Nature communications, 2017-12, Vol.8 (1), p.2193-11, Article 2193
- 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
2017
Details
- Autor(en) / Beteiligte
- 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
- Titel
- Mutational patterns in chemotherapy resistant muscle-invasive bladder cancer
- Ist Teil von
- Nature communications, 2017-12, Vol.8 (1), p.2193-11, Article 2193
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2017
- Link zum Volltext
- Quelle
- Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-1723eISSN: 2041-1723DOI: 10.1038/s41467-017-02320-7Titel-ID: cdi_doaj_primary_oai_doaj_org_article_a0719910fb0a4af896b5c3b5a29c89f7
- Format
- –
- Schlagworte
- 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, Cell survival, 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, Humans, Immune checkpoint, Invasiveness, Male, Middle Aged, Muscles, Mutation, Neoadjuvant Therapy - methods, Neoplasm Invasiveness, 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