DNA methylation subtypes guiding prognostic assessment and linking to responses the DNA methyltransferase inhibitor SGI-110 in urothelial carcinoma.

Azacitidine / analogs & derivatives Carcinoma, Transitional Cell / drug therapy DNA Methylation DNA Modification Methylases / antagonists & inhibitors Humans Prognosis Urinary Bladder Neoplasms / drug therapy
DNA methylation subtype DNA methyltransferase inhibitor Prognosis Upper tract urothelial carcinoma Urothelial carcinoma of the bladder Whole-genome bisulfite sequencing

Journal

BMC medicine
ISSN: 1741-7015
Titre abrégé: BMC Med
Pays: England
ID NLM: 101190723

Informations de publication

Date de publication:
18 07 2022
Historique:
received: 08 02 2022
accepted: 31 05 2022
entrez: 17 7 2022
pubmed: 18 7 2022
medline: 20 7 2022
Statut: epublish

Résumé

At present, the extent and clinical relevance of epigenetic differences between upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB) remain largely unknown. Here, we conducted a study to describe the global DNA methylation landscape of UTUC and UCB and to address the prognostic value of DNA methylation subtype and responses to the DNA methyltransferase inhibitor SGI-110 in urothelial carcinoma (UC). Using whole-genome bisulfite sequencing (n = 49 samples), we analyzed epigenomic features and profiles of UTUC (n = 36) and UCB (n = 9). Next, we characterized potential links between DNA methylation, gene expression (n = 9 samples), and clinical outcomes. Then, we integrated an independent UTUC cohort (Fujii et al., n = 86) and UCB cohort (TCGA, n = 411) to validate the prognostic significance. Furthermore, we performed an integrative analysis of genome-wide DNA methylation and gene expression in two UC cell lines following transient DNA methyltransferase inhibitor SGI-110 treatment to identify potential epigenetic driver events that contribute to drug efficacy. We showed that UTUC and UCB have very similar DNA methylation profiles. Unsupervised DNA methylation classification identified two epi-clusters, Methy-High and Methy-Low, associated with distinct muscle-invasive statuses and patient outcomes. Methy-High samples were hypermethylated, immune-infiltrated, and enriched for exhausted T cells, with poor clinical outcome. SGI-110 inhibited the migration and invasion of Methy-High UC cell lines (UMUC-3 and T24) by upregulating multiple antitumor immune pathways. DNA methylation subtypes pave the way for predicting patient prognosis in UC. Our results provide mechanistic rationale for evaluating SGI-110 in treating UC patients in the clinic.

Sections du résumé

BACKGROUND
At present, the extent and clinical relevance of epigenetic differences between upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB) remain largely unknown. Here, we conducted a study to describe the global DNA methylation landscape of UTUC and UCB and to address the prognostic value of DNA methylation subtype and responses to the DNA methyltransferase inhibitor SGI-110 in urothelial carcinoma (UC).
METHODS
Using whole-genome bisulfite sequencing (n = 49 samples), we analyzed epigenomic features and profiles of UTUC (n = 36) and UCB (n = 9). Next, we characterized potential links between DNA methylation, gene expression (n = 9 samples), and clinical outcomes. Then, we integrated an independent UTUC cohort (Fujii et al., n = 86) and UCB cohort (TCGA, n = 411) to validate the prognostic significance. Furthermore, we performed an integrative analysis of genome-wide DNA methylation and gene expression in two UC cell lines following transient DNA methyltransferase inhibitor SGI-110 treatment to identify potential epigenetic driver events that contribute to drug efficacy.
RESULTS
We showed that UTUC and UCB have very similar DNA methylation profiles. Unsupervised DNA methylation classification identified two epi-clusters, Methy-High and Methy-Low, associated with distinct muscle-invasive statuses and patient outcomes. Methy-High samples were hypermethylated, immune-infiltrated, and enriched for exhausted T cells, with poor clinical outcome. SGI-110 inhibited the migration and invasion of Methy-High UC cell lines (UMUC-3 and T24) by upregulating multiple antitumor immune pathways.
CONCLUSIONS
DNA methylation subtypes pave the way for predicting patient prognosis in UC. Our results provide mechanistic rationale for evaluating SGI-110 in treating UC patients in the clinic.

Identifiants

DOI: 10.1186/s12916-022-02426-w PMID: 35843958 PMC: PMC9290251
pubmed: 35843958
doi: 10.1186/s12916-022-02426-w
pii: 10.1186/s12916-022-02426-w
pmc: PMC9290251
doi:

Substances chimiques

guadecitabine 2KT4YN1DP7
DNA Modification Methylases EC 2.1.1.-
Azacitidine M801H13NRU

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

222

Informations de copyright

© 2022. The Author(s).

Références

Nature. 2018 Feb 22;554(7693):544-548
pubmed: 29443960
Clin Chem. 2021 Jan 30;67(2):394-403
pubmed: 33523215
Genome Biol. 2021 Jan 4;22(1):7
pubmed: 33397444
Epigenomics. 2015 Aug;7(5):733-44
pubmed: 25912368
Hepatology. 2018 Oct;68(4):1412-1428
pubmed: 29774579
Proc Natl Acad Sci U S A. 1996 Jul 9;93(14):7149-53
pubmed: 8692960
Front Cell Dev Biol. 2021 Sep 01;9:642650
pubmed: 34540821
Eur Urol. 2010 Sep;58(3):433-41
pubmed: 20646825
Cancer Cell. 2012 Mar 20;21(3):430-46
pubmed: 22439938
Clin Chem. 2020 Jan 1;66(1):188-198
pubmed: 31811000
Eur Urol. 2022 Jan;81(1):95-103
pubmed: 34742583
Cancer Res. 2007 Jul 1;67(13):6400-8
pubmed: 17616700
Urol Ann. 2011 Sep;3(3):119-26
pubmed: 21976923
Eur Urol. 2017 Oct;72(4):641-649
pubmed: 28601352
Clin Cancer Res. 2021 Apr 1;27(7):1882-1892
pubmed: 33472913
Oncotarget. 2014 Feb 15;5(3):587-98
pubmed: 24583822
Clin Epigenetics. 2018 Feb 12;10:19
pubmed: 29456764
Urology. 2008 Jun;71(6):1220-5
pubmed: 18538698
Cancer Res. 2018 Dec 1;78(23):6575-6580
pubmed: 30154154
Curr Urol Rep. 2018 Oct 24;19(12):102
pubmed: 30357502
Cancer Res. 2010 Oct 15;70(20):8169-78
pubmed: 20841482
Eur Urol. 2013 Feb;63(2):234-41
pubmed: 22877502
Genome Biol. 2016 Oct 20;17(1):218
pubmed: 27765066
Blood Cancer J. 2014 Mar 28;4:e197
pubmed: 24681961
Lancet. 2020 Apr 18;395(10232):1268-1277
pubmed: 32145825
Cell. 2015 Aug 27;162(5):961-73
pubmed: 26317465
Nat Commun. 2019 Jul 5;10(1):2977
pubmed: 31278255
Cancer Res. 1994 Apr 1;54(7):1766-71
pubmed: 7511051
Int J Oncol. 2015 Mar;46(3):1192-204
pubmed: 25501798
J Clin Oncol. 2000 Sep;18(17):3068-77
pubmed: 11001674
Cancer Cell. 2021 Jun 14;39(6):793-809.e8
pubmed: 34129823
Eur Urol. 2021 Jan;79(1):62-79
pubmed: 32593530
Cancer Cell. 2014 Oct 13;26(4):577-90
pubmed: 25263941
Nat Commun. 2013;4:2612
pubmed: 24113773
Nat Genet. 2017 Apr;49(4):635-642
pubmed: 28263317
Lancet. 1999 Aug 14;354(9178):533-40
pubmed: 10470696
Eur Urol. 2020 Feb;77(2):288-290
pubmed: 31744643
PLoS One. 2015 Aug 28;10(8):e0137141
pubmed: 26317352
J Clin Oncol. 2005 May 1;23(13):2903-10
pubmed: 15753461
Cell. 2015 Aug 27;162(5):974-86
pubmed: 26317466

Auteurs

Juan Li (J)

Department of Urology, Peking University First Hospital, Beijing, 100034, China.
CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.

Yuan Liang (Y)

CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.

Jian Fan (J)

Department of Urology, Peking University First Hospital, Beijing, 100034, China.
Institute of Urology, Peking University, Beijing, 100034, China.

Chunru Xu (C)

Department of Urology, Peking University First Hospital, Beijing, 100034, China.
Institute of Urology, Peking University, Beijing, 100034, China.
National Urological Cancer Center, Beijing Key Laboratory of Urogenital Diseases (Male) Molecular Diagnosis and Treatment Center, Beijing, 100034, China.

Bao Guan (B)

Department of Urology, Peking University First Hospital, Beijing, 100034, China.
Institute of Urology, Peking University, Beijing, 100034, China.
National Urological Cancer Center, Beijing Key Laboratory of Urogenital Diseases (Male) Molecular Diagnosis and Treatment Center, Beijing, 100034, China.

Jianye Zhang (J)

Department of Urology, Peking University First Hospital, Beijing, 100034, China.
Institute of Urology, Peking University, Beijing, 100034, China.
National Urological Cancer Center, Beijing Key Laboratory of Urogenital Diseases (Male) Molecular Diagnosis and Treatment Center, Beijing, 100034, China.

Bin Guo (B)

CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.

Yue Shi (Y)

CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.

Ping Wang (P)

CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.

Yezhen Tan (Y)

CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.

Qi Zhang (Q)

CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.

Changwei Yuan (C)

Department of Urology, Peking University First Hospital, Beijing, 100034, China.
Institute of Urology, Peking University, Beijing, 100034, China.
National Urological Cancer Center, Beijing Key Laboratory of Urogenital Diseases (Male) Molecular Diagnosis and Treatment Center, Beijing, 100034, China.

Yucai Wu (Y)

Department of Urology, Peking University First Hospital, Beijing, 100034, China.
Institute of Urology, Peking University, Beijing, 100034, China.
National Urological Cancer Center, Beijing Key Laboratory of Urogenital Diseases (Male) Molecular Diagnosis and Treatment Center, Beijing, 100034, China.

Liqun Zhou (L)

Department of Urology, Peking University First Hospital, Beijing, 100034, China. zhoulqmail@sina.com.
Institute of Urology, Peking University, Beijing, 100034, China. zhoulqmail@sina.com.
National Urological Cancer Center, Beijing Key Laboratory of Urogenital Diseases (Male) Molecular Diagnosis and Treatment Center, Beijing, 100034, China. zhoulqmail@sina.com.

Weimin Ci (W)

CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China. ciwm@big.ac.cn.
University of Chinese Academy of Sciences, Beijing, 100049, China. ciwm@big.ac.cn.
Institute for Stem cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China. ciwm@big.ac.cn.
ORCID: 0000-0002-4111-5360

Xuesong Li (X)

Department of Urology, Peking University First Hospital, Beijing, 100034, China. pineneedle@sina.com.
Institute of Urology, Peking University, Beijing, 100034, China. pineneedle@sina.com.
National Urological Cancer Center, Beijing Key Laboratory of Urogenital Diseases (Male) Molecular Diagnosis and Treatment Center, Beijing, 100034, China. pineneedle@sina.com.

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Classifications MeSH

questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Nucléosides › Ribonucléosides › Cytidine › Azacitidine › DNA methylation subtypes guiding prognostic...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs épithéliales épidermoïdes et glandulaires › Carcinomes › Carcinome transitionnel › DNA methylation subtypes guiding prognostic...
questionsmedicales.fr › Phénomènes génétiques › Méthylation de l'ADN › DNA methylation subtypes guiding prognostic...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › One-carbon group transferases › Methyltransferases › DNA modification methylases › DNA methylation subtypes guiding prognostic...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › DNA methylation subtypes guiding prognostic...
questionsmedicales.fr › Diagnostic › Pronostic › DNA methylation subtypes guiding prognostic...
questionsmedicales.fr › Maladies urogénitales › Maladies urologiques › Tumeurs urologiques › Tumeurs de la vessie urinaire › DNA methylation subtypes guiding prognostic...