DNA methylation and transcriptomic features are preserved throughout disease recurrence and chemoresistance in high grade serous ovarian cancers.
Chemoresistance
Computational methods
Epigenetics
High grade serous ovarian cancer
Methylation
Translational research
Whole genome bisulfite sequencing
Journal
Journal of experimental & clinical cancer research : CR
ISSN: 1756-9966
Titre abrégé: J Exp Clin Cancer Res
Pays: England
ID NLM: 8308647
Informations de publication
Date de publication:
27 Jul 2022
27 Jul 2022
Historique:
received:
29
12
2021
accepted:
13
07
2022
entrez:
26
7
2022
pubmed:
27
7
2022
medline:
29
7
2022
Statut:
epublish
Résumé
Little is known about the role of global DNA methylation in recurrence and chemoresistance of high grade serous ovarian cancer (HGSOC). We performed whole genome bisulfite sequencing and transcriptome sequencing in 62 primary and recurrent tumors from 28 patients with stage III/IV HGSOC, of which 11 patients carried germline, pathogenic BRCA1 and/or BRCA2 mutations. Landscapes of genome-wide methylation (on average 24.2 million CpGs per tumor) and transcriptomes in primary and recurrent tumors showed extensive heterogeneity between patients but were highly preserved in tumors from the same patient. We identified significant differences in the burden of differentially methylated regions (DMRs) in tumors from BRCA1/2 compared to non-BRCA1/2 carriers (mean 659 DMRs and 388 DMRs in paired comparisons respectively). We identified overexpression of immune pathways in BRCA1/2 carriers compared to non-carriers, implicating an increased immune response in improved survival (P = 0.006) in these BRCA1/2 carriers. These findings indicate methylome and gene expression programs established in the primary tumor are conserved throughout disease progression, even after extensive chemotherapy treatment, and that changes in methylation and gene expression are unlikely to serve as drivers for chemoresistance in HGSOC.
Sections du résumé
BACKGROUND
BACKGROUND
Little is known about the role of global DNA methylation in recurrence and chemoresistance of high grade serous ovarian cancer (HGSOC).
METHODS
METHODS
We performed whole genome bisulfite sequencing and transcriptome sequencing in 62 primary and recurrent tumors from 28 patients with stage III/IV HGSOC, of which 11 patients carried germline, pathogenic BRCA1 and/or BRCA2 mutations.
RESULTS
RESULTS
Landscapes of genome-wide methylation (on average 24.2 million CpGs per tumor) and transcriptomes in primary and recurrent tumors showed extensive heterogeneity between patients but were highly preserved in tumors from the same patient. We identified significant differences in the burden of differentially methylated regions (DMRs) in tumors from BRCA1/2 compared to non-BRCA1/2 carriers (mean 659 DMRs and 388 DMRs in paired comparisons respectively). We identified overexpression of immune pathways in BRCA1/2 carriers compared to non-carriers, implicating an increased immune response in improved survival (P = 0.006) in these BRCA1/2 carriers.
CONCLUSION
CONCLUSIONS
These findings indicate methylome and gene expression programs established in the primary tumor are conserved throughout disease progression, even after extensive chemotherapy treatment, and that changes in methylation and gene expression are unlikely to serve as drivers for chemoresistance in HGSOC.
Identifiants
pubmed: 35883104
doi: 10.1186/s13046-022-02440-z
pii: 10.1186/s13046-022-02440-z
pmc: PMC9327231
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
232Subventions
Organisme : NIH/NCI
ID : R01CA211575
Organisme : NIH HHS
ID : U01CA184826
Pays : United States
Organisme : NIH HHS
ID : U01CA184826
Pays : United States
Organisme : Ovarian Cancer Research Alliance Liz Tilberis Early Career Award
ID : 599175
Organisme : Ovarian Cancer Research Alliance Program Project Development Award
ID : 373356
Organisme : Research Scholar's Grant from the American Cancer Society
ID : 134005
Organisme : NCI NIH HHS
ID : K99CA256519
Pays : United States
Informations de copyright
© 2022. The Author(s).
Références
Oncotarget. 2017 Jul 26;8(40):68483-68492
pubmed: 28978132
Nucleic Acids Res. 2019 Jan 8;47(D1):D590-D595
pubmed: 30321428
Cancer Inform. 2019 Feb 11;18:1176935119828776
pubmed: 30792573
R J. 2016 Aug;8(1):289-317
pubmed: 27818791
Cell Rep. 2019 Dec 10;29(11):3726-3735.e4
pubmed: 31825847
Oncogene. 2020 Jan;39(3):617-636
pubmed: 31527668
Nat Biotechnol. 2015 Mar;33(3):290-5
pubmed: 25690850
BMC Med. 2017 Jun 23;15(1):116
pubmed: 28641578
Cancer Res. 2019 Dec 15;79(24):6238-6246
pubmed: 31641033
J Natl Cancer Inst. 2000 Apr 5;92(7):564-9
pubmed: 10749912
Onco Targets Ther. 2017 Nov 10;10:5377-5390
pubmed: 29180871
Sci Rep. 2019 Nov 29;9(1):17996
pubmed: 31784612
Oncol Rep. 2015 May;33(5):2227-34
pubmed: 25738998
Nucleic Acids Res. 2019 Jan 8;47(D1):D1066-D1072
pubmed: 30203047
Hum Mol Genet. 2011 Feb 15;20(4):670-80
pubmed: 21112978
Nucleic Acids Res. 2019 Jan 8;47(D1):D941-D947
pubmed: 30371878
Nat Rev Genet. 2016 May;17(5):284-99
pubmed: 26972587
Bioinformatics. 2014 May 15;30(10):1363-9
pubmed: 24478339
Genome Res. 2016 Feb;26(2):256-62
pubmed: 26631489
Nature. 2011 Jun 29;474(7353):609-15
pubmed: 21720365
Nature. 2015 May 28;521(7553):489-94
pubmed: 26017449
JAMA. 2012 Jan 25;307(4):382-90
pubmed: 22274685
Cell. 2016 Jan 14;164(1-2):69-80
pubmed: 26724866
OMICS. 2012 May;16(5):284-7
pubmed: 22455463
Genome Biol. 2014;15(12):550
pubmed: 25516281
Nat Biotechnol. 2016 May;34(5):525-7
pubmed: 27043002
Ann Oncol. 2007 Sep;18(9):1529-38
pubmed: 17761710
Br J Cancer. 2014 Apr 15;110(8):1923-9
pubmed: 24642620
Cancer Res. 2018 Feb 1;78(3):631-644
pubmed: 29229600
Clin Cancer Res. 2018 Mar 15;24(6):1389-1401
pubmed: 29263182
Oncogene. 1999 Feb 11;18(6):1313-24
pubmed: 10022813
Nat Cancer. 2020 Nov;1(11):1066-1081
pubmed: 34079956
Mol Cancer. 2021 Jul 5;20(1):94
pubmed: 34225755
Gynecol Oncol. 2012 Mar;124(3):582-8
pubmed: 22115852
Clin Cancer Res. 2020 Mar 1;26(5):1009-1016
pubmed: 31831561
Nat Med. 2020 Aug;26(8):1271-1279
pubmed: 32572264
EMBO Rep. 2015 Nov;16(11):1520-34
pubmed: 26412854
F1000Res. 2015 Dec 30;4:1521
pubmed: 26925227
Eur J Cancer. 2016 Jan;53:51-64
pubmed: 26693899
Genome Biol. 2015 May 21;16:105
pubmed: 25994056
Genome Med. 2021 Jul 9;13(1):111
pubmed: 34238352
BMC Bioinformatics. 2011 Aug 04;12:323
pubmed: 21816040
Bioinformatics. 2019 Jun 1;35(11):1974-1977
pubmed: 30364927
Bioinformatics. 2016 Oct 1;32(19):3047-8
pubmed: 27312411
Gynecol Oncol. 2018 Nov;151(2):327-336
pubmed: 30209015
Ann Surg. 2019 Mar;269(3):479-485
pubmed: 29384778
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Cancer Res. 1995 Oct 15;55(20):4525-30
pubmed: 7553621
BMC Bioinformatics. 2010 Nov 30;11:587
pubmed: 21118553
Bioinformatics. 2015 Jul 15;31(14):2382-3
pubmed: 25765347
Nat Genet. 2011 Nov 27;44(1):40-6
pubmed: 22120008
Nat Methods. 2016 Dec 29;14(1):18-22
pubmed: 28032624
Sci Rep. 2019 Jun 27;9(1):9354
pubmed: 31249361
Nucleic Acids Res. 2019 Jan 8;47(D1):D766-D773
pubmed: 30357393
Bioinformatics. 2017 Aug 01;33(15):2381-2383
pubmed: 28369316
Nat Genet. 2018 Apr;50(4):591-602
pubmed: 29610480
Nat Commun. 2018 Nov 9;9(1):4718
pubmed: 30413718
PLoS Genet. 2010 Sep 23;6(9):e1001134
pubmed: 20885785
Cell. 2018 Sep 20;175(1):159-170.e16
pubmed: 30241606
Nat Genet. 2016 Jul;48(7):758-67
pubmed: 27182968
Oncotarget. 2016 Sep 20;7(38):62547-62558
pubmed: 27566576
Cancer Discov. 2016 Dec;6(12):1342-1351
pubmed: 27856443
Nat Methods. 2017 Apr;14(4):417-419
pubmed: 28263959
Genome Biol. 2018 Sep 28;19(1):150
pubmed: 30266094
Nat Genet. 2011 Jun 26;43(8):768-75
pubmed: 21706001
Nat Genet. 2017 Jun;49(6):856-865
pubmed: 28436987
Cancer Res. 2014 Mar 15;74(6):1651-60
pubmed: 24473064
Bioinformatics. 2010 Mar 15;26(6):841-2
pubmed: 20110278
Genome Med. 2014 Aug 26;6(8):61
pubmed: 25191524
Genome Res. 2012 Feb;22(2):246-58
pubmed: 22156296
Nat Biotechnol. 2009 Apr;27(4):361-8
pubmed: 19329998
Genome Res. 2011 Oct;21(10):1583-91
pubmed: 21784875
Nucleic Acids Res. 2020 Jan 8;48(D1):D983-D991
pubmed: 31598699
Nat Commun. 2019 Apr 15;10(1):1749
pubmed: 30988298
Nature. 2016 Sep 15;537(7620):369-373
pubmed: 27602518
Biostatistics. 2019 Jul 1;20(3):367-383
pubmed: 29481604