Genomic Subtypes of Non-invasive Bladder Cancer with Distinct Metabolic Profile and Female Gender Bias in KDM6A Mutation Frequency

Carolyn D Hurst; Olivia Alder; Fiona M Platt; Alastair Droop; Lucy F Stead; Julie E Burns; George J Burghel; Sunjay Jain; Leszek J Klimczak; Helen Lindsay; Jo-An Roulson; Claire F Taylor; Helene Thygesen; Angus J Cameron; Anne J Ridley; Helen R Mott; Dmitry A Gordenin; Margaret A Knowles

doi:10.1016/j.ccell.2017.08.005

Genomic Subtypes of Non-invasive Bladder Cancer with Distinct Metabolic Profile and Female Gender Bias in KDM6A Mutation Frequency

Carolyn D Hurst, Olivia Alder, Fiona M Platt, Alastair Droop, Lucy F Stead, Julie E Burns, George J Burghel, Sunjay Jain, Leszek J Klimczak, Helen Lindsay, Jo-An Roulson, Claire F Taylor, Helene Thygesen, Angus J Cameron, Anne J Ridley, Helen R Mott, Dmitry A Gordenin, Margaret A Knowles

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Abstract

Bladder cancer incurs a higher lifetime treatment cost than other cancers due to frequent recurrence of non-invasive disease. Improved prognostic biomarkers and localized therapy are needed for this large patient group. We defined two major genomic subtypes of primary stage Ta tumors. One of these was characterized by loss of 9q including TSC1, increased KI67 labeling index, upregulated glycolysis, DNA repair, mTORC1 signaling, features of the unfolded protein response, and altered cholesterol homeostasis. Comparison with muscle-invasive bladder cancer mutation profiles revealed lower overall mutation rates and more frequent mutations in RHOB and chromatin modifier genes. More mutations in the histone lysine demethylase KDM6A were present in non-invasive tumors from females than males.

Original language	English
Pages (from-to)	701-715.e7
Number of pages	22
Journal	Cancer Cell
Volume	32
Issue number	5
Early online date	13 Nov 2017
DOIs	https://doi.org/10.1016/j.ccell.2017.08.005
Publication status	Published - 13 Nov 2017

Keywords

Carcinoma, Transitional Cell
Cell Line, Tumor
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Gene Frequency
Genomics
HEK293 Cells
Histone Demethylases
Humans
Male
Metabolome
Metabolomics
Mutation
Nuclear Proteins
Sex Factors
Urinary Bladder Neoplasms
Journal Article

UN SDGs

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

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10.1016/j.ccell.2017.08.005

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This is the accepted author manuscript (AAM). The final published version (version of record) is available online via Elsevier at https://doi.org/10.1016/j.ccell.2017.08.005 . Please refer to any applicable terms of use of the publisher.
Accepted author manuscript, 4.9 MBLicence: CC BY-NC-ND

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Hurst, C. D., Alder, O., Platt, F. M., Droop, A., Stead, L. F., Burns, J. E., Burghel, G. J., Jain, S., Klimczak, L. J., Lindsay, H., Roulson, J.-A., Taylor, C. F., Thygesen, H., Cameron, A. J., Ridley, A. J., Mott, H. R., Gordenin, D. A., & Knowles, M. A. (2017). Genomic Subtypes of Non-invasive Bladder Cancer with Distinct Metabolic Profile and Female Gender Bias in KDM6A Mutation Frequency. Cancer Cell, 32(5), 701-715.e7. https://doi.org/10.1016/j.ccell.2017.08.005

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title = "Genomic Subtypes of Non-invasive Bladder Cancer with Distinct Metabolic Profile and Female Gender Bias in KDM6A Mutation Frequency",

abstract = "Bladder cancer incurs a higher lifetime treatment cost than other cancers due to frequent recurrence of non-invasive disease. Improved prognostic biomarkers and localized therapy are needed for this large patient group. We defined two major genomic subtypes of primary stage Ta tumors. One of these was characterized by loss of 9q including TSC1, increased KI67 labeling index, upregulated glycolysis, DNA repair, mTORC1 signaling, features of the unfolded protein response, and altered cholesterol homeostasis. Comparison with muscle-invasive bladder cancer mutation profiles revealed lower overall mutation rates and more frequent mutations in RHOB and chromatin modifier genes. More mutations in the histone lysine demethylase KDM6A were present in non-invasive tumors from females than males.",

keywords = "Carcinoma, Transitional Cell, Cell Line, Tumor, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Frequency, Genomics, HEK293 Cells, Histone Demethylases, Humans, Male, Metabolome, Metabolomics, Mutation, Nuclear Proteins, Sex Factors, Urinary Bladder Neoplasms, Journal Article",

author = "Hurst, {Carolyn D} and Olivia Alder and Platt, {Fiona M} and Alastair Droop and Stead, {Lucy F} and Burns, {Julie E} and Burghel, {George J} and Sunjay Jain and Klimczak, {Leszek J} and Helen Lindsay and Jo-An Roulson and Taylor, {Claire F} and Helene Thygesen and Cameron, {Angus J} and Ridley, {Anne J} and Mott, {Helen R} and Gordenin, {Dmitry A} and Knowles, {Margaret A}",

year = "2017",

month = nov,

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doi = "10.1016/j.ccell.2017.08.005",

language = "English",

volume = "32",

pages = "701--715.e7",

journal = "Cancer Cell",

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Hurst, CD, Alder, O, Platt, FM, Droop, A, Stead, LF, Burns, JE, Burghel, GJ, Jain, S, Klimczak, LJ, Lindsay, H, Roulson, J-A, Taylor, CF, Thygesen, H, Cameron, AJ, Ridley, AJ, Mott, HR, Gordenin, DA & Knowles, MA 2017, 'Genomic Subtypes of Non-invasive Bladder Cancer with Distinct Metabolic Profile and Female Gender Bias in KDM6A Mutation Frequency', Cancer Cell, vol. 32, no. 5, pp. 701-715.e7. https://doi.org/10.1016/j.ccell.2017.08.005

TY - JOUR

T1 - Genomic Subtypes of Non-invasive Bladder Cancer with Distinct Metabolic Profile and Female Gender Bias in KDM6A Mutation Frequency

AU - Hurst, Carolyn D

AU - Alder, Olivia

AU - Platt, Fiona M

AU - Droop, Alastair

AU - Stead, Lucy F

AU - Burns, Julie E

AU - Burghel, George J

AU - Jain, Sunjay

AU - Klimczak, Leszek J

AU - Lindsay, Helen

AU - Roulson, Jo-An

AU - Taylor, Claire F

AU - Thygesen, Helene

AU - Cameron, Angus J

AU - Ridley, Anne J

AU - Mott, Helen R

AU - Gordenin, Dmitry A

AU - Knowles, Margaret A

PY - 2017/11/13

Y1 - 2017/11/13

N2 - Bladder cancer incurs a higher lifetime treatment cost than other cancers due to frequent recurrence of non-invasive disease. Improved prognostic biomarkers and localized therapy are needed for this large patient group. We defined two major genomic subtypes of primary stage Ta tumors. One of these was characterized by loss of 9q including TSC1, increased KI67 labeling index, upregulated glycolysis, DNA repair, mTORC1 signaling, features of the unfolded protein response, and altered cholesterol homeostasis. Comparison with muscle-invasive bladder cancer mutation profiles revealed lower overall mutation rates and more frequent mutations in RHOB and chromatin modifier genes. More mutations in the histone lysine demethylase KDM6A were present in non-invasive tumors from females than males.

AB - Bladder cancer incurs a higher lifetime treatment cost than other cancers due to frequent recurrence of non-invasive disease. Improved prognostic biomarkers and localized therapy are needed for this large patient group. We defined two major genomic subtypes of primary stage Ta tumors. One of these was characterized by loss of 9q including TSC1, increased KI67 labeling index, upregulated glycolysis, DNA repair, mTORC1 signaling, features of the unfolded protein response, and altered cholesterol homeostasis. Comparison with muscle-invasive bladder cancer mutation profiles revealed lower overall mutation rates and more frequent mutations in RHOB and chromatin modifier genes. More mutations in the histone lysine demethylase KDM6A were present in non-invasive tumors from females than males.

KW - Carcinoma, Transitional Cell

KW - Cell Line, Tumor

KW - Female

KW - Gene Expression Profiling

KW - Gene Expression Regulation, Neoplastic

KW - Gene Frequency

KW - Genomics

KW - HEK293 Cells

KW - Histone Demethylases

KW - Humans

KW - Male

KW - Metabolome

KW - Metabolomics

KW - Mutation

KW - Nuclear Proteins

KW - Sex Factors

KW - Urinary Bladder Neoplasms

KW - Journal Article

UR - http://eprints.whiterose.ac.uk/120223/

U2 - 10.1016/j.ccell.2017.08.005

DO - 10.1016/j.ccell.2017.08.005

M3 - Article (Academic Journal)

C2 - 29136510

SN - 1535-6108

VL - 32

SP - 701-715.e7

JO - Cancer Cell

JF - Cancer Cell

IS - 5

ER -

Genomic Subtypes of Non-invasive Bladder Cancer with Distinct Metabolic Profile and Female Gender Bias in KDM6A Mutation Frequency

Abstract

Keywords

UN SDGs

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Professor Anne J Ridley

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Genomic Subtypes of Non-invasive Bladder Cancer with Distinct Metabolic Profile and Female Gender Bias in KDM6A Mutation Frequency

Abstract

Keywords

UN SDGs

Access to Document

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Professor Anne J Ridley

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