Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
BMC Medicine
Published in: BMC Medicine 1/2022

Open Access 01-12-2022 | Bladder Carcinoma | Research article

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

Authors: Juan Li, Yuan Liang, Jian Fan, Chunru Xu, Bao Guan, Jianye Zhang, Bin Guo, Yue Shi, Ping Wang, Yezhen Tan, Qi Zhang, Changwei Yuan, Yucai Wu, Liqun Zhou, Weimin Ci, Xuesong Li

Published in: BMC Medicine | Issue 1/2022

Login to get access

Abstract

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.
Appendix
Available only for authorised users
Literature
1.
Roupret M, Babjuk M, Burger M, Capoun O, Cohen D, Comperat EM, et al. European Association of urology guidelines on upper urinary tract urothelial carcinoma: 2020 update. Eur Urol. 2021;79(1):62–79.CrossRef
2.
Moss TJ, Qi Y, Xi L, Peng B, Kim TB, Ezzedine NE, et al. Comprehensive genomic characterization of upper tract urothelial carcinoma. Eur Urol. 2017;72(4):641–9.CrossRef
3.
Porten SP. Epigenetic alterations in bladder cancer. Curr Urol Rep. 2018;19(12):102.CrossRef
4.
Wolff EM, Chihara Y, Pan F, Weisenberger DJ, Siegmund KD, Sugano K, et al. Unique DNA methylation patterns distinguish noninvasive and invasive urothelial cancers and establish an epigenetic field defect in premalignant tissue. Cancer Res. 2010;70(20):8169–78.CrossRef
5.
Fujii Y, Sato Y, Suzuki H, Kakiuchi N, Yoshizato T, Lenis AT, et al. Molecular classification and diagnostics of upper urinary tract urothelial carcinoma. Cancer Cell. 2021;39(6):793–809 e798.CrossRef
6.
Su X, Lu X, Bazai SK, Comperat E, Mouawad R, Yao H, et al. Comprehensive integrative profiling of upper tract urothelial carcinomas. Genome Biol. 2021;22(1):7.CrossRef
7.
Catto JW, Azzouzi AR, Rehman I, Feeley KM, Cross SS, Amira N, et al. Promoter hypermethylation is associated with tumor location, stage, and subsequent progression in transitional cell carcinoma. J Clin Oncol. 2005;23(13):2903–10.CrossRef
8.
Xiong G, Liu J, Tang Q, Fan Y, Fang D, Yang K, et al. Prognostic and predictive value of epigenetic biomarkers and clinical factors in upper tract urothelial carcinoma. Epigenomics. 2015;7(5):733–44.CrossRef
9.
Ge G, Peng D, Guan B, Zhou Y, Gong Y, Shi Y, et al. Urothelial carcinoma detection based on copy number profiles of urinary cell-free DNA by shallow whole-genome sequencing. Clin Chem. 2020;66(1):188–98.
10.
Han Y, Li X, Zhang M, Yang Y, Ge G, Wang K, et al. Enhanced detection of genitourinary cancers using fragmentation and copy number profiles obtained from urinary cell-free DNA. Clin Chem. 2021;67(2):394–403.CrossRef
11.
Xu Z, Ge G, Guan B, Lei Z, Hao X, Zhou Y, et al. Noninvasive detection and localization of genitourinary cancers using urinary sediment DNA methylomes and copy number profiles. Eur Urol. 2020;77(2):288–90.CrossRef
12.
Guo S, Diep D, Plongthongkum N, Fung HL, Zhang K, Zhang K. Identification of methylation haplotype blocks aids in deconvolution of heterogeneous tissue samples and tumor tissue-of-origin mapping from plasma DNA. Nat Genet. 2017;49(4):635–42.CrossRef
13.
Yoshihara K, Shahmoradgoli M, Martinez E, Vegesna R, Kim H, Torres-Garcia W, et al. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun. 2013;4:2612.CrossRef
14.
Xu L, Deng C, Pang B, Zhang X, Liu W, Liao G, et al. TIP: a web server for resolving tumor immunophenotype profiling. Cancer Res. 2018;78(23):6575–80.CrossRef
15.
Becht E, Giraldo NA, Lacroix L, Buttard B, Elarouci N, Petitprez F, et al. Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression. Genome Biol. 2016;17(1):218.CrossRef
16.
Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y, et al. TGFbeta attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018;554(7693):544–8.CrossRef
17.
Yoo CB, Jeong S, Egger G, Liang G, Phiasivongsa P, Tang C, et al. Delivery of 5-aza-2'-deoxycytidine to cells using oligodeoxynucleotides. Cancer Res. 2007;67(13):6400–8.CrossRef
18.
Tsai HC, Li H, Van Neste L, Cai Y, Robert C, Rassool FV, et al. Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells. Cancer Cell. 2012;21(3):430–46.CrossRef
19.
Yang X, Han H, De Carvalho DD, Lay FD, Jones PA, Liang G. Gene body methylation can alter gene expression and is a therapeutic target in cancer. Cancer Cell. 2014;26(4):577–90.CrossRef
20.
Roulois D, Loo Yau H, Singhania R, Wang Y, Danesh A, Shen SY, et al. DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts. Cell. 2015;162(5):961–73.CrossRef
21.
Chiappinelli KB, Strissel PL, Desrichard A, Li H, Henke C, Akman B, et al. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell. 2015;162(5):974–86.CrossRef
22.
Gang AO, Frosig TM, Brimnes MK, Lyngaa R, Treppendahl MB, Gronbaek K, et al. 5-Azacytidine treatment sensitizes tumor cells to T-cell mediated cytotoxicity and modulates NK cells in patients with myeloid malignancies. Blood Cancer J. 2014;4:e197.CrossRef
23.
De Smet C, De Backer O, Faraoni I, Lurquin C, Brasseur F, Boon T. The activation of human gene MAGE-1 in tumor cells is correlated with genome-wide demethylation. Proc Natl Acad Sci U S A. 1996;93(14):7149–53.CrossRef
24.
Weber J, Salgaller M, Samid D, Johnson B, Herlyn M, Lassam N, et al. Expression of the MAGE-1 tumor antigen is up-regulated by the demethylating agent 5-aza-2'-deoxycytidine. Cancer Res. 1994;54(7):1766–71.PubMed
25.
Sanford T, Porten S, Meng MV. Molecular analysis of upper tract and bladder urothelial carcinoma: results from a microarray comparison. PLoS One. 2015;10(8):e0137141.CrossRef
26.
Robinson BD, Vlachostergios PJ, Bhinder B, Liu W, Li K, Moss TJ, et al. Upper tract urothelial carcinoma has a luminal-papillary T-cell depleted contexture and activated FGFR3 signaling. Nat Commun. 2019;10(1):2977.CrossRef
27.
Sanford T, Meng MV, Railkar R, Agarwal PK, Porten SP. Integrative analysis of the epigenetic basis of muscle-invasive urothelial carcinoma. Clin Epigenetics. 2018;10:19.CrossRef
28.
Guo Y, Yin J, Dai Y, Guan Y, Chen P, Chen Y, et al. A novel CpG methylation risk indicator for predicting prognosis in bladder cancer. Front Cell Dev Biol. 2021;9:642650.CrossRef
29.
Burger M, Catto JW, Dalbagni G, Grossman HB, Herr H, Karakiewicz P, et al. Epidemiology and risk factors of urothelial bladder cancer. Eur Urol. 2013;63(2):234–41.CrossRef
30.
Alkhateeb SS, Neill M, Bar-Moshe S, Rhijn BV, Kakiashvili DM, Fleshner N, et al. Long-term prognostic value of the combination of EORTC risk group calculator and molecular markers in non-muscle-invasive bladder cancer patients treated with intravesical Bacille Calmette-Guerin. Urol Ann. 2011;3(3):119–26.CrossRef
31.
van Rhijn BW, Zuiverloon TC, Vis AN, Radvanyi F, van Leenders GJ, Ooms BC, et al. Molecular grade (FGFR3/MIB-1) and EORTC risk scores are predictive in primary non-muscle-invasive bladder cancer. Eur Urol. 2010;58(3):433–41.CrossRef
32.
von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000;18(17):3068–77.CrossRef
33.
Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: a randomised controlled trial. International collaboration of trialists. Lancet. 1999;354(9178):533–40.
34.
Birtle A, Johnson M, Chester J, Jones R, Dolling D, Bryan RT, et al. Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial. Lancet. 2020;395(10232):1268–77.CrossRef
35.
Shang D, Liu Y, Matsui Y, Ito N, Nishiyama H, Kamoto T, et al. Demethylating agent 5-aza-2'-deoxycytidine enhances susceptibility of bladder transitional cell carcinoma to Cisplatin. Urology. 2008;71(6):1220–5.CrossRef
36.
Fuller M, Klein M, Schmidt E, Rohde C, Gollner S, Schulze I, et al. 5-azacytidine enhances efficacy of multiple chemotherapy drugs in AML and lung cancer with modulation of CpG methylation. Int J Oncol. 2015;46(3):1192–204.CrossRef
37.
Crabb SJ, Danson S, Catto JWF, Hussain S, Chan D, Dunkley D, et al. Phase I trial of DNA methyltransferase inhibitor guadecitabine combined with cisplatin and gemcitabine for solid malignancies including urothelial carcinoma (SPIRE). Clin Cancer Res. 2021;27(7):1882–92.CrossRef
38.
Liu M, Zhang L, Li H, Hinoue T, Zhou W, Ohtani H, et al. Integrative epigenetic analysis reveals therapeutic targets to the DNA methyltransferase inhibitor guadecitabine (SGI-110) in hepatocellular carcinoma. Hepatology. 2018;68(4):1412–28.CrossRef
39.
Li H, Chiappinelli KB, Guzzetta AA, Easwaran H, Yen RW, Vatapalli R, et al. Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers. Oncotarget. 2014;5(3):587–98.CrossRef
40.
Cathomas R, Lorch A, Bruins HM, Comperat EM, Cowan NC, Efstathiou JA, et al. The 2021 Updated European Association of Urology Guidelines on Metastatic Urothelial Carcinoma. Eur Urol. 2022;81(1):95–103.
41.
Li J, Liang Y, Fan J, Xu CR, Guan B, Zhang JY, et al. DNA methylation subtypes guiding prognostic assessment and linking to responses the DNA methyltransferase inhibitor SGI-110 in urothelial carcinoma: NGDC; 2022. https://​ngdc.​cncb.​ac.​cn/​gsa/​
42.
Metadata
Title
DNA methylation subtypes guiding prognostic assessment and linking to responses the DNA methyltransferase inhibitor SGI-110 in urothelial carcinoma
Authors
Juan Li
Yuan Liang
Jian Fan
Chunru Xu
Bao Guan
Jianye Zhang
Bin Guo
Yue Shi
Ping Wang
Yezhen Tan
Qi Zhang
Changwei Yuan
Yucai Wu
Liqun Zhou
Weimin Ci
Xuesong Li
Publication date
01-12-2022
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2022
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-022-02426-w

Other articles of this Issue 1/2022

BMC Medicine 1/2022 Go to the issue

Research article

Development and validation of a simple tool composed of items on dyspnea, respiration rates, and C-reactive protein for pneumonia prediction among acute febrile respiratory illness patients in primary care settings

Research article

Identification of risk factors for incident cervical insufficiency in nulliparous and parous women: a population-based case-control study

Research article

Intermittent screening and treatment for malaria complementary to routine immunisation in the first year of life in Papua, Indonesia: a cluster randomised superiority trial

Research article

Preparing for pandemics: a systematic review of pandemic influenza clinical management guidelines

Research article

Placenta-derived proteins across gestation in healthy pregnancies—a novel approach to assess placental function?

Research article

Weight loss-induced improvement of body weight and insulin sensitivity is not amplified by a subsequent 12-month weight maintenance intervention but is predicted by adaption of adipose atrial natriuretic peptide system: 48-month results of a randomized controlled trial