NDLI: Integrative multi-omics analysis depicts the methylome and hydroxymethylome in recurrent bladder cancers and identifies biomarkers for predicting PD-L1 expression

Content Provider	Springer Nature : BioMed Central
Author	Shi, Zhen-Duo Han, Xiao-Xiao Song, Zi-Jian Dong, Yang Pang, Kun Wang, Xin-Lei Liu, Xin-Yu Lu, Hao Xu, Guang-Zhi Hao, Lin Dong, Bing-Zheng Liang, Qing Wu, Xiao-Ke Han, Cong-Hui
Abstract	Background Urinary bladder cancer (UBC) is a common malignancy of the urinary tract; however, the mechanism underlying its high recurrence and responses to immunotherapy remains unclear, making clinical outcome predictions difficult. Epigenetic alterations, especially DNA methylation, play important roles in bladder cancer development and are increasingly being investigated as biomarkers for diagnostic or prognostic predictions. However, little is known about hydroxymethylation since previous studies based on bisulfite-sequencing approaches could not differentiate between 5mC and 5hmC signals, resulting in entangled methylation results. Methods Tissue samples of bladder cancer patients who underwent laparoscopic radical cystectomy (LRC), partial cystectomy (PC), or transurethral resection of bladder tumor (TURBT) were collected. We utilized a multi-omics approach to analyze both primary and recurrent bladder cancer samples. By integrating various techniques including RNA sequencing, oxidative reduced-representation bisulfite sequencing (oxRRBS), reduced-representation bisulfite sequencing (RRBS), and whole exome sequencing, a comprehensive analysis of the genome, transcriptome, methylome, and hydroxymethylome landscape of these cancers was possible. Results By whole exome sequencing, we identified driver mutations involved in the development of UBC, including those in FGFR3, KDMTA, and KDMT2C. However, few of these driver mutations were associated with the down-regulation of programmed death-ligand 1 (PD-L1) or recurrence in UBC. By integrating RRBS and oxRRBS data, we identified fatty acid oxidation-related genes significantly enriched in 5hmC-associated transcription alterations in recurrent bladder cancers. We also observed a series of 5mC hypo differentially methylated regions (DMRs) in the gene body of NFATC1, which is highly involved in T-cell immune responses in bladder cancer samples with high expression of PD-L1. Since 5mC and 5hmC alternations are globally anti-correlated, RRBS-seq-based markers that combine the 5mC and 5hmC signals, attenuate cancer-related signals, and therefore, are not optimal as clinical biomarkers. Conclusions By multi-omics profiling of UBC samples, we showed that epigenetic alternations are more involved compared to genetic mutations in the PD-L1 regulation and recurrence of UBC. As proof of principle, we demonstrated that the combined measurement of 5mC and 5hmC levels by the bisulfite-based method compromises the prediction accuracy of epigenetic biomarkers.
Related Links	https://biomarkerres.biomedcentral.com/counter/pdf/10.1186/s40364-023-00488-3.pdf
Ending Page	13
Page Count	13
Starting Page	1
File Format	HTM / HTML
ISSN	20507771
DOI	10.1186/s40364-023-00488-3
Journal	Biomarker Research
Issue Number	1
Volume Number	11
Language	English
Publisher	BioMed Central
Publisher Date	2023-05-03
Access Restriction	Open
Subject Keyword	Biomedicine Cancer Research
Content Type	Text
Resource Type	Article
Subject	Biochemistry (medical) Molecular Medicine Clinical Biochemistry
Journal Impact Factor	9.5/2023
5-Year Journal Impact Factor	9.4/2023

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