Article - White Rose Research Onlineeprints.whiterose.ac.uk/113339/2/[Bladder_cancer]_Figures...TERT mutation and 9q LOH Flat dysplasia TP53 mutation, 9p LOH and 9q LOH T1 Invasive

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Article:

Sanli, O, Dobruch,, J, Knowles, MA orcid.org/0000-0002-9363-8657 et al. (4 more authors)(2017) Bladder Cancer. Nature Reviews Disease Primers, 3. 17022. ISSN 2056-676X

https://doi.org/10.1038/nrdp.2017.22

© 2017 Macmillan Publishers Limited, part of Springer Nature. This is an author produced version of a paper published in Nature Reviews Disease Primers. Uploaded in accordancewith the publisher's self-archiving policy. The final publication is available at https://doi.org/10.1038/nrdp.2017.22.

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Fig 1

Nature Reviews | Disease Primers

Manuscript number NRDP_16_022 Lotan 7|3|17


Bladder

Urethra

Ureter

Lamina propria

Bladder lumen

Tis

Ta T1

T2a T2b T3 T4

Perivesical fat

Urothelium

Muscularispropria

Muscle-invasiveNon-muscle-invasive

PUNLMP Low grade High grade 2004 WHO/ISUP

Grade 1 Grade 2 Grade 3 1973 WHO

Fig 3

Fig 2




Expanded clone of altered cells with ‘normal’ appearance

Low grade (Ta)papillary tumoursPIK3CA and STAG2

mutations

Metastasis

High grade (Ta)papillary tumours

Hyperplasiaand dysplasia

Normal urothelium

HyperplasiaFGFR3 mutation,

TERT mutation and 9q LOH

Flat dysplasiaTP53 mutation,

9p LOH and 9q LOH

T1

Invasive carcinoma (ﾋT2)RB1 and PTEN loss,

many alterations

CDKN2A loss

CIS


aUROMOL NMIBCClass 1 Class 2 Class 3

Early cell cycle↑Uroplakin expression

Late cell cycle↑KRT14, KRT20 uroplakin expression

↑KRT5, KRT14, KRT15and IncRNA expression

NMIBC+ MIBCLund InむltratedUro A SCC-like Uro BGenomically unstable

Transcriptionfactors

b UNC

MIBCMDA

TCGA I IVII III

Luminal Basal

Luminal BasalTP53-like

PPARG, RXRA, GATA3, and FOXA1

PPARG, RXRA, GATA3,FOXA1 and FOXM1

SNAI1and ZEB2

STAT3and FOXM1

Noneidentiむed

Actionabletargets

FGFR3, ERBB2

and EGFR ERBB2Immune

checkpoints

Immunecheckpoints,

EGFR

FGFR3

andEGFR

Fig 4

Fig 5




a c

d e f

b

g h

100 μm

a


II

IV

III

I

Ureter

Lymphnode

AortaInternal iliac artery Common iliac arteryBladder

Dissectionboundary

II

IV

III

I External iliac lymph nodes

Obturator fossa lymph nodes

Internal iliac lymph nodes

Common iliac lymph nodes

b

Rectum

Obturatorynerve

Externaliliac vein

Externaliliac artery

Genitofemoralnerve

Internaliliac artery

Fig 6




CD3

TCR

CART-19

CTLA4

CD80CD86

CD137

CD137L

CD40L

CD40

CD134

CD134L

PD-1

PD-L1PD-L2CD276

Enoblituzumab

CP-870, 893 AtezolizumabDurvalumab

AvelumabBMS-936559

Antigen-presentingor tumour cell

PembrolizumabNivolumabPidilizumab

AMP-514Ipilimumab

Tremelimumab

Anti-OX40 Urelumab

T cell

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Article - White Rose Research Onlineeprints.whiterose.ac.uk/113339/2/[Bladder_cancer]_Figures...TERT mutation and 9q LOH Flat dysplasia TP53 mutation, 9p LOH and 9q LOH T1 Invasive