

295)

FLRT1

(chr

11:6

3885

305)

ESRP1

(chr

8:95

6866

10)

EIF2B3

(chr

1:45

4071

81)

MIS18BP

1 (c

hr14

:456

9372

1)TR

IM59

(chr

3:16

0156

367)

SMC6

(chr

2:17

8981

25)

LRRIQ3

(chr

1:74

5752

12)

GRK4

(chr

4:30

1546

9)SLC16A4

(chr

1:11

0906

426)

MYO

1A (c

hr12

:574

2257

2)PD

S5B

(chr

13:3

3344

887)

Supplementary Figure 7: Coding MSI loci recurrently subject to frameshift MSI events in the 22 cancer types studied (Table 1). This analysis included MSI-H, MSI-L and MSS tumors. The heatmapshows the fraction of tumors from each cancer type harboring frameshift MSI mutations in MS locilocated within the coding sequence of the genes indicated on the x axis. The total count of frameshift MSI events at those MSI loci across all tumor types is depicted in the above barplot.

0

2000

4000

6000

0 200 400 600MSI events WXS (coding, 3'UTR and 5'UTR)

MSI

eve

nts

WG

S (c

odin

g, 3

'UTR

and

5'U

TR)

0

1000

2000

3000

4000

0 100 200 300MSI events WXS (3'UTR)

MSI

eve

nts

WG

S (3

'UTR

)

0

100

200

0 20 40 60MSI events WXS (5'UTR)

MSI

eve

nts

WG

S (5

'UTR

)

0

500

1000

0 100 200 300MSI events WXS (coding)

MSI

eve

nts

WG

S (c

odin

g)

a b

c d

Supplementary Figure 8: Cross-platform comparison of MSI calls in exonic (coding and 3’/5’ UTR) (a), 3’UTR (b), 5’UTR (c) and coding (d) MS repeats.

0

25

50

75

100

0 25 50 75 100

% of reads subsampled from tumor (82X)

% re

ads

subs

ampl

ed fr

om m

atch

ed n

orm

al (4

8X)

0 1 2 3 4 5log10 # MSI events

0

25

50

75

100

0 25 50 75 100

% of reads subsampled from tumor (82X)

% re

ads

subs

ampl

ed fr

om m

atch

ed n

orm

al (4

8X)

25 50 75 100Percentage of MSI events recovered

a

b

Supplementary Figure 9: Influence of read depth on MSI calling across increasing larger random subsamples of reads from the tumor (82X) and matched normal (42X) bam files corresponding to the patient TCGA-AD-A5EJ. The total number of MSI events and the percentage of MSI called at different subsampling levels are depicted in (a) and (b), respectively.

50

75

100

125

40 60 80 100Coverage matched normal

Cov

erag

e tu

mor

BRCACOADGBMHNSCKICHKIRCKIRPLIHCLUADLUSCOVREADSKCMSTADTHCAUCEC

MSI events0e+00

1e+05

2e+05

3e+05

4e+05

Supplementary Figure 10: Average read depth of the tumor (y-axis) and matched normal (x-axis) samples.

0.4

0.6

0.8

1.0

0 2 4log10 # MSI events

Tum

or p

urity

(CPE

, Ara

n et

al.,

201

6 N

at. C

omm

un.)

BRCA

COAD

GBM

HNSC

KICH

KIRC

KIRP

LIHC

LUAD

LUSC

OV

READ

SKCM

THCA

UCEC

Supplementary Figure 11: Correlation between MSI rates vs tumor purity.

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●●

●

●

●

●

●

●

●

●

●

●

●●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

−0.25

0.00

0.25

0.50

0.75

100Kb 1MB 10MB

Pear

son'

s co

r. co

eff.

SNV

vs M

SI e

vent

s

Supplementary Figure 12: Distribution of Pearson correlation coefficients for SNV and MSI rates measured in (a) 1Mb, (b) 10Mb and (c) 100Kb bins. Blue points indicate the median and the interquartile range (25th-75th percentile), whereas red points indicate the mean value.

●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

80

25_Q

uies

8_Tx

Wk

5_Tx

5'7_

Tx3'

24_R

eprP

C17

_Enh

W2

21_H

et19

_DNa

se2_

Prom

U1_

TssA

12_T

xEnh

W3_

Prom

D115

_Enh

AF18

_Enh

Ac6_

Tx22

_Pro

mP

10_T

xEnh

5'14

_Enh

A223

_Pro

mBi

v16

_Enh

W1

9_Tx

Reg

4_Pr

omD2

13_E

nhA1

20_Z

NF/R

pts

11_T

xEnh

3'

MSI

freq

uenc

y (%

)

TCGA−06−0152 (GBM)

●

●

● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

80

25_Q

uies

8_Tx

Wk

5_Tx

5'7_

Tx3'

24_R

eprP

C19

_DNa

se18

_Enh

Ac17

_Enh

W2

15_E

nhAF

21_H

et12

_TxE

nhW

6_Tx

22_P

rom

P14

_Enh

A22_

Prom

U4_

Prom

D216

_Enh

W1

3_Pr

omD1

1_Ts

sA23

_Pro

mBi

v10

_TxE

nh5'

20_Z

NF/R

pts

9_Tx

Reg

11_T

xEnh

3'13

_Enh

A1

MSI

freq

uenc

y (%

)

TCGA−09−2050 (OV)

●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

80

25_Q

uies

8_Tx

Wk

5_Tx

5'7_

Tx3'

24_R

eprP

C18

_Enh

Ac19

_DNa

se17

_Enh

W2

22_P

rom

P12

_TxE

nhW

15_E

nhAF

21_H

et6_

Tx2_

Prom

U1_

TssA

4_Pr

omD2

10_T

xEnh

5'3_

Prom

D114

_Enh

A223

_Pro

mBi

v16

_Enh

W1

20_Z

NF/R

pts

9_Tx

Reg

13_E

nhA1

11_T

xEnh

3'

MSI

freq

uenc

y (%

)

TCGA−13−1491 (OV)

●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

80

25_Q

uies

8_Tx

Wk

5_Tx

5'7_

Tx3'

24_R

eprP

C17

_Enh

W2

19_D

Nase

21_H

et15

_Enh

AF12

_TxE

nhW

18_E

nhAc

2_Pr

omU

10_T

xEnh

5'14

_Enh

A26_

Tx16

_Enh

W1

3_Pr

omD1

9_Tx

Reg

13_E

nhA1

4_Pr

omD2

22_P

rom

P23

_Pro

mBi

v11

_TxE

nh3'

1_Ts

sA20

_ZNF

/Rpt

s

MSI

freq

uenc

y (%

)

TCGA−14−1034 (GBM)

●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

80

25_Q

uies

8_Tx

Wk

5_Tx

5'7_

Tx3'

24_R

eprP

C19

_DNa

se18

_Enh

Ac17

_Enh

W2

21_H

et12

_TxE

nhW

15_E

nhAF

6_Tx

22_P

rom

P10

_TxE

nh5'

14_E

nhA2

2_Pr

omU

1_Ts

sA16

_Enh

W1

23_P

rom

Biv

3_Pr

omD1

4_Pr

omD2

11_T

xEnh

3'9_

TxRe

g13

_Enh

A120

_ZNF

/Rpt

s

MSI

freq

uenc

y (%

)

TCGA−24−1557 (OV)

●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

25_Q

uies

8_Tx

Wk

5_Tx

5'7_

Tx3'

24_R

eprP

C18

_Enh

Ac19

_DNa

se17

_Enh

W2

6_Tx

12_T

xEnh

W15

_Enh

AF21

_Het

22_P

rom

P23

_Pro

mBi

v2_

Prom

U3_

Prom

D116

_Enh

W1

1_Ts

sA10

_TxE

nh5'

4_Pr

omD2

20_Z

NF/R

pts

14_E

nhA2

11_T

xEnh

3'13

_Enh

A19_

TxRe

g

MSI

freq

uenc

y (%

)

TCGA−24−1614 (OV)

●

●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

80

25_Q

uies

8_Tx

Wk

7_Tx

3'5_

Tx5'

24_R

eprP

C19

_DNa

se17

_Enh

W2

18_E

nhAc

21_H

et15

_Enh

AF13

_Enh

A122

_Pro

mP

14_E

nhA2

6_Tx

16_E

nhW

110

_TxE

nh5'

9_Tx

Reg

4_Pr

omD2

23_P

rom

Biv

12_T

xEnh

W2_

Prom

U3_

Prom

D111

_TxE

nh3'

20_Z

NF/R

pts

1_Ts

sA

MSI

freq

uenc

y (%

)

TCGA−34−2600 (LUSC)

●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

80

25_Q

uies

8_Tx

Wk

5_Tx

5'7_

Tx3'

24_R

eprP

C21

_Het

17_E

nhW

219

_DNa

se18

_Enh

Ac15

_Enh

AF6_

Tx12

_TxE

nhW

2_Pr

omU

14_E

nhA2

13_E

nhA1

3_Pr

omD1

10_T

xEnh

5'9_

TxRe

g22

_Pro

mP

23_P

rom

Biv

16_E

nhW

11_

TssA

4_Pr

omD2

11_T

xEnh

3'20

_ZNF

/Rpt

s

MSI

freq

uenc

y (%

)

TCGA−37−4135 (LUSC)

●

●

●●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

25_Q

uies

8_Tx

Wk

5_Tx

5'7_

Tx3'

18_E

nhAc

24_R

eprP

C6_

Tx19

_DNa

se12

_TxE

nhW

13_E

nhA1

17_E

nhW

29_

TxRe

g15

_Enh

AF14

_Enh

A210

_TxE

nh5'

2_Pr

omU

4_Pr

omD2

22_P

rom

P21

_Het

3_Pr

omD1

16_E

nhW

111

_TxE

nh3'

20_Z

NF/R

pts

1_Ts

sA23

_Pro

mBi

v

MSI

freq

uenc

y (%

)

TCGA−A5−A0G9 (UCEC)

●

●

●●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

25_Q

uies

8_Tx

Wk

5_Tx

5'7_

Tx3'

18_E

nhAc

6_Tx

24_R

eprP

C19

_DNa

se12

_TxE

nhW

13_E

nhA1

10_T

xEnh

5'14

_Enh

A29_

TxRe

g17

_Enh

W2

15_E

nhAF

22_P

rom

P21

_Het

4_Pr

omD2

3_Pr

omD1

2_Pr

omU

16_E

nhW

111

_TxE

nh3'

1_Ts

sA20

_ZNF

/Rpt

s23

_Pro

mBi

v

MSI

freq

uenc

y (%

)

TCGA−A5−A0GA (UCEC)

●

●

● ●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

6025

_Qui

es8_

TxW

k5_

Tx5'

7_Tx

3'12

_TxE

nhW

24_R

eprP

C6_

Tx17

_Enh

W2

21_H

et19

_DNa

se10

_TxE

nh5'

15_E

nhAF

18_E

nhAc

14_E

nhA2

4_Pr

omD2

22_P

rom

P9_

TxRe

g2_

Prom

U20

_ZNF

/Rpt

s16

_Enh

W1

3_Pr

omD1

11_T

xEnh

3'13

_Enh

A123

_Pro

mBi

v1_

TssA

MSI

freq

uenc

y (%

)TCGA−A6−6781 (COAD)

●

●

● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

25_Q

uies

8_Tx

Wk

5_Tx

5'7_

Tx3'

24_R

eprP

C12

_TxE

nhW

17_E

nhW

26_

Tx19

_DNa

se21

_Het

10_T

xEnh

5'15

_Enh

AF18

_Enh

Ac14

_Enh

A24_

Prom

D222

_Pro

mP

9_Tx

Reg

2_Pr

omU

16_E

nhW

13_

Prom

D120

_ZNF

/Rpt

s13

_Enh

A111

_TxE

nh3'

23_P

rom

Biv

1_Ts

sA

MSI

freq

uenc

y (%

)

TCGA−AA−3518 (COAD)

a b c

d e f

g h i

j k l

Supplementary Figure 13: Frequency of MSI events in the 25 states of the chromatin state map averaged across 127 epigenomes for samples TCGA-06-0152 (a), TCGA-24-1557 (b), TCGA-A5-A0G9 (c), TCGA-09-2050 (d), TCGA-24-1614 (e), TCGA-A5-A0GA (f), TCGA-13-1491 (g), TCGA-34-2600 (h), TCGA-A6-6781 (i), TCGA-14-1034 (j), TCGA-37-4135 (k) and TCGA-AA-3518 (l).

●

●

●●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

25_Q

uies

8_Tx

Wk

5_Tx

5'7_

Tx3'

24_R

eprP

C12

_TxE

nhW

6_Tx

17_E

nhW

221

_Het

10_T

xEnh

5'15

_Enh

AF4_

Prom

D218

_Enh

Ac19

_DNa

se2_

Prom

U9_

TxRe

g22

_Pro

mP

14_E

nhA2

3_Pr

omD1

20_Z

NF/R

pts

16_E

nhW

111

_TxE

nh3'

13_E

nhA1

23_P

rom

Biv

1_Ts

sA

MSI

freq

uenc

y (%

)

TCGA−AA−A00R (COAD)

●

●

● ●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

25_Q

uies

8_Tx

Wk

5_Tx

5'7_

Tx3'

12_T

xEnh

W17

_Enh

W2

24_R

eprP

C6_

Tx21

_Het

19_D

Nase

15_E

nhAF

10_T

xEnh

5'18

_Enh

Ac14

_Enh

A222

_Pro

mP

4_Pr

omD2

9_Tx

Reg

2_Pr

omU

16_E

nhW

120

_ZNF

/Rpt

s3_

Prom

D111

_TxE

nh3'

13_E

nhA1

23_P

rom

Biv

1_Ts

sA

MSI

freq

uenc

y (%

)

TCGA−AA−A01R (COAD)

●

●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

80

25_Q

uies

8_Tx

Wk

5_Tx

5'7_

Tx3'

24_R

eprP

C17

_Enh

W2

19_D

Nase

21_H

et6_

Tx15

_Enh

AF18

_Enh

Ac12

_TxE

nhW

14_E

nhA2

10_T

xEnh

5'13

_Enh

A14_

Prom

D216

_Enh

W1

2_Pr

omU

22_P

rom

P9_

TxRe

g3_

Prom

D123

_Pro

mBi

v20

_ZNF

/Rpt

s1_

TssA

11_T

xEnh

3'

MSI

freq

uenc

y (%

)

TCGA−AC−A2BK (BRCA)

●

●

● ●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

25_Q

uies

8_Tx

Wk

5_Tx

5'7_

Tx3'

12_T

xEnh

W6_

Tx17

_Enh

W2

24_R

eprP

C21

_Het

19_D

Nase

10_T

xEnh

5'15

_Enh

AF18

_Enh

Ac14

_Enh

A24_

Prom

D222

_Pro

mP

9_Tx

Reg

2_Pr

omU

20_Z

NF/R

pts

16_E

nhW

13_

Prom

D111

_TxE

nh3'

13_E

nhA1

23_P

rom

Biv

1_Ts

sA

MSI

freq

uenc

y (%

)

TCGA−AD−6964 (COAD)

●

●

● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

25_Q

uies

8_Tx

Wk

5_Tx

5'7_

Tx3'

12_T

xEnh

W24

_Rep

rPC

6_Tx

17_E

nhW

221

_Het

19_D

Nase

18_E

nhAc

15_E

nhAF

10_T

xEnh

5'4_

Prom

D222

_Pro

mP

14_E

nhA2

2_Pr

omU

9_Tx

Reg

16_E

nhW

120

_ZNF

/Rpt

s3_

Prom

D113

_Enh

A111

_TxE

nh3'

23_P

rom

Biv

1_Ts

sA

MSI

freq

uenc

y (%

)

TCGA−AD−A5EJ (COAD)

●

●

● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

80

25_Q

uies

8_Tx

Wk

5_Tx

5'7_

Tx3'

24_R

eprP

C17

_Enh

W2

21_H

et19

_DNa

se6_

Tx15

_Enh

AF12

_TxE

nhW

18_E

nhAc

10_T

xEnh

5'2_

Prom

U14

_Enh

A216

_Enh

W1

9_Tx

Reg

4_Pr

omD2

20_Z

NF/R

pts

13_E

nhA1

3_Pr

omD1

1_Ts

sA23

_Pro

mBi

v22

_Pro

mP

11_T

xEnh

3'

MSI

freq

uenc

y (%

)

TCGA−AO−A124 (BRCA)

●

●

● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

25_Q

uies

8_Tx

Wk

5_Tx

5'7_

Tx3'

18_E

nhAc

24_R

eprP

C6_

Tx13

_Enh

A112

_TxE

nhW

19_D

Nase

15_E

nhAF

17_E

nhW

29_

TxRe

g10

_TxE

nh5'

14_E

nhA2

2_Pr

omU

4_Pr

omD2

22_P

rom

P3_

Prom

D121

_Het

16_E

nhW

111

_TxE

nh3'

23_P

rom

Biv

1_Ts

sA20

_ZNF

/Rpt

s

MSI

freq

uenc

y (%

)

TCGA−AP−A051 (UCEC)

●

●

●●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

25_Q

uies

8_Tx

Wk

5_Tx

5'7_

Tx3'

18_E

nhAc

24_R

eprP

C6_

Tx19

_DNa

se13

_Enh

A112

_TxE

nhW

17_E

nhW

29_

TxRe

g15

_Enh

AF14

_Enh

A210

_TxE

nh5'

21_H

et2_

Prom

U22

_Pro

mP

4_Pr

omD2

3_Pr

omD1

16_E

nhW

120

_ZNF

/Rpt

s11

_TxE

nh3'

1_Ts

sA23

_Pro

mBi

v

MSI

freq

uenc

y (%

)

TCGA−AP−A054 (UCEC)

●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

80

25_Q

uies

8_Tx

Wk

7_Tx

3'5_

Tx5'

24_R

eprP

C18

_Enh

Ac19

_DNa

se21

_Het

13_E

nhA1

6_Tx

17_E

nhW

23_

Prom

D12_

Prom

U9_

TxRe

g15

_Enh

AF10

_TxE

nh5'

14_E

nhA2

12_T

xEnh

W22

_Pro

mP

1_Ts

sA23

_Pro

mBi

v16

_Enh

W1

4_Pr

omD2

20_Z

NF/R

pts

11_T

xEnh

3'

MSI

freq

uenc

y (%

)

TCGA−AP−A0L8 (UCEC)

●

●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

80

25_Q

uies

8_Tx

Wk

5_Tx

5'7_

Tx3'

24_R

eprP

C18

_Enh

Ac19

_DNa

se13

_Enh

A117

_Enh

W2

6_Tx

15_E

nhAF

14_E

nhA2

12_T

xEnh

W22

_Pro

mP

9_Tx

Reg

21_H

et10

_TxE

nh5'

2_Pr

omU

4_Pr

omD2

16_E

nhW

13_

Prom

D111

_TxE

nh3'

1_Ts

sA23

_Pro

mBi

v20

_ZNF

/Rpt

s

MSI

freq

uenc

y (%

)

TCGA−AP−A0L9 (UCEC)

●

●

● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

6025

_Qui

es8_

TxW

k5_

Tx5'

7_Tx

3'18

_Enh

Ac24

_Rep

rPC

6_Tx

19_D

Nase

13_E

nhA1

12_T

xEnh

W17

_Enh

W2

15_E

nhAF

9_Tx

Reg

14_E

nhA2

10_T

xEnh

5'21

_Het

22_P

rom

P2_

Prom

U4_

Prom

D23_

Prom

D116

_Enh

W1

11_T

xEnh

3'20

_ZNF

/Rpt

s1_

TssA

23_P

rom

Biv

MSI

freq

uenc

y (%

)TCGA−AP−A0LD (UCEC)

●

●

● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

25_Q

uies

8_Tx

Wk

5_Tx

5'7_

Tx3'

18_E

nhAc

24_R

eprP

C6_

Tx19

_DNa

se13

_Enh

A112

_TxE

nhW

17_E

nhW

29_

TxRe

g15

_Enh

AF10

_TxE

nh5'

14_E

nhA2

21_H

et22

_Pro

mP

2_Pr

omU

4_Pr

omD2

3_Pr

omD1

16_E

nhW

111

_TxE

nh3'

20_Z

NF/R

pts

1_Ts

sA23

_Pro

mBi

v

MSI

freq

uenc

y (%

)

TCGA−AP−A0LE (UCEC)

a b c

d e f

g h i

j k l

Supplementary Figure 14: Frequency of MSI events in the 25 states of the chromatin state map averaged across 127 epigenomes for samples TCGA-AA-A00R (a), TCGA-AD-A5EJ (b), TCGA-AP-A0L8 (c), TCGA-AA-A01R (d), TCGA-AO-A124 (e), TCGA-AP-A0L9 (f), TCGA-AC-A2BK (g), TCGA-AP-A051 (h), TCGA-AP-A0LD (i), TCGA-AD-6964 (j), TCGA-AP-A054 (k) and TCGA-AP-A0LE (l).

●

●

●●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

25_Q

uies

8_Tx

Wk

5_Tx

5'7_

Tx3'

24_R

eprP

C18

_Enh

Ac6_

Tx12

_TxE

nhW

13_E

nhA1

9_Tx

Reg

19_D

Nase

17_E

nhW

210

_TxE

nh5'

2_Pr

omU

15_E

nhAF

3_Pr

omD1

4_Pr

omD2

22_P

rom

P21

_Het

14_E

nhA2

16_E

nhW

11_

TssA

20_Z

NF/R

pts

11_T

xEnh

3'23

_Pro

mBi

v

MSI

freq

uenc

y (%

)

TCGA−AX−A05S (UCEC)

●

●

● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

25_Q

uies

8_Tx

Wk

5_Tx

5'7_

Tx3'

18_E

nhAc

24_R

eprP

C6_

Tx19

_DNa

se12

_TxE

nhW

13_E

nhA1

9_Tx

Reg

17_E

nhW

215

_Enh

AF10

_TxE

nh5'

14_E

nhA2

21_H

et22

_Pro

mP

2_Pr

omU

4_Pr

omD2

3_Pr

omD1

16_E

nhW

120

_ZNF

/Rpt

s11

_TxE

nh3'

1_Ts

sA23

_Pro

mBi

v

MSI

freq

uenc

y (%

)

TCGA−AX−A0J1 (UCEC)

●

●

●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

80

25_Q

uies

8_Tx

Wk

5_Tx

5'7_

Tx3'

18_E

nhAc

24_R

eprP

C19

_DNa

se6_

Tx12

_TxE

nhW

13_E

nhA1

17_E

nhW

221

_Het

9_Tx

Reg

10_T

xEnh

5'14

_Enh

A215

_Enh

AF22

_Pro

mP

4_Pr

omD2

2_Pr

omU

3_Pr

omD1

16_E

nhW

120

_ZNF

/Rpt

s11

_TxE

nh3'

23_P

rom

Biv

1_Ts

sA

MSI

freq

uenc

y (%

)

TCGA−B5−A11G (UCEC)

●

●

● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

25_Q

uies

8_Tx

Wk

5_Tx

5'7_

Tx3'

18_E

nhAc

24_R

eprP

C6_

Tx19

_DNa

se13

_Enh

A112

_TxE

nhW

17_E

nhW

215

_Enh

AF14

_Enh

A210

_TxE

nh5'

9_Tx

Reg

21_H

et22

_Pro

mP

2_Pr

omU

4_Pr

omD2

3_Pr

omD1

16_E

nhW

120

_ZNF

/Rpt

s11

_TxE

nh3'

1_Ts

sA23

_Pro

mBi

v

MSI

freq

uenc

y (%

)

TCGA−B5−A11H (UCEC)

●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

80

25_Q

uies

8_Tx

Wk

5_Tx

5'7_

Tx3'

24_R

eprP

C17

_Enh

W2

19_D

Nase

6_Tx

21_H

et15

_Enh

AF18

_Enh

Ac12

_TxE

nhW

4_Pr

omD2

10_T

xEnh

5'14

_Enh

A216

_Enh

W1

13_E

nhA1

9_Tx

Reg

2_Pr

omU

22_P

rom

P23

_Pro

mBi

v3_

Prom

D120

_ZNF

/Rpt

s11

_TxE

nh3'

1_Ts

sA

MSI

freq

uenc

y (%

)

TCGA−B6−A0I6 (BRCA)

●

●

● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

25_Q

uies

8_Tx

Wk

7_Tx

3'5_

Tx5'

24_R

eprP

C17

_Enh

W2

6_Tx

12_T

xEnh

W19

_DNa

se21

_Het

18_E

nhAc

15_E

nhAF

10_T

xEnh

5'2_

Prom

U14

_Enh

A23_

Prom

D14_

Prom

D29_

TxRe

g22

_Pro

mP

16_E

nhW

113

_Enh

A111

_TxE

nh3'

23_P

rom

Biv

20_Z

NF/R

pts

1_Ts

sA

MSI

freq

uenc

y (%

)

TCGA−BR−4280 (STAD)

●

●

● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

25_Q

uies

8_Tx

Wk

7_Tx

3'5_

Tx5'

24_R

eprP

C17

_Enh

W2

6_Tx

12_T

xEnh

W19

_DNa

se21

_Het

18_E

nhAc

15_E

nhAF

10_T

xEnh

5'2_

Prom

U14

_Enh

A222

_Pro

mP

3_Pr

omD1

4_Pr

omD2

16_E

nhW

19_

TxRe

g13

_Enh

A120

_ZNF

/Rpt

s11

_TxE

nh3'

23_P

rom

Biv

1_Ts

sA

MSI

freq

uenc

y (%

)

TCGA−BR−6452 (STAD)

●

●

● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

25_Q

uies

8_Tx

Wk

5_Tx

5'7_

Tx3'

18_E

nhAc

24_R

eprP

C6_

Tx13

_Enh

A119

_DNa

se12

_TxE

nhW

17_E

nhW

210

_TxE

nh5'

9_Tx

Reg

15_E

nhAF

21_H

et14

_Enh

A22_

Prom

U3_

Prom

D14_

Prom

D222

_Pro

mP

16_E

nhW

120

_ZNF

/Rpt

s11

_TxE

nh3'

1_Ts

sA23

_Pro

mBi

v

MSI

freq

uenc

y (%

)

TCGA−BS−A0TE (UCEC)

●

●

● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

25_Q

uies

8_Tx

Wk

7_Tx

3'5_

Tx5'

24_R

eprP

C17

_Enh

W2

6_Tx

12_T

xEnh

W19

_DNa

se21

_Het

18_E

nhAc

15_E

nhAF

10_T

xEnh

5'2_

Prom

U14

_Enh

A23_

Prom

D122

_Pro

mP

4_Pr

omD2

16_E

nhW

19_

TxRe

g13

_Enh

A120

_ZNF

/Rpt

s11

_TxE

nh3'

23_P

rom

Biv

1_Ts

sA

MSI

freq

uenc

y (%

)

TCGA−CG−4442 (STAD)

●

●

● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

25_Q

uies

8_Tx

Wk

7_Tx

3'5_

Tx5'

24_R

eprP

C17

_Enh

W2

6_Tx

12_T

xEnh

W21

_Het

15_E

nhAF

19_D

Nase

18_E

nhAc

10_T

xEnh

5'2_

Prom

U9_

TxRe

g14

_Enh

A213

_Enh

A116

_Enh

W1

11_T

xEnh

3'3_

Prom

D120

_ZNF

/Rpt

s22

_Pro

mP

4_Pr

omD2

23_P

rom

Biv

1_Ts

sA

MSI

freq

uenc

y (%

)

TCGA−CG−5723 (STAD)

●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

8025

_Qui

es8_

TxW

k5_

Tx5'

7_Tx

3'24

_Rep

rPC

19_D

Nase

17_E

nhW

221

_Het

6_Tx

15_E

nhAF

18_E

nhAc

12_T

xEnh

W14

_Enh

A210

_TxE

nh5'

2_Pr

omU

4_Pr

omD2

16_E

nhW

13_

Prom

D113

_Enh

A19_

TxRe

g22

_Pro

mP

11_T

xEnh

3'23

_Pro

mBi

v20

_ZNF

/Rpt

s1_

TssA

MSI

freq

uenc

y (%

)TCGA−CN−6011 (HNSC)

●

●

● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

25_Q

uies

8_Tx

Wk

5_Tx

5'7_

Tx3'

24_R

eprP

C12

_TxE

nhW

17_E

nhW

26_

Tx21

_Het

19_D

Nase

15_E

nhAF

18_E

nhAc

10_T

xEnh

5'14

_Enh

A24_

Prom

D222

_Pro

mP

2_Pr

omU

9_Tx

Reg

16_E

nhW

120

_ZNF

/Rpt

s3_

Prom

D111

_TxE

nh3'

13_E

nhA1

23_P

rom

Biv

1_Ts

sA

MSI

freq

uenc

y (%

)

TCGA−D5−6540 (COAD)

a b c

d e f

g h i

j k l

Supplementary Figure 15: Frequency of MSI events in the 25 states of the chromatin state map averaged across 127 epigenomes for samples TCGA-AX-A05S (a), TCGA-B6-A0I6 (b), TCGA-CG-4442 (c), TCGA-AX-A0J1 (d), TCGA-BR-4280 (e), TCGA-CG-5723 (f), TCGA-B5-A11G (g), TCGA-BR-6452 (h), TCGA-CN-6011 (i), TCGA-B5-A11H (j), TCGA-BS-A0TE (k) and TCGA-D5-6540 (l).

●

●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20406080

25_Q

uies

8_Tx

Wk

5_Tx

5'7_

Tx3'

19_D

Nase

24_R

eprP

C17

_Enh

W2

21_H

et6_

Tx15

_Enh

AF18

_Enh

Ac12

_TxE

nhW

14_E

nhA2

10_T

xEnh

5'13

_Enh

A116

_Enh

W1

2_Pr

omU

22_P

rom

P4_

Prom

D23_

Prom

D111

_TxE

nh3'

9_Tx

Reg

20_Z

NF/R

pts

1_Ts

sA23

_Pro

mBi

v

MSI

freq

uenc

y (%

)

TCGA−EW−A1PC (BRCA)

●

●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

25

50

75

25_Q

uies

8_Tx

Wk

5_Tx

5'7_

Tx3'

18_E

nhAc

24_R

eprP

C19

_DNa

se21

_Het

6_Tx

2_Pr

omU

22_P

rom

P13

_Enh

A110

_TxE

nh5'

12_T

xEnh

W15

_Enh

AF17

_Enh

W2

9_Tx

Reg

4_Pr

omD2

14_E

nhA2

16_E

nhW

123

_Pro

mBi

v3_

Prom

D111

_TxE

nh3'

20_Z

NF/R

pts

1_Ts

sA

MSI

freq

uenc

y (%

)

TCGA−EY−A1GS (UCEC)

●

●

● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

25_Q

uies

8_Tx

Wk

7_Tx

3'5_

Tx5'

24_R

eprP

C17

_Enh

W2

6_Tx

12_T

xEnh

W21

_Het

19_D

Nase

18_E

nhAc

15_E

nhAF

10_T

xEnh

5'2_

Prom

U14

_Enh

A222

_Pro

mP

3_Pr

omD1

4_Pr

omD2

9_Tx

Reg

16_E

nhW

113

_Enh

A111

_TxE

nh3'

20_Z

NF/R

pts

23_P

rom

Biv

1_Ts

sA

MSI

freq

uenc

y (%

)

TCGA−F1−6177 (STAD)

●

●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20406080

25_Q

uies

8_Tx

Wk

7_Tx

3'5_

Tx5'

24_R

eprP

C17

_Enh

W2

21_H

et19

_DNa

se6_

Tx12

_TxE

nhW

18_E

nhAc

15_E

nhAF

2_Pr

omU

10_T

xEnh

5'3_

Prom

D114

_Enh

A216

_Enh

W1

23_P

rom

Biv

22_P

rom

P13

_Enh

A111

_TxE

nh3'

9_Tx

Reg

1_Ts

sA4_

Prom

D220

_ZNF

/Rpt

s

MSI

freq

uenc

y (%

)

TCGA−F1−6875 (STAD)

●

●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20406080

25_Q

uies

8_Tx

Wk

7_Tx

3'5_

Tx5'

24_R

eprP

C17

_Enh

W2

19_D

Nase

21_H

et18

_Enh

Ac12

_TxE

nhW

6_Tx

15_E

nhAF

4_Pr

omD2

16_E

nhW

12_

Prom

U14

_Enh

A222

_Pro

mP

3_Pr

omD1

23_P

rom

Biv

10_T

xEnh

5'11

_TxE

nh3'

20_Z

NF/R

pts

1_Ts

sA9_

TxRe

g13

_Enh

A1

MSI

freq

uenc

y (%

)

TCGA−IA−A40Y (KIRP)

●

●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20406080

25_Q

uies

8_Tx

Wk

7_Tx

3'5_

Tx5'

24_R

eprP

C17

_Enh

W2

19_D

Nase

21_H

et18

_Enh

Ac6_

Tx12

_TxE

nhW

15_E

nhAF

16_E

nhW

14_

Prom

D222

_Pro

mP

2_Pr

omU

14_E

nhA2

10_T

xEnh

5'23

_Pro

mBi

v3_

Prom

D120

_ZNF

/Rpt

s11

_TxE

nh3'

13_E

nhA1

9_Tx

Reg

1_Ts

sA

MSI

freq

uenc

y (%

)

TCGA−KL−8330 (KICH)

●

●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20406080

25_Q

uies

8_Tx

Wk

7_Tx

3'5_

Tx5'

17_E

nhW

224

_Rep

rPC

19_D

Nase

21_H

et18

_Enh

Ac6_

Tx12

_TxE

nhW

15_E

nhAF

4_Pr

omD2

14_E

nhA2

16_E

nhW

13_

Prom

D122

_Pro

mP

23_P

rom

Biv

2_Pr

omU

11_T

xEnh

3'10

_TxE

nh5'

20_Z

NF/R

pts

9_Tx

Reg

13_E

nhA1

1_Ts

sA

MSI

freq

uenc

y (%

)TCGA−KL−8337 (KICH)

●

●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20406080

25_Q

uies

8_Tx

Wk

7_Tx

3'5_

Tx5'

24_R

eprP

C17

_Enh

W2

21_H

et18

_Enh

Ac19

_DNa

se12

_TxE

nhW

6_Tx

15_E

nhAF

16_E

nhW

14_

Prom

D220

_ZNF

/Rpt

s22

_Pro

mP

14_E

nhA2

2_Pr

omU

23_P

rom

Biv

9_Tx

Reg

10_T

xEnh

5'11

_TxE

nh3'

3_Pr

omD1

13_E

nhA1

1_Ts

sA

MSI

freq

uenc

y (%

)


●

●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

80

25_Q

uies

8_Tx

Wk

7_Tx

3'5_

Tx5'

24_R

eprP

C17

_Enh

W2

21_H

et19

_DNa

se18

_Enh

Ac6_

Tx12

_TxE

nhW

16_E

nhW

115

_Enh

AF14

_Enh

A222

_Pro

mP

2_Pr

omU

4_Pr

omD2

23_P

rom

Biv

10_T

xEnh

5'20

_ZNF

/Rpt

s3_

Prom

D111

_TxE

nh3'

9_Tx

Reg

13_E

nhA1

1_Ts

sA

MSI

freq

uenc

y (%

)


●

●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

80

25_Q

uies

8_Tx

Wk

7_Tx

3'5_

Tx5'

24_R

eprP

C17

_Enh

W2

19_D

Nase

21_H

et18

_Enh

Ac6_

Tx12

_TxE

nhW

16_E

nhW

115

_Enh

AF2_

Prom

U22

_Pro

mP

3_Pr

omD1

4_Pr

omD2

10_T

xEnh

5'14

_Enh

A223

_Pro

mBi

v9_

TxRe

g20

_ZNF

/Rpt

s11

_TxE

nh3'

1_Ts

sA13

_Enh

A1

MSI

freq

uenc

y (%

)

TCGA−KM−8440 (KICH)

●

●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20406080

25_Q

uies

8_Tx

Wk

7_Tx

3'5_

Tx5'

24_R

eprP

C17

_Enh

W2

21_H

et19

_DNa

se6_

Tx18

_Enh

Ac12

_TxE

nhW

15_E

nhAF

16_E

nhW

14_

Prom

D214

_Enh

A210

_TxE

nh5'

22_P

rom

P2_

Prom

U23

_Pro

mBi

v11

_TxE

nh3'

20_Z

NF/R

pts

1_Ts

sA13

_Enh

A13_

Prom

D19_

TxRe

g

MSI

freq

uenc

y (%

)


●

●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

80

25_Q

uies

8_Tx

Wk

7_Tx

3'5_

Tx5'

24_R

eprP

C17

_Enh

W2

19_D

Nase

21_H

et18

_Enh

Ac12

_TxE

nhW

15_E

nhAF

6_Tx

16_E

nhW

12_

Prom

U4_

Prom

D210

_TxE

nh5'

14_E

nhA2

22_P

rom

P3_

Prom

D123

_Pro

mBi

v1_

TssA

11_T

xEnh

3'13

_Enh

A120

_ZNF

/Rpt

s9_

TxRe

g

MSI

freq

uenc

y (%

)


●

●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20406080

25_Q

uies

8_Tx

Wk

7_Tx

3'5_

Tx5'

24_R

eprP

C17

_Enh

W2

21_H

et19

_DNa

se12

_TxE

nhW

18_E

nhAc

6_Tx

15_E

nhAF

16_E

nhW

12_

Prom

U14

_Enh

A222

_Pro

mP

23_P

rom

Biv

4_Pr

omD2

20_Z

NF/R

pts

3_Pr

omD1

10_T

xEnh

5'11

_TxE

nh3'

9_Tx

Reg

13_E

nhA1

1_Ts

sA

MSI

freq

uenc

y (%

)

TCGA−KO−8409 (KICH)

●

●

● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●0

20

40

60

25_Q

uies

8_Tx

Wk

5_Tx

5'7_

Tx3'

12_T

xEnh

W6_

Tx17

_Enh

W2

24_R

eprP

C21

_Het

19_D

Nase

18_E

nhAc

15_E

nhAF

10_T

xEnh

5'14

_Enh

A24_

Prom

D222

_Pro

mP

2_Pr

omU

9_Tx

Reg

16_E

nhW

120

_ZNF

/Rpt

s3_

Prom

D113

_Enh

A111

_TxE

nh3'

23_P

rom

Biv

1_Ts

sA

MSI

freq

uenc

y (%

)

TCGA−QG−A5Z2 (COAD)

a b c

d e f

g h i

j k l

m n

Supplementary Figure 16: Frequency of MSI events in the 25 states of the chromatin state map averaged across 127 epigenomes for samples TCGA-EW-A1PC (a), TCGA-KL-8330 (b), TCGA-KM-8442 (c), TCGA-EY-A1GS (d), TCGA-KL-8337 (e), TCGA-KM-8443 (f), TCGA-F1-6177 (g), TCGA-KL-8341 (h), TCGA-KO-8409 (i), TCGA-F1-6875 (j), TCGA-KL-8346 (k), TCGA-QG-A5Z2 (l), (m) TCGA−IA−A40Y and(n) TCGA−KM−8440.

25_Quies

24_ReprPC

23_PromBiv

22_PromP

21_Het

20_ZNF/Rpts

19_DNase

18_EnhAc

17_EnhW2

16_EnhW1

15_EnhAF

14_EnhA2

13_EnhA1

12_TxEnhW

11_TxEnh3'

10_TxEnh5'

9_TxReg

8_TxWk

7_Tx3'

6_Tx

5_Tx5'

4_PromD2

3_PromD1

2_PromU

1_TssA

1

2

Odds ratio

25_Quies

24_ReprPC

23_PromBiv

22_PromP

21_Het

20_ZNF/Rpts

19_DNase

18_EnhAc

17_EnhW2

16_EnhW1

15_EnhAF

14_EnhA2

13_EnhA1

12_TxEnhW

11_TxEnh3'

10_TxEnh5'

9_TxReg

8_TxWk

7_Tx3'

6_Tx

5_Tx5'

4_PromD2

3_PromD1

2_PromU

1_TssA

TCG

A−06−0

152

(GBM

) unk

nown

TCG

A−09−2

050

(OV)

unk

nown

TCG

A−13−1

491

(OV)

unk

nown

TCG

A−14−1

034

(GBM

) unk

nown

TCG

A−24−1

557

(OV)

unk

nown

TCG

A−24−1

614

(OV)

unk

nown

TCG

A−34−2

600

(LUS

C) u

nkno

wnTC

GA−

37−4

135

(LUS

C) u

nkno

wnTC

GA−

A5−A

0G9

(UCE

C) M

SI−H

TCG

A−A5−A

0GA

(UCE

C) M

SI−H

TCG

A−A6−6

781

(CO

AD) u

nkno

wnTC

GA−

AA−3

518

(CO

AD) M

SI−H

TCG

A−AA

−A00

R (C

OAD

) MSI−H

TCG

A−AA

−A01

R (C

OAD

) MSI−H

TCG

A−AC

−A2B

K (B

RCA)

unk

nown

TCG

A−AD

−696

4 (C

OAD

) unk

nown

TCG

A−AD

−A5E

J (C

OAD

) unk

nown

TCG

A−AO

−A12

4 (B

RCA)

unk

nown

TCG

A−AP

−A05

1 (U

CEC)

MSI−H

TCG

A−AP

−A05

4 (U

CEC)

MSI−H

TCG

A−AP

−A0L

8 (U

CEC)

MSS

TCG

A−AP

−A0L

9 (U

CEC)

MSS

TCG

A−AP

−A0L

D (U

CEC)

MSI−H

TCG

A−AP

−A0L

E (U

CEC)

MSI−H

TCG

A−AX

−A05

S (U

CEC)

MSI−H

TCG

A−AX

−A0J

1 (U

CEC)

MSI−H

TCG

A−B5−A

11G

(UCE

C) M

SI−H

TCG

A−B5−A

11H

(UCE

C) M

SI−H

TCG

A−B6−A

0I6

(BRC

A) u

nkno

wnTC

GA−

BR−4

280

(STA

D) M

SI−H

TCG

A−BR

−645

2 (S

TAD)

MSI−H

TCG

A−BS

−A0T

E (U

CEC)

MSI−H

TCG

A−CG

−444

2 (S

TAD)

MSI−H

TCG

A−CG

−572

3 (S

TAD)

MSI−H

TCG

A−CN

−601

1 (H

NSC)

unk

nown

TCG

A−D5

−654

0 (C

OAD

) unk

nown

TCG

A−EW

−A1P

C (B

RCA)

unk

nown

TCG

A−EY

−A1G

S (U

CEC)

MSS

TCG

A−F1−6

177

(STA

D) M

SI−H

TCG

A−F1−6

875

(STA

D) M

SSTC

GA−

IA−A

40Y

(KIR

P) u

nkno

wnTC

GA−

KL−8

330

(KIC

H) u

nkno

wnTC

GA−

KL−8

337

(KIC

H) u

nkno

wnTC

GA−

KL−8

341

(KIC

H) u

nkno

wnTC

GA−

KL−8

346

(KIC

H) u

nkno

wnTC

GA−

KM−8

440

(KIC

H) u

nkno

wnTC

GA−

KM−8

442

(KIC

H) u

nkno

wnTC

GA−

KM−8

443

(KIC

H) u

nkno

wnTC

GA−

KO−8

409

(KIC

H) u

nkno

wnTC

GA−

QG−A

5Z2

(CO

AD) u

nkno

wn

P value(Fisher's test)

Non Significant

Significant

a

b

Supplementary Figure 17: Enrichment of MSI events in the 25 states of the chromatin state map. Odds ratio (a) and p values (b) for each chromatin state in the 30 whole-genomes displaying the highestMSI rates. Enrichment of MSI events in each chromatin state was tested using Fisher’s exact test (Methods).

0

5

10

15

20

25

30

Rel

ativ

e fr

eque

ncy

(%)

MSI-H MSI-H (P) MSI-L/MSS

AC

N>A

C

CN

>A

GC

N>A

TC

N>A

AC

N>G

C

CN

>G

GC

N>G

TC

N>G

AC

N>T

C

CN

>T

GC

N>T

TC

N>T

ATN

>A

CTN

>A

GTN

>A

TTN

>A

ATN

>C

CTN

>C

GTN

>C

TTN

>C

ATN

>G

CTN

>G

GTN

>G

TTN

>G

Supplementary Figure 18: Mutation signatures of predicted MSI-H genomes. The relative frequencies of the 96 trinucleotide mutation contexts (strand symmetric) are shown for MSI-H, MSI-H (predicted) and MSI-L/MSS cases (red, orange and green, respectively). Mutations were pooled across the genomes of three MSI-prone tumor types of COAD/READ, STAD and UCEC. Arrows indicate known mutation features of MSI-H genomes, e.g., C>T transitions in (A/C/G)pCpN sequence contexts and C>A transversions at an CpCpN context, which are enriched in both MSI-H and MSI-H (predicted) genomes compared to MSI-L/MSS genomes.

343-53678-9-4:78;

Documents