Combined exome and transcriptome sequencing of non-muscle-invasive bladder cancer: associations between genomic changes, expression subtypes, and clinical outcomes

Anshita Goel; Douglas G. Ward; Boris Noyvert; Minghao Yu; Naheema S. Gordon; Ben Abbotts; John K. Colbourne; Stephen Kissane; Nicholas D. James; Maurice P. Zeegers; Kar Keung Cheng; Jean-baptiste Cazier; Celina M. Whalley; Andrew D. Beggs; Claire Palles; Roland Arnold; Richard T. Bryan

doi:10.1186/s13073-022-01056-4

Combined exome and transcriptome sequencing of non-muscle-invasive bladder cancer: associations between genomic changes, expression subtypes, and clinical outcomes

Anshita Goel, Douglas G. Ward, Boris Noyvert, Minghao Yu, Naheema S. Gordon, Ben Abbotts, John K. Colbourne, Stephen Kissane, Nicholas D. James, Maurice P. Zeegers, Kar Keung Cheng, Jean-baptiste Cazier, Celina M. Whalley, Andrew D. Beggs, Claire Palles, Roland Arnold, Richard T. Bryan

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Abstract

Background: Three-quarters of bladder cancer patients present with early-stage disease (non-muscle-invasive bladder cancer, NMIBC, UICC TNM stages Ta, T1 and Tis); however, most next-generation sequencing studies to date have concentrated on later-stage disease (muscle-invasive BC, stages T2+). We used exome and transcriptome sequencing to comprehensively characterise NMIBCs of all grades and stages to identify prognostic genes and pathways that could facilitate treatment decisions. Tumour grading is based upon microscopy and cellular appearances (grade 1 BCs are less aggressive, and grade 3 BCs are most aggressive), and we chose to also focus on the most clinically complex NMIBC subgroup, those patients with grade 3 pathological stage T1 (G3 pT1) disease.

Methods: Whole-exome and RNA sequencing were performed in total on 96 primary NMIBCs including 22 G1 pTa, 14 G3 pTa and 53 G3 pT1s, with both exome and RNA sequencing data generated from 75 of these individual samples. Associations between genomic alterations, expression profiles and progression-free survival (PFS) were investigated.

Results: NMIBCs clustered into 3 expression subtypes with different somatic alteration characteristics. Amplifications of ARNT and ERBB2 were significant indicators of worse PFS across all NMIBCs. High APOBEC mutagenesis and high tumour mutation burden were both potential indicators of better PFS in G3pT1 NMIBCs. The expression of individual genes was not prognostic in BCG-treated G3pT1 NMIBCs; however, downregulated interferon-alpha and gamma response pathways were significantly associated with worse PFS (adjusted p-value < 0.005).

Conclusions: Multi-omic data may facilitate better prognostication and selection of therapeutic interventions in patients with G3pT1 NMIBC. These findings demonstrate the potential for improving the management of high-risk NMIBC patients and warrant further prospective validation.

Original language	English
Article number	59
Number of pages	16
Journal	Genome medicine
Volume	14
Issue number	1
Early online date	3 Jun 2022
DOIs	https://doi.org/10.1186/s13073-022-01056-4
Publication status	Published - Dec 2022

Bibliographical note

Funding Information:
ND James has contributed to the advisory boards for Merck USA and Pierre Fabre. RT Bryan has contributed to the advisory boards for Olympus Medical Systems, Janssen and Nonacus Limited and has undertaken research funded by UroGen Pharma, QED Therapeutics and Janssen. DG Ward has contributed to the advisory boards for Nonacus Limited. The remaining authors declare that they have no competing interests.

The Bladder Cancer Prognosis Programme (BCPP) was funded by Cancer Research UK (C1343/A5738), the University of Birmingham and the Birmingham and The Black Country and West Midlands North and South Comprehensive Local Research Networks. Sequencing and arrays were funded by philanthropic donations to the Bladder Cancer Research Centre at the University of Birmingham. B Noyvert was funded through the Cancer Research UK Birmingham Centre award C17422/A25154. We gratefully acknowledge the contribution made by the University of Birmingham’s Human Biomaterials Resource Centre supported through the Birmingham Science City – Experimental Medicine Network of Excellence project. Sequencing was carried out by Genomics Birmingham, Department of Experimental Medicine, University of Birmingham, UK. We are grateful to the urologists and urology nurses of the West Midlands for the recruitment and follow-up of BCPP participants. The work described in this paper used the CaStLeS infrastructure at the University of Birmingham.

Publisher Copyright:
© 2022, The Author(s).

Keywords

Urothelial carcinoma
Bladder cancer
Exome
Transcriptome
Sequencing
Mutations
Subtypes
Prognosis
Therapy

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology
Genetics
Genetics(clinical)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1186/s13073-022-01056-4Licence: Creative Commons: Attribution (CC BY)

GoelA2022CombinedFinal published version, 7.01 MBLicence: Creative Commons: Attribution (CC BY)

Understanding the role of Tet2 loss in adult mouse gliomagenesis
Bardella, C.
Cancer Research Uk
1/03/19 → 29/02/20
Project: Research
Identification of genetic factors that predispose to immune checkpoint inhibitor toxicity
Tomlinson, I.
Cancer Research Uk
1/02/19 → 31/01/20
Project: Research
Cancer Research UK Birmingham Centre - Consumables for Claire Bryer - See RCPV19991
Willcox, B.
Cancer Research Uk
1/04/17 → 31/03/22
Project: Research
Recurrence and Progression of Non-Muscle-Invasive Bladder Cancer
Cheng, K., Zeegers, M., James, N., Billingham, L., Hussain, S. & Murray, P.
Cancer Research UK, NIHR, DUDLEY GROUP OF HOSPITALS
1/05/05 → 31/08/11
Project: Research

Cite this

Goel, A., Ward, D. G., Noyvert, B., Yu, M., Gordon, N. S., Abbotts, B., Colbourne, J. K., Kissane, S., James, N. D., Zeegers, M. P., Cheng, K. K., Cazier, J., Whalley, C. M., Beggs, A. D., Palles, C., Arnold, R., & Bryan, R. T. (2022). Combined exome and transcriptome sequencing of non-muscle-invasive bladder cancer: associations between genomic changes, expression subtypes, and clinical outcomes. Genome medicine, 14(1), Article 59 . https://doi.org/10.1186/s13073-022-01056-4

@article{4f6659332e9e44abaf8b5326c12c1ccf,

title = "Combined exome and transcriptome sequencing of non-muscle-invasive bladder cancer: associations between genomic changes, expression subtypes, and clinical outcomes",

abstract = "Background: Three-quarters of bladder cancer patients present with early-stage disease (non-muscle-invasive bladder cancer, NMIBC, UICC TNM stages Ta, T1 and Tis); however, most next-generation sequencing studies to date have concentrated on later-stage disease (muscle-invasive BC, stages T2+). We used exome and transcriptome sequencing to comprehensively characterise NMIBCs of all grades and stages to identify prognostic genes and pathways that could facilitate treatment decisions. Tumour grading is based upon microscopy and cellular appearances (grade 1 BCs are less aggressive, and grade 3 BCs are most aggressive), and we chose to also focus on the most clinically complex NMIBC subgroup, those patients with grade 3 pathological stage T1 (G3 pT1) disease.Methods: Whole-exome and RNA sequencing were performed in total on 96 primary NMIBCs including 22 G1 pTa, 14 G3 pTa and 53 G3 pT1s, with both exome and RNA sequencing data generated from 75 of these individual samples. Associations between genomic alterations, expression profiles and progression-free survival (PFS) were investigated.Results: NMIBCs clustered into 3 expression subtypes with different somatic alteration characteristics. Amplifications of ARNT and ERBB2 were significant indicators of worse PFS across all NMIBCs. High APOBEC mutagenesis and high tumour mutation burden were both potential indicators of better PFS in G3pT1 NMIBCs. The expression of individual genes was not prognostic in BCG-treated G3pT1 NMIBCs; however, downregulated interferon-alpha and gamma response pathways were significantly associated with worse PFS (adjusted p-value < 0.005).Conclusions: Multi-omic data may facilitate better prognostication and selection of therapeutic interventions in patients with G3pT1 NMIBC. These findings demonstrate the potential for improving the management of high-risk NMIBC patients and warrant further prospective validation.",

keywords = "Urothelial carcinoma, Bladder cancer, Exome, Transcriptome, Sequencing, Mutations, Subtypes, Prognosis, Therapy",

author = "Anshita Goel and Ward, {Douglas G.} and Boris Noyvert and Minghao Yu and Gordon, {Naheema S.} and Ben Abbotts and Colbourne, {John K.} and Stephen Kissane and James, {Nicholas D.} and Zeegers, {Maurice P.} and Cheng, {Kar Keung} and Jean-baptiste Cazier and Whalley, {Celina M.} and Beggs, {Andrew D.} and Claire Palles and Roland Arnold and Bryan, {Richard T.}",

note = "Funding Information: ND James has contributed to the advisory boards for Merck USA and Pierre Fabre. RT Bryan has contributed to the advisory boards for Olympus Medical Systems, Janssen and Nonacus Limited and has undertaken research funded by UroGen Pharma, QED Therapeutics and Janssen. DG Ward has contributed to the advisory boards for Nonacus Limited. The remaining authors declare that they have no competing interests. The Bladder Cancer Prognosis Programme (BCPP) was funded by Cancer Research UK (C1343/A5738), the University of Birmingham and the Birmingham and The Black Country and West Midlands North and South Comprehensive Local Research Networks. Sequencing and arrays were funded by philanthropic donations to the Bladder Cancer Research Centre at the University of Birmingham. B Noyvert was funded through the Cancer Research UK Birmingham Centre award C17422/A25154. We gratefully acknowledge the contribution made by the University of Birmingham{\textquoteright}s Human Biomaterials Resource Centre supported through the Birmingham Science City – Experimental Medicine Network of Excellence project. Sequencing was carried out by Genomics Birmingham, Department of Experimental Medicine, University of Birmingham, UK. We are grateful to the urologists and urology nurses of the West Midlands for the recruitment and follow-up of BCPP participants. The work described in this paper used the CaStLeS infrastructure at the University of Birmingham. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1186/s13073-022-01056-4",

language = "English",

volume = "14",

journal = "Genome medicine",

issn = "1756-994X",

publisher = "Springer",

number = "1",

}

Goel, A , Ward, DG , Noyvert, B, Yu, M, Gordon, NS, Abbotts, B , Colbourne, JK, Kissane, S, James, ND, Zeegers, MP, Cheng, KK, Cazier, J, Whalley, CM, Beggs, AD , Palles, C , Arnold, R & Bryan, RT 2022, 'Combined exome and transcriptome sequencing of non-muscle-invasive bladder cancer: associations between genomic changes, expression subtypes, and clinical outcomes', Genome medicine, vol. 14, no. 1, 59 . https://doi.org/10.1186/s13073-022-01056-4

TY - JOUR

T1 - Combined exome and transcriptome sequencing of non-muscle-invasive bladder cancer

T2 - associations between genomic changes, expression subtypes, and clinical outcomes

AU - Goel, Anshita

AU - Ward, Douglas G.

AU - Noyvert, Boris

AU - Yu, Minghao

AU - Gordon, Naheema S.

AU - Abbotts, Ben

AU - Colbourne, John K.

AU - Kissane, Stephen

AU - James, Nicholas D.

AU - Zeegers, Maurice P.

AU - Cheng, Kar Keung

AU - Cazier, Jean-baptiste

AU - Whalley, Celina M.

AU - Beggs, Andrew D.

AU - Palles, Claire

AU - Arnold, Roland

AU - Bryan, Richard T.

N1 - Funding Information: ND James has contributed to the advisory boards for Merck USA and Pierre Fabre. RT Bryan has contributed to the advisory boards for Olympus Medical Systems, Janssen and Nonacus Limited and has undertaken research funded by UroGen Pharma, QED Therapeutics and Janssen. DG Ward has contributed to the advisory boards for Nonacus Limited. The remaining authors declare that they have no competing interests. The Bladder Cancer Prognosis Programme (BCPP) was funded by Cancer Research UK (C1343/A5738), the University of Birmingham and the Birmingham and The Black Country and West Midlands North and South Comprehensive Local Research Networks. Sequencing and arrays were funded by philanthropic donations to the Bladder Cancer Research Centre at the University of Birmingham. B Noyvert was funded through the Cancer Research UK Birmingham Centre award C17422/A25154. We gratefully acknowledge the contribution made by the University of Birmingham’s Human Biomaterials Resource Centre supported through the Birmingham Science City – Experimental Medicine Network of Excellence project. Sequencing was carried out by Genomics Birmingham, Department of Experimental Medicine, University of Birmingham, UK. We are grateful to the urologists and urology nurses of the West Midlands for the recruitment and follow-up of BCPP participants. The work described in this paper used the CaStLeS infrastructure at the University of Birmingham. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - Background: Three-quarters of bladder cancer patients present with early-stage disease (non-muscle-invasive bladder cancer, NMIBC, UICC TNM stages Ta, T1 and Tis); however, most next-generation sequencing studies to date have concentrated on later-stage disease (muscle-invasive BC, stages T2+). We used exome and transcriptome sequencing to comprehensively characterise NMIBCs of all grades and stages to identify prognostic genes and pathways that could facilitate treatment decisions. Tumour grading is based upon microscopy and cellular appearances (grade 1 BCs are less aggressive, and grade 3 BCs are most aggressive), and we chose to also focus on the most clinically complex NMIBC subgroup, those patients with grade 3 pathological stage T1 (G3 pT1) disease.Methods: Whole-exome and RNA sequencing were performed in total on 96 primary NMIBCs including 22 G1 pTa, 14 G3 pTa and 53 G3 pT1s, with both exome and RNA sequencing data generated from 75 of these individual samples. Associations between genomic alterations, expression profiles and progression-free survival (PFS) were investigated.Results: NMIBCs clustered into 3 expression subtypes with different somatic alteration characteristics. Amplifications of ARNT and ERBB2 were significant indicators of worse PFS across all NMIBCs. High APOBEC mutagenesis and high tumour mutation burden were both potential indicators of better PFS in G3pT1 NMIBCs. The expression of individual genes was not prognostic in BCG-treated G3pT1 NMIBCs; however, downregulated interferon-alpha and gamma response pathways were significantly associated with worse PFS (adjusted p-value < 0.005).Conclusions: Multi-omic data may facilitate better prognostication and selection of therapeutic interventions in patients with G3pT1 NMIBC. These findings demonstrate the potential for improving the management of high-risk NMIBC patients and warrant further prospective validation.

AB - Background: Three-quarters of bladder cancer patients present with early-stage disease (non-muscle-invasive bladder cancer, NMIBC, UICC TNM stages Ta, T1 and Tis); however, most next-generation sequencing studies to date have concentrated on later-stage disease (muscle-invasive BC, stages T2+). We used exome and transcriptome sequencing to comprehensively characterise NMIBCs of all grades and stages to identify prognostic genes and pathways that could facilitate treatment decisions. Tumour grading is based upon microscopy and cellular appearances (grade 1 BCs are less aggressive, and grade 3 BCs are most aggressive), and we chose to also focus on the most clinically complex NMIBC subgroup, those patients with grade 3 pathological stage T1 (G3 pT1) disease.Methods: Whole-exome and RNA sequencing were performed in total on 96 primary NMIBCs including 22 G1 pTa, 14 G3 pTa and 53 G3 pT1s, with both exome and RNA sequencing data generated from 75 of these individual samples. Associations between genomic alterations, expression profiles and progression-free survival (PFS) were investigated.Results: NMIBCs clustered into 3 expression subtypes with different somatic alteration characteristics. Amplifications of ARNT and ERBB2 were significant indicators of worse PFS across all NMIBCs. High APOBEC mutagenesis and high tumour mutation burden were both potential indicators of better PFS in G3pT1 NMIBCs. The expression of individual genes was not prognostic in BCG-treated G3pT1 NMIBCs; however, downregulated interferon-alpha and gamma response pathways were significantly associated with worse PFS (adjusted p-value < 0.005).Conclusions: Multi-omic data may facilitate better prognostication and selection of therapeutic interventions in patients with G3pT1 NMIBC. These findings demonstrate the potential for improving the management of high-risk NMIBC patients and warrant further prospective validation.

KW - Urothelial carcinoma

KW - Bladder cancer

KW - Exome

KW - Transcriptome

KW - Sequencing

KW - Mutations

KW - Subtypes

KW - Prognosis

KW - Therapy

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U2 - 10.1186/s13073-022-01056-4

DO - 10.1186/s13073-022-01056-4

M3 - Article

C2 - 35655252

SN - 1756-994X

VL - 14

JO - Genome medicine

JF - Genome medicine

IS - 1

M1 - 59

ER -

Combined exome and transcriptome sequencing of non-muscle-invasive bladder cancer: associations between genomic changes, expression subtypes, and clinical outcomes

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Fingerprint

Projects

Understanding the role of Tet2 loss in adult mouse gliomagenesis

Identification of genetic factors that predispose to immune checkpoint inhibitor toxicity

Cancer Research UK Birmingham Centre - Consumables for Claire Bryer - See RCPV19991

Recurrence and Progression of Non-Muscle-Invasive Bladder Cancer

Cite this