Discovery of Molecular DNA Methylation-Based Biomarkers through Genome-Wide Analysis of Response Patterns to BCG for Bladder Cancer.
Adjuvants, Immunologic
/ therapeutic use
Aged
Aged, 80 and over
BCG Vaccine
/ therapeutic use
Biomarkers, Tumor
/ genetics
CpG Islands
DNA Methylation
Female
Genome-Wide Association Study
Heterochromatin
Humans
Immunotherapy
Male
Middle Aged
Promoter Regions, Genetic
Treatment Outcome
Urinary Bladder Neoplasms
/ drug therapy
BCG refractory
Bacillus Calmette-Guérin
DNA methylation marker
Illumina MethylationEPIC BeadChip
bladder cancer
high-risk bladder cancer
urothelial cancer
Journal
Cells
ISSN: 2073-4409
Titre abrégé: Cells
Pays: Switzerland
ID NLM: 101600052
Informations de publication
Date de publication:
05 08 2020
05 08 2020
Historique:
received:
15
07
2020
revised:
31
07
2020
accepted:
03
08
2020
entrez:
9
8
2020
pubmed:
9
8
2020
medline:
11
3
2021
Statut:
epublish
Résumé
Bacillus Calmette-Guérin (BCG) immunotherapy, the standard adjuvant intravesical therapy for some intermediate and most high-risk non-muscle invasive bladder cancers (NMIBCs), suffers from a heterogenous response rate. Molecular markers to help guide responses are scarce and currently not used in the clinical setting. To identify novel biomarkers and pathways involved in response to BCG immunotherapy, we performed a genome-wide DNA methylation analysis of NMIBCs before BCG therapy. Genome-wide DNA methylation profiles of DNA isolated from tumors of 26 BCG responders and 27 failures were obtained using the Infinium MethylationEPIC BeadChip. Distinct DNA methylation patterns were found by genome-wide analysis in the two groups. Differentially methylated CpG sites were predominantly located in gene promoters and gene bodies associated with bacterial invasion of epithelial cells, chemokine signaling, endocytosis, and focal adhesion. In total, 40 genomic regions with a significant difference in methylation between responders and failures were detected. The differential methylation state of six of these regions, localized in the promoters of the genes Tumors from BCG responders and BCG failures harbor distinct DNA methylation profiles. Differentially methylated DNA regions were detected in genes related to pathways involved in bacterial invasion of cells or focal adhesion. We identified candidate DNA methylation biomarkers that may help to predict patient prognosis after external validation in larger, well-designed cohorts.
Sections du résumé
BACKGROUND
Bacillus Calmette-Guérin (BCG) immunotherapy, the standard adjuvant intravesical therapy for some intermediate and most high-risk non-muscle invasive bladder cancers (NMIBCs), suffers from a heterogenous response rate. Molecular markers to help guide responses are scarce and currently not used in the clinical setting.
METHODS
To identify novel biomarkers and pathways involved in response to BCG immunotherapy, we performed a genome-wide DNA methylation analysis of NMIBCs before BCG therapy. Genome-wide DNA methylation profiles of DNA isolated from tumors of 26 BCG responders and 27 failures were obtained using the Infinium MethylationEPIC BeadChip.
RESULTS
Distinct DNA methylation patterns were found by genome-wide analysis in the two groups. Differentially methylated CpG sites were predominantly located in gene promoters and gene bodies associated with bacterial invasion of epithelial cells, chemokine signaling, endocytosis, and focal adhesion. In total, 40 genomic regions with a significant difference in methylation between responders and failures were detected. The differential methylation state of six of these regions, localized in the promoters of the genes
CONCLUSIONS
Tumors from BCG responders and BCG failures harbor distinct DNA methylation profiles. Differentially methylated DNA regions were detected in genes related to pathways involved in bacterial invasion of cells or focal adhesion. We identified candidate DNA methylation biomarkers that may help to predict patient prognosis after external validation in larger, well-designed cohorts.
Identifiants
pubmed: 32764425
pii: cells9081839
doi: 10.3390/cells9081839
pmc: PMC7464079
pii:
doi:
Substances chimiques
Adjuvants, Immunologic
0
BCG Vaccine
0
Biomarkers, Tumor
0
Heterochromatin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Références
Am J Pathol. 2010 Jun;176(6):2997-3006
pubmed: 20395438
Eur Urol Oncol. 2019 May;2(3):286-293
pubmed: 31200843
J Urol. 1991 Jun;145(6):1316-24
pubmed: 2033723
Biomark Cancer. 2018 Jan 08;10:1179299X17751920
pubmed: 29343995
Eur Urol. 2011 Jul;60(1):131-40
pubmed: 21514719
Cancer Immunol Immunother. 1992;34(5):306-12
pubmed: 1540977
Transl Oncol. 2017 Apr;10(2):168-177
pubmed: 28167242
J Urol. 2009 Apr;181(4):1571-80
pubmed: 19230924
Urol Oncol. 2013 Aug;31(6):836-42
pubmed: 21868260
PLoS One. 2015 Feb 18;10(2):e0117758
pubmed: 25693195
Int J Epidemiol. 2012 Feb;41(1):200-9
pubmed: 22422453
Nat Rev Urol. 2018 Oct;15(10):615-625
pubmed: 29991725
Cytokine. 2003 Jan 7;21(1):17-26
pubmed: 12668155
J Clin Invest. 1993 Jan;91(1):69-76
pubmed: 8423234
Eur Urol. 2019 Nov;76(5):639-657
pubmed: 31443960
Bioinformatics. 2001 Jun;17(6):520-5
pubmed: 11395428
Prostate. 2015 Dec;75(16):1941-50
pubmed: 26383847
Eur Urol. 2017 Mar;71(3):447-461
pubmed: 27324428
J Biol Chem. 2015 May 29;290(22):13622-39
pubmed: 25792749
Epigenetics. 2020 Jan - Feb;15(1-2):174-182
pubmed: 31538540
Cell Rep. 2018 Sep 18;24(12):3353-3366.e5
pubmed: 30232014
Nat Protoc. 2009;4(1):44-57
pubmed: 19131956
Urol Res. 1992;20(3):219-28
pubmed: 1615584
J Urol. 2003 Sep;170(3):964-9
pubmed: 12913751
J Clin Endocrinol Metab. 2012 Jun;97(6):E1004-13
pubmed: 22472567
J Urol. 1999 Aug;162(2):600-5
pubmed: 10411094
Cancer Inform. 2019 Feb 11;18:1176935119828776
pubmed: 30792573
PLoS One. 2015 Sep 02;10(9):e0137003
pubmed: 26332997
Eur Urol. 2015 Jan;67(1):74-82
pubmed: 25043942
Cancer Res. 2006 Aug 15;66(16):8250-7
pubmed: 16912205
J Clin Invest. 1990 Jan;85(1):62-7
pubmed: 2404029
Cancer Res. 2006 Jul 15;66(14):7103-10
pubmed: 16849556
Nucleic Acids Res. 2015 Apr 20;43(7):e47
pubmed: 25605792
Int J Urol. 2002 Jan;9(1):29-35
pubmed: 11972647
Cancer Res. 2013 Feb 1;73(3):1156-67
pubmed: 23378476
PLoS One. 2013;8(2):e57843
pubmed: 23451275
PLoS One. 2016 Jul 28;11(7):e0160227
pubmed: 27467908
Genome Biol. 2016 Oct 7;17(1):208
pubmed: 27717381
Eur Urol. 2013 Feb;63(2):364-70
pubmed: 22682992
J Urol. 2002 Nov;168(5):1964-70
pubmed: 12394686
Expert Rev Mol Diagn. 2018 Apr;18(4):347-356
pubmed: 29542328
Nucleic Acids Res. 2009 Jan;37(1):1-13
pubmed: 19033363
Oncol Rep. 2007 Nov;18(5):1315-20
pubmed: 17914591
J Cell Biol. 2000 Mar 6;148(5):957-70
pubmed: 10704446
Urology. 2004 Apr;63(4):682-6; discussion 686-7
pubmed: 15072879
Cancer Inform. 2007 Feb 04;3:11-7
pubmed: 19455231
J Urol. 1989 Jun;141(6):1449-53
pubmed: 2657113
Genome Biol. 2012 Oct 03;13(10):R96
pubmed: 23034089
Br J Cancer. 2013 Sep 17;109(6):1460-6
pubmed: 23982601
Cytokine. 2012 Aug;59(2):423-32
pubmed: 22617682