Integrative multi-omics analysis depicts the methylome and hydroxymethylome in recurrent bladder cancers and identifies biomarkers for predicting PD-L1 expression
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...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-05-01
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| Series: | Biomarker Research |
| Online Access: | https://doi.org/10.1186/s40364-023-00488-3 |
| _version_ | 1797831926701096960 |
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| author | Zhen-Duo Shi Xiao-Xiao Han Zi-Jian Song Yang Dong Kun Pang Xin-Lei Wang Xin-Yu Liu Hao Lu Guang-Zhi Xu Lin Hao Bing-Zheng Dong Qing Liang Xiao-Ke Wu Cong-Hui Han |
| author_facet | Zhen-Duo Shi Xiao-Xiao Han Zi-Jian Song Yang Dong Kun Pang Xin-Lei Wang Xin-Yu Liu Hao Lu Guang-Zhi Xu Lin Hao Bing-Zheng Dong Qing Liang Xiao-Ke Wu Cong-Hui Han |
| author_sort | Zhen-Duo Shi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T14:00:40Z |
| format | Article |
| id | doaj.art-038d1cd255194af0a4f73dcf72cecac9 |
| institution | Directory Open Access Journal |
| issn | 2050-7771 |
| language | English |
| last_indexed | 2024-04-09T14:00:40Z |
| publishDate | 2023-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Biomarker Research |
| spelling | doaj.art-038d1cd255194af0a4f73dcf72cecac92023-05-07T11:19:18ZengBMCBiomarker Research2050-77712023-05-0111111310.1186/s40364-023-00488-3Integrative multi-omics analysis depicts the methylome and hydroxymethylome in recurrent bladder cancers and identifies biomarkers for predicting PD-L1 expressionZhen-Duo Shi0Xiao-Xiao Han1Zi-Jian Song2Yang Dong3Kun Pang4Xin-Lei Wang5Xin-Yu Liu6Hao Lu7Guang-Zhi Xu8Lin Hao9Bing-Zheng Dong10Qing Liang11Xiao-Ke Wu12Cong-Hui Han13Department of Urology, Xuzhou Clinical School of Xuzhou Medical UniversityClinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji UniversityDepartment of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Urology, Xuzhou Clinical School of Xuzhou Medical UniversityDepartment of Urology, Xuzhou Clinical School of Xuzhou Medical UniversityDepartment of Urology, Xuzhou Clinical School of Xuzhou Medical UniversityDepartment of Urology, Xuzhou Clinical School of Xuzhou Medical UniversityDepartment of Urology, Heilongjiang Provincial HospitalDepartment of Urology, Heilongjiang Provincial HospitalDepartment of Urology, Xuzhou Clinical School of Xuzhou Medical UniversityDepartment of Urology, Xuzhou Clinical School of Xuzhou Medical UniversityDepartment of Urology, Xuzhou Clinical School of Xuzhou Medical UniversityDepartment of Reproductive Medicine, Heilongjiang Provincial HospitalDepartment of Urology, Xuzhou Clinical School of Xuzhou Medical UniversityAbstract 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.https://doi.org/10.1186/s40364-023-00488-3 |
| spellingShingle | Zhen-Duo Shi Xiao-Xiao Han Zi-Jian Song Yang Dong Kun Pang Xin-Lei Wang Xin-Yu Liu Hao Lu Guang-Zhi Xu Lin Hao Bing-Zheng Dong Qing Liang Xiao-Ke Wu Cong-Hui Han Integrative multi-omics analysis depicts the methylome and hydroxymethylome in recurrent bladder cancers and identifies biomarkers for predicting PD-L1 expression Biomarker Research |
| title | Integrative multi-omics analysis depicts the methylome and hydroxymethylome in recurrent bladder cancers and identifies biomarkers for predicting PD-L1 expression |
| title_full | Integrative multi-omics analysis depicts the methylome and hydroxymethylome in recurrent bladder cancers and identifies biomarkers for predicting PD-L1 expression |
| title_fullStr | Integrative multi-omics analysis depicts the methylome and hydroxymethylome in recurrent bladder cancers and identifies biomarkers for predicting PD-L1 expression |
| title_full_unstemmed | Integrative multi-omics analysis depicts the methylome and hydroxymethylome in recurrent bladder cancers and identifies biomarkers for predicting PD-L1 expression |
| title_short | Integrative multi-omics analysis depicts the methylome and hydroxymethylome in recurrent bladder cancers and identifies biomarkers for predicting PD-L1 expression |
| title_sort | integrative multi omics analysis depicts the methylome and hydroxymethylome in recurrent bladder cancers and identifies biomarkers for predicting pd l1 expression |
| url | https://doi.org/10.1186/s40364-023-00488-3 |
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