A Whole-genome CRISPR Screen Identifies a Role of MSH2 in Cisplatin-mediated Cell Death in Muscle-invasive Bladder Cancer.
Antineoplastic Agents
/ pharmacology
Biomarkers, Tumor
/ genetics
CRISPR-Cas Systems
Cell Death
/ drug effects
Cell Line, Tumor
Cisplatin
/ pharmacology
Databases, Genetic
Drug Resistance, Neoplasm
/ genetics
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
MutS Homolog 2 Protein
/ genetics
Neoplasm Invasiveness
Phenotype
Urinary Bladder Neoplasms
/ drug therapy
Whole Genome Sequencing
/ methods
Bladder cancer
CRISPR screen
Chemotherapy
Cisplatin
MSH2
Mismatch repair
Patient stratification
Journal
European urology
ISSN: 1873-7560
Titre abrégé: Eur Urol
Pays: Switzerland
ID NLM: 7512719
Informations de publication
Date de publication:
02 2019
02 2019
Historique:
received:
29
06
2018
accepted:
15
10
2018
pubmed:
12
11
2018
medline:
20
6
2019
entrez:
12
11
2018
Statut:
ppublish
Résumé
The response to first-line, platinum-based treatment of muscle-invasive bladder cancer has not improved in 3 decades. To identify genes that influence cisplatin resistance in bladder cancer. We performed a whole-genome CRISPR screen in a bladder cancer cell line to identify genes that mediate resistance to cisplatin. Targeted validation was performed in two bladder cancer cell lines. The top gene candidate was validated in a publicly available bladder cancer dataset. From the CRISPR screen, we identified MSH2 as the most significantly enriched gene and mismatch repair as the most significantly enriched pathway that promoted resistance to cisplatin. Bladder cancer cells with knockdown of MSH2 showed a reduction in cisplatin-mediated apoptosis. MSH2 loss did not impact the sensitivity to other chemotherapies, including the cisplatin analog oxaliplatin. Bladder tumors with low MSH2 protein levels, quantified using reverse-phase protein array, showed poorer survival when treated with cisplatin- or carboplatin-based therapy; these results require future validation using immunohistochemistry. Additionally, results are retrospective from patients with primarily high-grade tumors; thus, validation in a controlled clinical trial is needed. We generated in vitro evidence that bladder cancer cell lines depleted of MSH2 are more resistant to cisplatin. We additionally found an association between low MSH2 in bladder tumors and poorer patient survival when treated with platinum-based chemotherapy. If successfully validated prospectively, MSH2 protein level could assist in the selection of patients for chemotherapy. We report the first evidence that MSH2 protein level may contribute to chemotherapy resistance observed in muscle-invasive bladder cancer. MSH2 has potential as a biomarker predictive of response to platinum-based therapy.
Sections du résumé
BACKGROUND
The response to first-line, platinum-based treatment of muscle-invasive bladder cancer has not improved in 3 decades.
OBJECTIVE
To identify genes that influence cisplatin resistance in bladder cancer.
DESIGN, SETTING, AND PARTICIPANTS
We performed a whole-genome CRISPR screen in a bladder cancer cell line to identify genes that mediate resistance to cisplatin.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
Targeted validation was performed in two bladder cancer cell lines. The top gene candidate was validated in a publicly available bladder cancer dataset.
RESULTS AND LIMITATIONS
From the CRISPR screen, we identified MSH2 as the most significantly enriched gene and mismatch repair as the most significantly enriched pathway that promoted resistance to cisplatin. Bladder cancer cells with knockdown of MSH2 showed a reduction in cisplatin-mediated apoptosis. MSH2 loss did not impact the sensitivity to other chemotherapies, including the cisplatin analog oxaliplatin. Bladder tumors with low MSH2 protein levels, quantified using reverse-phase protein array, showed poorer survival when treated with cisplatin- or carboplatin-based therapy; these results require future validation using immunohistochemistry. Additionally, results are retrospective from patients with primarily high-grade tumors; thus, validation in a controlled clinical trial is needed.
CONCLUSIONS
We generated in vitro evidence that bladder cancer cell lines depleted of MSH2 are more resistant to cisplatin. We additionally found an association between low MSH2 in bladder tumors and poorer patient survival when treated with platinum-based chemotherapy. If successfully validated prospectively, MSH2 protein level could assist in the selection of patients for chemotherapy.
PATIENT SUMMARY
We report the first evidence that MSH2 protein level may contribute to chemotherapy resistance observed in muscle-invasive bladder cancer. MSH2 has potential as a biomarker predictive of response to platinum-based therapy.
Identifiants
pubmed: 30414698
pii: S0302-2838(18)30835-2
doi: 10.1016/j.eururo.2018.10.040
pmc: PMC6339584
mid: NIHMS1510205
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
Biomarkers, Tumor
0
MSH2 protein, human
EC 3.6.1.3
MutS Homolog 2 Protein
EC 3.6.1.3
Cisplatin
Q20Q21Q62J
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
242-250Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA046934
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA221675
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007635
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Références
Bioinformatics. 2015 Jan 15;31(2):166-9
pubmed: 25260700
Oncogene. 2008 Feb 14;27(8):1183-8
pubmed: 17700524
Cancer. 1999 Jan 15;85(2):478-84
pubmed: 10023718
Br J Cancer. 2001 Feb 2;84(3):321-8
pubmed: 11161395
Cell. 2006 Mar 24;124(6):1283-98
pubmed: 16564017
Clin Cancer Res. 2004 Jul 1;10(13):4420-6
pubmed: 15240532
Br J Cancer. 1999 Jul;80(10):1665-71
pubmed: 10408416
Clin Cancer Res. 2000 Apr;6(4):1415-21
pubmed: 10778972
Nucleic Acids Res. 2016 May 5;44(8):e71
pubmed: 26704973
J Clin Oncol. 2000 Sep;18(17):3068-77
pubmed: 11001674
Int J Cancer. 2003 Jul 1;105(4):484-90
pubmed: 12712438
Nat Methods. 2013 Nov;10(11):1046-7
pubmed: 24037243
Science. 2014 Jan 3;343(6166):84-87
pubmed: 24336571
APMIS. 2008 Jan;116(1):59-65
pubmed: 18254781
Nat Protoc. 2009;4(1):44-57
pubmed: 19131956
Cancer Res. 1996 Nov 1;56(21):4881-6
pubmed: 8895738
Asian Pac J Cancer Prev. 2016;17(1):381-6
pubmed: 26838243
Genome Biol. 2014;15(12):550
pubmed: 25516281
Neoplasia. 2010 Aug;12(8):628-36
pubmed: 20689757
Oncotarget. 2017 Jan 17;8(3):4313-4329
pubmed: 28008145
Urology. 2005 Jun;65(6):1233-7
pubmed: 15922421
Cancer Discov. 2012 May;2(5):401-4
pubmed: 22588877
Nature. 1999 Jun 24;399(6738):806-9
pubmed: 10391249
Chemotherapy. 2009;55(5):321-6
pubmed: 19641314
Nucleic Acids Res. 2016 Jan 4;44(D1):D457-62
pubmed: 26476454
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Nat Methods. 2012 Mar 04;9(4):357-9
pubmed: 22388286
Cell. 2017 Oct 19;171(3):540-556.e25
pubmed: 28988769
Nat Methods. 2014 Aug;11(8):783-784
pubmed: 25075903
Oncogene. 2017 Jan 5;36(1):35-46
pubmed: 27270441
Sci Signal. 2013 Apr 02;6(269):pl1
pubmed: 23550210
Br J Cancer. 2009 Jul 21;101(2):269-77
pubmed: 19603033
Clin Cancer Res. 2010 Feb 15;16(4):1206-15
pubmed: 20145178
Ann Oncol. 2011 Jan;22(1):139-44
pubmed: 20603439
Mol Cell Biol. 2004 Jul;24(14):6430-44
pubmed: 15226443
Microarrays (Basel). 2015 Mar 24;4(2):98-114
pubmed: 27600215
Oncogene. 1997 Jul 3;15(1):45-52
pubmed: 9233776
Nat Med. 2016 Nov;22(11):1342-1350
pubmed: 27694933