Mutational patterns in chemotherapy resistant muscle-invasive bladder cancer

Despite continued widespread use, the genomic effects of cisplatin-based chemotherapy and implications for subsequent treatment are incompletely characterized. Here, we analyze whole exome sequencing of matched pre- and post-neoadjuvant cisplatin-based chemotherapy primary bladder tumor samples from...

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Published inNature communications Vol. 8; no. 1; pp. 2193 - 11
Main Authors Liu, David, Abbosh, Philip, Keliher, Daniel, Reardon, Brendan, Miao, Diana, Mouw, Kent, Weiner-Taylor, Amaro, Wankowicz, Stephanie, Han, Garam, Teo, Min Yuen, Cipolla, Catharine, Kim, Jaegil, Iyer, Gopa, Al-Ahmadie, Hikmat, Dulaimi, Essel, Chen, David Y. T., Alpaugh, R. Katherine, Hoffman-Censits, Jean, Garraway, Levi A., Getz, Gad, Carter, Scott L., Bellmunt, Joaquim, Plimack, Elizabeth R., Rosenberg, Jonathan E., Van Allen, Eliezer M.
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 19.12.2017
Nature Publishing Group
Nature Portfolio
Subjects
631/67/2329
631/67/589/1336
631/67/69
Adult
Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols - pharmacology
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Biomarkers
Biomarkers, Tumor - genetics
Bladder
Bladder cancer
Cancer
Carcinoma - drug therapy
Carcinoma - genetics
Carcinoma - mortality
Carcinoma - pathology
Chemotherapy
Cisplatin
Cisplatin - pharmacology
Cisplatin - therapeutic use
Clinical trials
Clonal Evolution - drug effects
Cohort Studies
Cystectomy
DNA Mutational Analysis
Drug Resistance, Neoplasm - drug effects
Drug Resistance, Neoplasm - genetics
Female
Gene expression
Gene regulation
Heterogeneity
Humanities and Social Sciences
Humans
Immune checkpoint
Invasiveness
Male
Middle Aged
multidisciplinary
Muscles
Mutation
Neoadjuvant Therapy - methods
Neoplasm Invasiveness
Science
Science (multidisciplinary)
Spatial heterogeneity
Survival Rate
Transcriptome - genetics
Treatment Outcome
Tumors
Urinary bladder
Urinary Bladder - pathology
Urinary Bladder - surgery
Urinary Bladder Neoplasms - drug therapy
Urinary Bladder Neoplasms - genetics
Urinary Bladder Neoplasms - mortality
Urinary Bladder Neoplasms - surgery
Whole Exome Sequencing
Online AccessGet full text
ISSN2041-1723
2041-1723
DOI10.1038/s41467-017-02320-7

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Abstract Despite continued widespread use, the genomic effects of cisplatin-based chemotherapy and implications for subsequent treatment are incompletely characterized. Here, we analyze whole exome sequencing of matched pre- and post-neoadjuvant cisplatin-based chemotherapy primary bladder tumor samples from 30 muscle-invasive bladder cancer patients. We observe no overall increase in tumor mutational burden post-chemotherapy, though a significant proportion of subclonal mutations are unique to the matched pre- or post-treatment tumor, suggesting chemotherapy-induced and/or spatial heterogeneity. We subsequently identify and validate a novel mutational signature in post-treatment tumors consistent with known characteristics of cisplatin damage and repair. We find that post-treatment tumor heterogeneity predicts worse overall survival, and further observe alterations in cell-cycle and immune checkpoint regulation genes in post-treatment tumors. These results provide insight into the clinical and genomic dynamics of tumor evolution with cisplatin-based chemotherapy, suggest mechanisms of clinical resistance, and inform development of clinically relevant biomarkers and trials of combination therapies. The impact of cisplatin-based chemotherapy on tumor genomes is complex. Here, the authors study matched pre- and post-chemotherapy primary samples in muscle-invasive bladder cancer, finding a cisplatin-based mutational signature, and highlighting the impact of intratumor heterogeneity on survival.
AbstractList The impact of cisplatin-based chemotherapy on tumor genomes is complex. Here, the authors study matched pre- and post-chemotherapy primary samples in muscle-invasive bladder cancer, finding a cisplatin-based mutational signature, and highlighting the impact of intratumor heterogeneity on survival.
Despite continued widespread use, the genomic effects of cisplatin-based chemotherapy and implications for subsequent treatment are incompletely characterized. Here, we analyze whole exome sequencing of matched pre- and post-neoadjuvant cisplatin-based chemotherapy primary bladder tumor samples from 30 muscle-invasive bladder cancer patients. We observe no overall increase in tumor mutational burden post-chemotherapy, though a significant proportion of subclonal mutations are unique to the matched pre- or post-treatment tumor, suggesting chemotherapy-induced and/or spatial heterogeneity. We subsequently identify and validate a novel mutational signature in post-treatment tumors consistent with known characteristics of cisplatin damage and repair. We find that post-treatment tumor heterogeneity predicts worse overall survival, and further observe alterations in cell-cycle and immune checkpoint regulation genes in post-treatment tumors. These results provide insight into the clinical and genomic dynamics of tumor evolution with cisplatin-based chemotherapy, suggest mechanisms of clinical resistance, and inform development of clinically relevant biomarkers and trials of combination therapies.
Despite continued widespread use, the genomic effects of cisplatin-based chemotherapy and implications for subsequent treatment are incompletely characterized. Here, we analyze whole exome sequencing of matched pre- and post-neoadjuvant cisplatin-based chemotherapy primary bladder tumor samples from 30 muscle-invasive bladder cancer patients. We observe no overall increase in tumor mutational burden post-chemotherapy, though a significant proportion of subclonal mutations are unique to the matched pre- or post-treatment tumor, suggesting chemotherapy-induced and/or spatial heterogeneity. We subsequently identify and validate a novel mutational signature in post-treatment tumors consistent with known characteristics of cisplatin damage and repair. We find that post-treatment tumor heterogeneity predicts worse overall survival, and further observe alterations in cell-cycle and immune checkpoint regulation genes in post-treatment tumors. These results provide insight into the clinical and genomic dynamics of tumor evolution with cisplatin-based chemotherapy, suggest mechanisms of clinical resistance, and inform development of clinically relevant biomarkers and trials of combination therapies. The impact of cisplatin-based chemotherapy on tumor genomes is complex. Here, the authors study matched pre- and post-chemotherapy primary samples in muscle-invasive bladder cancer, finding a cisplatin-based mutational signature, and highlighting the impact of intratumor heterogeneity on survival.
Despite continued widespread use, the genomic effects of cisplatin-based chemotherapy and implications for subsequent treatment are incompletely characterized. Here, we analyze whole exome sequencing of matched pre- and post-neoadjuvant cisplatin-based chemotherapy primary bladder tumor samples from 30 muscle-invasive bladder cancer patients. We observe no overall increase in tumor mutational burden post-chemotherapy, though a significant proportion of subclonal mutations are unique to the matched pre- or post-treatment tumor, suggesting chemotherapy-induced and/or spatial heterogeneity. We subsequently identify and validate a novel mutational signature in post-treatment tumors consistent with known characteristics of cisplatin damage and repair. We find that post-treatment tumor heterogeneity predicts worse overall survival, and further observe alterations in cell-cycle and immune checkpoint regulation genes in post-treatment tumors. These results provide insight into the clinical and genomic dynamics of tumor evolution with cisplatin-based chemotherapy, suggest mechanisms of clinical resistance, and inform development of clinically relevant biomarkers and trials of combination therapies.Despite continued widespread use, the genomic effects of cisplatin-based chemotherapy and implications for subsequent treatment are incompletely characterized. Here, we analyze whole exome sequencing of matched pre- and post-neoadjuvant cisplatin-based chemotherapy primary bladder tumor samples from 30 muscle-invasive bladder cancer patients. We observe no overall increase in tumor mutational burden post-chemotherapy, though a significant proportion of subclonal mutations are unique to the matched pre- or post-treatment tumor, suggesting chemotherapy-induced and/or spatial heterogeneity. We subsequently identify and validate a novel mutational signature in post-treatment tumors consistent with known characteristics of cisplatin damage and repair. We find that post-treatment tumor heterogeneity predicts worse overall survival, and further observe alterations in cell-cycle and immune checkpoint regulation genes in post-treatment tumors. These results provide insight into the clinical and genomic dynamics of tumor evolution with cisplatin-based chemotherapy, suggest mechanisms of clinical resistance, and inform development of clinically relevant biomarkers and trials of combination therapies.
ArticleNumber 2193
Author Han, Garam
Liu, David
Iyer, Gopa
Alpaugh, R. Katherine
Bellmunt, Joaquim
Wankowicz, Stephanie
Reardon, Brendan
Carter, Scott L.
Plimack, Elizabeth R.
Abbosh, Philip
Van Allen, Eliezer M.
Al-Ahmadie, Hikmat
Keliher, Daniel
Rosenberg, Jonathan E.
Miao, Diana
Cipolla, Catharine
Dulaimi, Essel
Teo, Min Yuen
Kim, Jaegil
Hoffman-Censits, Jean
Mouw, Kent
Garraway, Levi A.
Chen, David Y. T.
Weiner-Taylor, Amaro
Getz, Gad
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/29259186$$D View this record in MEDLINE/PubMed
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ContentType Journal Article
Copyright The Author(s) 2017
2017. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
Copyright_xml – notice: The Author(s) 2017
– notice: 2017. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
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SSID ssj0000391844
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Snippet Despite continued widespread use, the genomic effects of cisplatin-based chemotherapy and implications for subsequent treatment are incompletely characterized....
The impact of cisplatin-based chemotherapy on tumor genomes is complex. Here, the authors study matched pre- and post-chemotherapy primary samples in...
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631/67/589/1336
631/67/69
Adult
Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols - pharmacology
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Biomarkers
Biomarkers, Tumor - genetics
Bladder
Bladder cancer
Cancer
Carcinoma - drug therapy
Carcinoma - genetics
Carcinoma - mortality
Carcinoma - pathology
Chemotherapy
Cisplatin
Cisplatin - pharmacology
Cisplatin - therapeutic use
Clinical trials
Clonal Evolution - drug effects
Cohort Studies
Cystectomy
DNA Mutational Analysis
Drug Resistance, Neoplasm - drug effects
Drug Resistance, Neoplasm - genetics
Female
Gene expression
Gene regulation
Heterogeneity
Humanities and Social Sciences
Humans
Immune checkpoint
Invasiveness
Male
Middle Aged
multidisciplinary
Muscles
Mutation
Neoadjuvant Therapy - methods
Neoplasm Invasiveness
Science
Science (multidisciplinary)
Spatial heterogeneity
Survival Rate
Transcriptome - genetics
Treatment Outcome
Tumors
Urinary bladder
Urinary Bladder - pathology
Urinary Bladder - surgery
Urinary Bladder Neoplasms - drug therapy
Urinary Bladder Neoplasms - genetics
Urinary Bladder Neoplasms - mortality
Urinary Bladder Neoplasms - surgery
Whole Exome Sequencing
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Title Mutational patterns in chemotherapy resistant muscle-invasive bladder cancer
URI https://link.springer.com/article/10.1038/s41467-017-02320-7
https://www.ncbi.nlm.nih.gov/pubmed/29259186
https://www.proquest.com/docview/1983426646
https://www.proquest.com/docview/1979175519
https://pubmed.ncbi.nlm.nih.gov/PMC5736752
https://doaj.org/article/a0719910fb0a4af896b5c3b5a29c89f7
Volume 8
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