In vivo disruption of an Rb-E2f-ezh2 signaling loop causes bladder cancer Mirentxu Santos1, 2



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Supp Table S9 Comparative transcriptome studies in Oncomine Database of genes upregulated in mouse bladder tumors


Genes Upregulated in mouse tumors
















Analysis Type:

Cancer vs. Normal Analysis



















Concept Name

Overlap

P-Value

Q-Value

Odds Ratio

Dataset




Infiltrating Bladder Urothelial Carcinoma vs. Normal - Top 10% Over-expressed (Sanchez-Carbayo Bladder 2)

306

1.31E-114

1.05E-111

7.4

Sanchez-Carbayo Bladder 2




Infiltrating Bladder Urothelial Carcinoma vs. Normal - Top 1% Over-expressed (Lee Bladder)

108

1.06E-90

3.63E-88

28.6

Lee Bladder




Superficial Bladder Cancer vs. Normal - Top 5% Over-expressed (Lee Bladder)

164

6.88E-47

7.72E-45

4.6

Lee Bladder




Superficial Bladder Cancer vs. Normal - Top 10% Over-expressed (Sanchez-Carbayo Bladder 2)

198

5.70E-38

5.20E-36

3.5

Sanchez-Carbayo Bladder 2




Infiltrating Bladder Urothelial Carcinoma vs. Normal - Top 10% Over-expressed (Dyrskjot Bladder 3)

191

2.88E-34

2.33E-32

3.3

Dyrskjot Bladder 3




Superficial Bladder Cancer vs. Normal - Top 10% Over-expressed (Dyrskjot Bladder 3)

166

1.93E-22

1.04E-20

2.7

Dyrskjot Bladder 3




Stage 0is Bladder Urothelial Carcinoma vs. Normal - Top 10% Over-expressed (Dyrskjot Bladder 3)

121

3.55E-07

7.94E-06

1.7

Dyrskjot Bladder 3




Infiltrating Bladder Urothelial Carcinoma vs. Normal - Top 10% Over-expressed (Blaveri Bladder 2)

70

5.37E-07

1.17E-05

2.1

Blaveri Bladder 2




Superficial Bladder Cancer vs. Normal - Top 10% Over-expressed (Blaveri Bladder 2)

69

1.13E-06

2.37E-05

2

Blaveri Bladder 2




Infiltrating Bladder Urothelial Carcinoma vs. Normal - Top 5% Over-expressed (Modlich Bladder)

13

0.005

0.056

2.6

Modlich Bladder











































Analysis Type:

Clinical Outcome Analysis
















Concept Type

Concept Name

Overlap

P-Value

Q-Value

Odds Ratio

Dataset




Infiltrating Bladder Urothelial Carcinoma - Dead at 1 Year - Top 10% Over-expressed (Blaveri Bladder 2)

107

1.91E-19

9.01E-18

3.2

Blaveri Bladder 2




Superficial Bladder Cancer - Dead at 1 Year - Top 10% Over-expressed (Blaveri Bladder 2)

90

1.32E-13

4.80E-12

2.8

Blaveri Bladder 2




Infiltrating Bladder Urothelial Carcinoma - Dead at 5 Years - Top 10% Over-expressed (Blaveri Bladder 2)

89

2.96E-12

9.99E-11

2.6

Blaveri Bladder 2




Infiltrating Bladder Urothelial Carcinoma - Dead at 1 Year - Top 10% Over-expressed (Lee Bladder)

153

1.06E-09

2.98E-08

1.8

Lee Bladder




Superficial Bladder Cancer - Dead at 5 Years - Top 10% Over-expressed (Blaveri Bladder 2)

78

7.14E-09

1.86E-07

2.3

Blaveri Bladder 2




Infiltrating Bladder Urothelial Carcinoma - Dead at 3 Years - Top 10% Over-expressed (Blaveri Bladder 2)

80

4.09E-08

9.98E-07

2.1

Blaveri Bladder 2




Superficial Bladder Cancer - Dead at 3 Years - Top 10% Over-expressed (Lee Bladder)

140

1.26E-06

2.62E-05

1.6

Lee Bladder




Superficial Bladder Cancer - Dead at 3 Years - Top 10% Over-expressed (Blaveri Bladder 2)

70

5.34E-06

1.03E-04

1.9

Blaveri Bladder 2




Superficial Bladder Cancer - Dead at 1 Year - Top 1% Over-expressed (Dyrskjot Bladder 5)

4

5.99E-04

0.008

34.7

Dyrskjot Bladder 5











































Analysis Type:

Mutation Analysis



















Concept Name

Overlap

P-Value

Q-Value

Odds Ratio

Dataset




Multi-cancer Cell Line - RB1 Mutation - Top 10% Over-expressed (Garnett CellLine)

242

6.47E-65

1.17E-62

4.8

Garnett CellLine




Bladder Cancer Cell Line - RB1 Mutation - Top 10% Over-expressed (Garnett CellLine)

185

3.16E-31

2.32E-29

3.1

Garnett CellLine




Bladder Urothelial Carcinoma - TP53 Mutation - Top 10% Over-expressed (Lindgren Bladder)

119

3.27E-24

1.86E-22

3.6

Lindgren Bladder




Multi-cancer Cell Line - TP53 Mutation - Top 10% Over-expressed (Garnett CellLine)

159

1.55E-19

7.35E-18

2.5

Garnett CellLine




Bladder Cancer Cell Line - TP53 Mutation - Top 10% Over-expressed (Garnett CellLine)

135

4.95E-11

1.54E-09

2

Garnett CellLine




Multi-cancer Cell Line - KDM6A Mutation - Top 10% Over-expressed (Garnett CellLine)

126

1.87E-08

4.71E-07

1.8

Garnett CellLine




Multi-cancer Cell Line - KRAS Mutation - Top 5% Over-expressed (Garnett CellLine)

69

1.96E-06

3.99E-05

2

Garnett CellLine




Multi-cancer Cell Line - MAP2K4 Mutation - Top 5% Over-expressed (Garnett CellLine)

69

1.96E-06

4.00E-05

2

Garnett CellLine




Multi-cancer Cell Line - PIK3CA Mutation - Top 10% Over-expressed (Garnett CellLine)

109

1.44E-04

0.002

1.5

Garnett CellLine











































Analysis Type:

Recurrence vs. Primary Analysis
















Concept Type

Concept Name

Overlap

P-Value

Q-Value

Odds Ratio

Dataset




Superficial Bladder Cancer - Recurrence - Top 10% Over-expressed (Lee Bladder)

225

7.18E-37

6.34E-35

3

Lee Bladder











































Analysis Type:

Drug Sensitivity Analysis
















Concept Type

Concept Name

Overlap

P-Value

Q-Value

Odds Ratio

Dataset




Topotecan Sensitive - Multi-cancer Cell Line - Top 10% Over-expressed (Barretina CellLine)

348

1.82E-113

1.41E-110

6

Barretina CellLine




Irinotecan Sensitive - Multi-cancer Cell Line - Top 10% Over-expressed (Barretina CellLine)

327

1.25E-97

5.68E-95

5.4

Barretina CellLine




Dovitinib Lactate Sensitive - Multi-cancer Cell Line - Top 10% Over-expressed (Barretina CellLine)

258

6.90E-53

9.18E-51

3.6

Barretina CellLine




Paclitaxel Sensitive - Multi-cancer Cell Line - Top 10% Over-expressed (Barretina CellLine)

252

1.49E-49

1.82E-47

3.5

Barretina CellLine




NVP-TAE684 Sensitive - Multi-cancer Cell Line - Top 10% Over-expressed (Barretina CellLine)

243

9.97E-45

1.06E-42

3.3

Barretina CellLine




Metformin Sensitive - Multi-cancer Cell Line - Top 10% Over-expressed (Garnett CellLine)

183

3.06E-30

2.16E-28

3.1

Garnett CellLine




Vorinostat Sensitive - Multi-cancer Cell Line - Top 10% Over-expressed (Garnett CellLine)

178

7.72E-28

5.02E-26

2.9

Garnett CellLine




WZ-1-84 Sensitive - Multi-cancer Cell Line - Top 10% Over-expressed (Garnett CellLine)

165

5.16E-22

2.71E-20

2.6

Garnett CellLine




GSK661637 Sensitive - Multi-cancer Cell Line - Top 10% Over-expressed (Wooster CellLine)

189

1.81E-20

8.93E-19

2.3

Wooster CellLine




PD-0332991 Sensitive - Multi-cancer Cell Line - Top 10% Over-expressed (Garnett CellLine)

159

1.55E-19

7.34E-18

2.5

Garnett CellLine




Paclitaxel Sensitive - Bladder Cancer Cell Line - Top 5% Over-expressed (Lee CellLine 2)

100

5.39E-19

2.50E-17

3.1

Lee CellLine 2




Cisplatin Sensitive - Multi-cancer Cell Line - Top 10% Over-expressed (Garnett CellLine)

150

4.45E-16

1.83E-14

2.3

Garnett CellLine




Vandetanib Sensitive - Multi-cancer Cell Line - Top 10% Over-expressed (Barretina CellLine)

174

2.87E-15

1.14E-13

2.1

Barretina CellLine




NVP-TAE684 Sensitive - Bladder Cancer Cell Line - Top 10% Over-expressed (Barretina CellLine)

167

4.33E-13

1.53E-11

2

Barretina CellLine




BAY 61-3606 Sensitive - Multi-cancer Cell Line - Top 10% Over-expressed (Garnett CellLine)

141

6.11E-13

2.14E-11

2.1

Garnett CellLine




BI-D1870 Sensitive - Multi-cancer Cell Line - Top 5% Over-expressed (Garnett CellLine)

85

3.83E-12

1.28E-10

2.5

Garnett CellLine




BX-795 Sensitive - Multi-cancer Cell Line - Top 10% Over-expressed (Garnett CellLine)

138

5.74E-12

1.90E-10

2.1

Garnett CellLine








































Literature Defined

Concept Name

Overlap

P-Value

Q-Value

Odds Ratio




Upregulated in Human Embryonic Stem Cells vs Differentiated Counterparts

142

3.09E-77

7.74E-75

9.5




Activated upon Polycomb Group knockdown

71

4.94E-47

5.55E-45

12.4




Upregulated genes in U2OS cells upon E2F3 expression

38

2.82E-15

1.12E-13

5.4




Hypermethylated genes in cancer

38

7.80E-15

3.04E-13

5.2




Upregulated genes in G1 arrested osteosarcoma cells expressing E2F1

14

2.01E-12

6.83E-11

18.1




Upregulated genes in U2OS cells upon E2F2 expression

20

4.54E-09

1.20E-07

5.6




Downregulated in Human Embryonic Stem Cells vs Differentiated Counterparts

50

1.59E-06

3.28E-05

2.2




Up-regulated genes in human osteosarcoma cell line (U2OS) expressing E2F1 compared to U2OS controls

42

3.11E-04

0.004

1.9




Upregulated known p53 inducible genes in colon cancer cells in response to p53 activity when exposed to 0, 10, and 30 J/m2 of UV radiation

4

5.39E-04

0.007

13


Supp Table S13 Summary of significant overlapping concepts in genes deregulated in human recurrent tumors identified by GSEA

NAME

SIZE

ES

NES

NOM p-val

FDR q-val

LINDGREN_BLADDER_CANCER_WITH_LOH_IN_CHR9Q

99

-0.5683617

-2.4477775

<10E-4

<10E-4

LINDGREN_BLADDER_CANCER_CLUSTER_1_UP

97

-0.54273623

-2.348918

<10E-4

<10E-4

MEISSNER_BRAIN_HCP_WITH_H3K27ME3

249

-0.29283035

-1.4513581

0.0031746

0.66136503

OSMAN_BLADDER_CANCER_DN

322

-0.24423261

-1.2499238

0.03833866

0.9144992

MIKKELSEN_NPC_HCP_WITH_H3K27ME3

312

-0.24677056

-1.2500254

0.04140128

0.91777986

BOQUEST_STEM_CELL_DN

199

-0.23433977

-1.1298443

0.18241042

0.9955357

CONRAD_STEM_CELL

34

-0.33490142

-1.1636229

0.267658

0.9963693

LEE_LIVER_CANCER_MYC_E2F1_DN

61

-0.2555857

-1.0213377

0.41582492

1

BENPORATH_ES_WITH_H3K27ME3

1020

-0.17910784

-1.0009633

0.46573427

1

ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_DN

164

0.36750537

1.81686

<10E-4

0.02562591

LINDGREN_BLADDER_CANCER_CLUSTER_3_UP

290

0.50620544

2.6778705

<10E-4

<10E-4

LINDGREN_BLADDER_CANCER_CLUSTER_1_DN

339

0.48045695

2.562943

<10E-4

<10E-4

LINDGREN_BLADDER_CANCER_CLUSTER_2B

351

0.4650538

2.4755237

<10E-4

<10E-4

KONG_E2F3_TARGETS

88

0.6839294

3.0061781

<10E-4

<10E-4

ISHIDA_E2F_TARGETS

49

0.74725294

2.913319

<10E-4

<10E-4

MARSON_BOUND_BY_E2F4_UNSTIMULATED

587

0.48318762

2.7070239

<10E-4

<10E-4

REN_BOUND_BY_E2F

55

0.6455674

2.601544

<10E-4

<10E-4

OLSSON_E2F3_TARGETS_DN

41

0.62058544

2.3284936

<10E-4

6.09E-05

IWANAGA_E2F1_TARGETS_INDUCED_BY_SERUM

27

0.53554803

1.8374923

<10E-4

0.0218777

PID_E2F_PATHWAY

64

0.42672348

1.7681849

<10E-4

0.03608666

BILD_E2F3_ONCOGENIC_SIGNATURE

212

0.32416812

1.6302713

<10E-4

0.08469941

BOQUEST_STEM_CELL_UP

246

0.45026714

2.3569524

<10E-4

6.29E-05

WONG_EMBRYONIC_STEM_CELL_CORE

306

0.3885407

2.0561104

<10E-4

0.00267043

LINDGREN_BLADDER_CANCER_HIGH_RECURRENCE

46

0.41827217

1.6153848

0.00458716

0.09274466

IGLESIAS_E2F_TARGETS_UP

140

0.30163878

1.4556586

0.00501253

0.18671837

KALMA_E2F1_TARGETS

10

0.6923494

1.7758254

0.00656455

0.03464273

REACTOME_E2F_MEDIATED_REGULATION_OF_DNA_REPLICATION

23

0.5138701

1.6966859

0.00867679

0.05822635

RAMALHO_STEMNESS_UP

189

0.28251323

1.3979288

0.01234568

0.22758876

WU_SILENCED_BY_METHYLATION_IN_BLADDER_CANCER

52

0.3653663

1.4928603

0.01956522

0.16009462

IGLESIAS_E2F_TARGETS_DN

13

0.5402426

1.4846903

0.05936073

0.16450033




NES: normalized enrichment score.

NES <0: enrichment in human non recurrent tumors

NES >0: enrichment in human recurrent tumors

FDR: False discovery rate.

SIZE: Number of genes within each gene set



Supp Table S14 Comparative transcriptome studies in Oncomine Database (yellow denotes opposite trend)

Genes Downregulated in Recurrent Tumors




























Concept Name

Overlap

P-Value

Q-Value

Odds Ratio

Dataset

Property

Expression




Bladder Urothelial Carcinoma Type: Infiltrating Bladder Urothelial Carcinoma - Top 10% Under-expressed (Lee Bladder)

32

2.08E-05

0.098

2.5

Lee Bladder

Bladder Urothelial Carcinoma Type

Under-expressed




Infiltrating Bladder Urothelial Carcinoma vs. Normal - Top 10% Under-expressed (Lee Bladder)

30

1.30E-04

0.323

2.3

Lee Bladder

Cancer and Normal Type

Under-expressed




Bladder Cancer Cell Line - CDKN2A Mutation - Top 1% Over-expressed (Garnett CellLine)

4

0.006

0.946

5.9

Garnett CellLine

CDKN2A Mutation Status (Bladder Cancer Cell Line)

Over-expressed




Bladder Cancer Cell Line - TP53 Mutation - Top 10% Under-expressed (Garnett CellLine)

15

0.005

0.99

2.3

Garnett CellLine

TP53 Mutation Status (Bladder Cancer Cell Line)

Under-expressed




Bladder Urothelial Carcinoma Type: Infiltrating Bladder Urothelial Carcinoma - Top 10% Under-expressed (Stransky Bladder)

11

0.009

1.059

2.6

Stransky Bladder

Bladder Urothelial Carcinoma Type

Under-expressed




Superficial Bladder Cancer - Recurrence at 5 Years - Top 5% Under-expressed (Lee Bladder)

15

0.007

1.065

2.2

Lee Bladder

Recurrence Status at 5 Years (Superficial Bladder Cancer)

Under-expressed




























Genes Upregulated in Recurrent Tumors




























Concept Name

Overlap

P-Value

Q-Value

Odds Ratio

Dataset

Property

Expression




Infiltrating Bladder Urothelial Carcinoma vs. Normal - Top 1% Over-expressed (Lee Bladder)

19

9.22E-18

2.30E-14

20.7

Lee Bladder

Cancer and Normal Type

Over-expressed




Infiltrating Bladder Urothelial Carcinoma vs. Normal - Top 1% Over-expressed (Sanchez-Carbayo Bladder 2)

13

7.91E-12

3.19E-09

17.6

Sanchez-Carbayo Bladder 2

Cancer and Normal Type

Over-expressed




Superficial Bladder Cancer - High Grade - Top 5% Over-expressed (Sanchez-Carbayo Bladder 2)

22

8.74E-10

2.08E-07

6

Sanchez-Carbayo Bladder 2

Grade (Superficial Bladder Cancer)

Over-expressed




Superficial Bladder Cancer - Recurrence - Top 10% Over-expressed (Lee Bladder)

36

8.69E-10

2.09E-07

3.9

Lee Bladder

Sample Recurrence Status (Superficial Bladder Cancer)

Over-expressed




Bladder Cancer Cell Line - RB1 Mutation - Top 10% Over-expressed (Garnett CellLine)

27

2.77E-07

3.34E-05

3.7

Garnett CellLine

RB1 Mutation Status (Bladder Cancer Cell Line)

Over-expressed




Bladder Urothelial Carcinoma Type: Infiltrating Bladder Urothelial Carcinoma - Top 10% Over-expressed (Stransky Bladder)

21

1.91E-06

1.79E-04

4

Stransky Bladder

Bladder Urothelial Carcinoma Type

Over-expressed




Superficial Bladder Cancer vs. Normal - Top 10% Over-expressed (Lee Bladder)

29

5.24E-06

4.41E-04

2.9

Lee Bladder

Cancer and Normal Type

Over-expressed




Bladder Urothelial Carcinoma - High Grade - Top 10% Over-expressed (Lindgren Bladder)

18

7.44E-06

6.04E-04

4.2

Lindgren Bladder

Grade (Bladder Urothelial Carcinoma)

Over-expressed




Multi-cancer Cell Line - RB1 Mutation - Top 10% Over-expressed (Garnett CellLine)

24

1.20E-05

9.31E-04

3.1

Garnett CellLine

RB1 Mutation Status (Cell Line)

Over-expressed




Superficial Bladder Cancer vs. Normal - Top 10% Over-expressed (Sanchez-Carbayo Bladder 2)

24

1.20E-05

9.41E-04

3.1

Sanchez-Carbayo Bladder 2

Cancer and Normal Type

Over-expressed




Superficial Bladder Cancer - High Grade - Top 10% Over-expressed (Dyrskjot Bladder 3)

24

1.20E-05

9.45E-04

3.1

Dyrskjot Bladder 3

Grade (Superficial Bladder Cancer)

Over-expressed




Superficial Bladder Cancer vs. Normal - Top 10% Over-expressed (Dyrskjot Bladder 3)

22

1.13E-04

0.007

2.8

Dyrskjot Bladder 3

Cancer and Normal Type

Over-expressed




Infiltrating Bladder Urothelial Carcinoma vs. Normal - Top 10% Over-expressed (Dyrskjot Bladder 3)

21

3.18E-04

0.016

2.6

Dyrskjot Bladder 3

Cancer and Normal Type

Over-expressed




Infiltrating Bladder Urothelial Carcinoma - High Grade - Top 10% Over-expressed (Stransky Bladder)

17

3.21E-04

0.016

3

Stransky Bladder

Grade (Infiltrating Bladder Urothelial Carcinoma)

Over-expressed




Bladder Urothelial Carcinoma Type: Infiltrating Bladder Urothelial Carcinoma - Top 5% Over-expressed (Lee Bladder)

15

9.49E-04

0.04

2.7

Lee Bladder

Bladder Urothelial Carcinoma Type

Over-expressed




Superficial Bladder Cancer - High Grade - Top 10% Over-expressed (Stransky Bladder)

16

9.71E-04

0.041

2.8

Stransky Bladder

Grade (Superficial Bladder Cancer)

Over-expressed




Multi-cancer Cell Line - TP53 Mutation - Top 10% Over-expressed (Garnett CellLine)

19

0.002

0.079

2.3

Garnett CellLine

TP53 Mutation Status (Cell Line)

Over-expressed




Bladder Urothelial Carcinoma - TP53 Mutation - Top 10% Over-expressed (Lindgren Bladder)

13

0.004

0.13

2.6

Lindgren Bladder

TP53 Mutation Status (Bladder Urothelial Carcinoma)

Over-expressed




Stage 0is Bladder Urothelial Carcinoma vs. Normal - Top 10% Over-expressed (Dyrskjot Bladder 3)

18

0.005

0.161

2.1

Dyrskjot Bladder 3

Cancer and Normal Type

Over-expressed




Infiltrating Bladder Urothelial Carcinoma - High Grade - Top 10% Over-expressed (Dyrskjot Bladder 3)

18

0.005

0.161

2.1

Dyrskjot Bladder 3

Grade (Infiltrating Bladder Urothelial Carcinoma)

Over-expressed

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