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Splice variants as novel targets in pancrea0c ductal adenocarcinoma Jun Wang 1 , Laurent Dumar0n 1 , Andrea Mafficini 2 , Pinar Ulug 1 , Ajanthah Sangaralingam 1 , Namaa Audi Alamiry 1 , Tomasz P Radon 1 , Roberto Salvia 2 , Rita T Lawlor 2 , Nicholas R Lemoine 1 , Aldo Scarpa 2 , Claude Chelala 1,# and Tatjana Crnogorac-Jurcevic 1,# 1 Centre for Molecular Oncology, Barts Cancer Ins0tute, Queen Mary University of London, London, UK; 2 ARC-Net Research Centre and Department of Diagnos0cs and Publich Health, Sec0on of Pathology, University and Hospital Trust of Verona, Verona, Italy # These authors jointly supervised this work Correspondence and requests for materials should be addressed to J.W. (email: [email protected]) or T.C.J. (email: [email protected])

Splice variants as novel targets in pancreac ductal ...€¦ · Splice variants as novel targets in pancreac ductal adenocarcinoma Jun Wang 1, Laurent Dumar0n , Andrea Mafficini2,

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Page 1: Splice variants as novel targets in pancreac ductal ...€¦ · Splice variants as novel targets in pancreac ductal adenocarcinoma Jun Wang 1, Laurent Dumar0n , Andrea Mafficini2,

Splicevariantsasnoveltargetsinpancrea0cductaladenocarcinoma

JunWang1,LaurentDumar0n1,AndreaMafficini2,PinarUlug1,AjanthahSangaralingam1,NamaaAudiAlamiry1,TomaszPRadon1,RobertoSalvia2,RitaTLawlor2,NicholasRLemoine1,AldoScarpa2,ClaudeChelala1,#andTatjanaCrnogorac-Jurcevic1,#

1CentreforMolecularOncology,BartsCancerIns0tute,QueenMaryUniversityofLondon,London,UK;2ARC-NetResearchCentreandDepartmentofDiagnos0csandPublichHealth,Sec0onofPathology,UniversityandHospitalTrustofVerona,Verona,Italy#TheseauthorsjointlysupervisedthisworkCorrespondenceandrequestsformaterialsshouldbeaddressedtoJ.W.(email:[email protected])orT.C.J.(email:[email protected])

Page 2: Splice variants as novel targets in pancreac ductal ...€¦ · Splice variants as novel targets in pancreac ductal adenocarcinoma Jun Wang 1, Laurent Dumar0n , Andrea Mafficini2,

Figure S1. Unsupervised hierarchical clustering based on probeset (A) and transcript (B) expression level

A B

Page 3: Splice variants as novel targets in pancreac ductal ...€¦ · Splice variants as novel targets in pancreac ductal adenocarcinoma Jun Wang 1, Laurent Dumar0n , Andrea Mafficini2,

Figure S2. Gene expression and sample clustering of Collisson signature (62 genes) in BCI and Zhang merged dataset

Page 4: Splice variants as novel targets in pancreac ductal ...€¦ · Splice variants as novel targets in pancreac ductal adenocarcinoma Jun Wang 1, Laurent Dumar0n , Andrea Mafficini2,

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log2 (Probeset expression) mean

log2 (FIRMA score) mean

log2 (FIRMA FC)

p_37

6220

0p_

3762

201

p_37

6220

2p_

3762

203

p_37

6220

4p_

3762

206

p_37

6220

7p_

3762

208

p_37

6221

0p_

3762

211

p_37

6221

2p_

3762

213

p_37

6221

5p_

3762

217

p_37

6221

8p_

3762

221

p_37

6222

2p_

3762

227

p_37

6222

8p_

3762

234

p_37

6223

6p_

3762

238

p_37

6223

9p_

3762

241

p_37

6224

2p_

3762

244

p_37

6224

5p_

3762

250

p_37

6225

7p_

3762

258

p_37

6226

0p_

3762

262

p_37

6226

3p_

3762

267

p_37

6226

8p_

3762

269

p_37

6227

0

−10

−5

0

5

10

15

−10

−5

0

5

10

15

−10

−5

0

5

10

15

● Normal PDAC log2FC(PDAC/normal)

Transcription direction

Figure S3A. alternative splicing in COL1A1

Page 5: Splice variants as novel targets in pancreac ductal ...€¦ · Splice variants as novel targets in pancreac ductal adenocarcinoma Jun Wang 1, Laurent Dumar0n , Andrea Mafficini2,

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log2 (Probeset expression) mean

log2 (FIRMA score) mean

log2 (FIRMA FC)

p_32

8419

1

p_32

8419

8

p_32

8419

9

p_32

8420

4

p_32

8420

5

p_32

8420

6

p_32

8420

7

p_32

8420

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p_32

8421

0

p_32

8421

1

p_32

8421

3

p_32

8421

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p_32

8421

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p_32

8421

7

p_32

8421

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p_32

8422

1

p_32

8423

0

p_32

8423

2

−5

0

5

10

−5

0

5

10

−5

0

5

10

● Normal PDAC log2FC(PDAC/normal)

Transcription direction

Figure S3B. alternative splicing in ITGB1

Page 6: Splice variants as novel targets in pancreac ductal ...€¦ · Splice variants as novel targets in pancreac ductal adenocarcinoma Jun Wang 1, Laurent Dumar0n , Andrea Mafficini2,

0 1 2 3 4 5 6

Expr

essi

on ra

tio

(PD

AC

ove

r nor

mal

)

0 1 2 3 4 5 6

Expr

essi

on ra

tio

(PD

AC

ove

r nor

mal

)

A B

Figure S4. The expression ratio (PDAC over normal) of AS probesets and gene for ROBO1 and LRP8

Page 7: Splice variants as novel targets in pancreac ductal ...€¦ · Splice variants as novel targets in pancreac ductal adenocarcinoma Jun Wang 1, Laurent Dumar0n , Andrea Mafficini2,

A B

Figure S5A/B. Expression fold changes for TGFBR1, CALD1 and MACF1 in gene and probeset/exon levels

Page 8: Splice variants as novel targets in pancreac ductal ...€¦ · Splice variants as novel targets in pancreac ductal adenocarcinoma Jun Wang 1, Laurent Dumar0n , Andrea Mafficini2,

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log2 (Probeset expression) mean

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8176

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8176

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8176

5

p_31

8176

6

p_31

8176

7

● Normal PDAC log2FC(PDAC/normal)

Transcription direction

Figure S5C. Alternative splicing in TGFBR1

Page 9: Splice variants as novel targets in pancreac ductal ...€¦ · Splice variants as novel targets in pancreac ductal adenocarcinoma Jun Wang 1, Laurent Dumar0n , Andrea Mafficini2,

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10

p_30

2555

3p_

3025

554

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2558

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587

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2558

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3025

612

p_30

2562

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3025

628

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2562

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3025

630

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632

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2563

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644

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653

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2565

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655

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659

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661

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663

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2566

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3025

673

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2567

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3025

675

p_30

2567

6p_

3025

677

● Normal PDAC log2FC(PDAC/normal)

Transcription direction

Figure S5D. Alternative splicing in CALD1

Page 10: Splice variants as novel targets in pancreac ductal ...€¦ · Splice variants as novel targets in pancreac ductal adenocarcinoma Jun Wang 1, Laurent Dumar0n , Andrea Mafficini2,

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p_23

3122

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3127

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282

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3128

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2331

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3130

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3130

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2331

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3134

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2331

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3135

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353

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3135

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355

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3135

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2331

357

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3135

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359

p_23

3136

0p_

2331

361

p_23

3136

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2331

364

p_23

3136

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2331

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p_23

3137

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372

p_23

3137

3p_

2331

374

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3137

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2331

376

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3137

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p_23

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2331

383

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3138

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387

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3138

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2331

390

p_23

3139

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2331

392

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3139

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2331

395

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3139

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2331

398

p_23

3141

9p_

2331

420

p_23

3142

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3142

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2331

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431

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436

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438

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2331

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3144

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3144

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3144

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2331

446

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3144

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2331

448

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3144

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2331

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3145

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2331

454

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3145

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2331

457

p_23

3145

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2331

461

p_23

3146

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2331

465

p_23

3146

6p_

2331

468

p_23

3147

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2331

479

p_23

3148

1p_

2331

484

p_23

3148

5p_

2331

486

p_23

3148

7p_

2331

488

p_23

3148

9

● Normal PDAC log2FC(PDAC/normal)

Transcription direction

Figure S5E. Alternative splicing in MACF1

Page 11: Splice variants as novel targets in pancreac ductal ...€¦ · Splice variants as novel targets in pancreac ductal adenocarcinoma Jun Wang 1, Laurent Dumar0n , Andrea Mafficini2,

Down Adj. p < 0.05 Up

Adj. p < 0.05

Figure S6. The DE signatures for previously reported spliceosomal genes