PMID- 35968916
OWN - NLM
STAT- MEDLINE
DCOM- 20220816
LR  - 20231105
IS  - 2001-1326 (Electronic)
IS  - 2001-1326 (Linking)
VI  - 12
IP  - 8
DP  - 2022 Aug
TI  - Non-invasive diagnosis and surveillance of bladder cancer with driver and 
      passenger DNA methylation in a prospective cohort study.
PG  - e1008
LID - 10.1002/ctm2.1008 [doi]
LID - e1008
AB  - BACKGROUND: State-of-art non-invasive diagnosis processes for bladder cancer 
      (BLCA) harbour shortcomings such as low sensitivity and specificity, unable to 
      distinguish between high- (HG) and low-grade (LG) tumours, as well as inability 
      to differentiate muscle-invasive bladder cancer (MIBC) and non-muscle-invasive 
      bladder cancer (NMIBC). This study investigates a comprehensive characterization 
      of the entire DNA methylation (DNAm) landscape of BLCA to determine the relevant 
      biomarkers for the non-invasive diagnosis of BLCA. METHODS: A total of 304 
      samples from 224 donors were enrolled in this multi-centre, prospective cohort 
      study. BLCA-specific DNAm signature discovery was carried out with genome-wide 
      bisulfite sequencing in 32 tumour tissues and 12 normal urine samples. A targeted 
      sequencing assay for BLCA-specific DNAm signatures was developed to categorize 
      tumour tissue against normal urine, or MIBC against NMIBC. Independent validation 
      was performed with targeted sequencing of 259 urine samples in a double-blinded 
      manner to determine the clinical diagnosis and prognosis value of DNAm-based 
      classification models. Functions of genomic region harbouring BLCA-specific DNAm 
      signature were validated with biological assays. Concordances of pathology to 
      urine tumour DNA (circulating tumour DNA [ctDNA]) methylation, genomic mutations 
      or other state-of-the-art diagnosis methods were measured. RESULTS: Genome-wide 
      DNAm profile could accurately classify LG tumour from HG tumour (LG NMIBC vs. HG 
      NMIBC: p = .038; LG NMIBC vs. HG MIBC, p = .00032; HG NMIBC vs. HG MIBC: p = .82; 
      Student's t-test). Overall, the DNAm profile distinguishes MIBC from NMIBC and 
      normal urine. Targeted-sequencing-based DNAm signature classifiers accurately 
      classify LG NMIBC tissues from HG MIBC and could detect tumours in urine at a 
      limit of detection of less than .5%. In tumour tissues, DNAm accurately 
      classifies pathology, thus outperforming genomic mutation or RNA expression 
      profiles. In the independent validation cohort, pre-surgery urine ctDNA 
      methylation outperforms fluorescence in situ hybridization (FISH) assay to detect 
      HG BLCA (n = 54) with 100% sensitivity (95% CI: 82.5%-100%) and LG BLCA (n = 26) 
      with 62% sensitivity (95% CI: 51.3%-72.7%), both at 100% specificity (non-BLCA: 
      n = 72; 95% CI: 84.1%-100%). Pre-surgery urine ctDNA methylation signature 
      correlates with pathology and predicts recurrence and metastasis. Post-surgery 
      urine ctDNA methylation (n = 61) accurately predicts recurrence-free survival 
      within 180 days, with 100% accuracy. CONCLUSION: With the discovery of 
      BLCA-specific DNAm signatures, targeted sequencing of ctDNA methylation 
      outperforms FISH and DNA mutation to detect tumours, predict recurrence and make 
      prognoses.
CI  - (c) 2022 The Authors. Clinical and Translational Medicine published by John Wiley & 
      Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.
FAU - Xiao, Yu
AU  - Xiao Y
AUID- ORCID: 0000-0003-1377-9685
AD  - Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China.
AD  - Department of Biological Repositories, Zhongnan Hospital of Wuhan University, 
      Wuhan, China.
FAU - Ju, Lingao
AU  - Ju L
AD  - Human Genetic Resource Preservation Center of Hubei Province, Wuhan, China.
FAU - Qian, Kaiyu
AU  - Qian K
AD  - Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China.
AD  - Department of Biological Repositories, Zhongnan Hospital of Wuhan University, 
      Wuhan, China.
FAU - Jin, Wan
AU  - Jin W
AD  - Department of Biological Repositories, Zhongnan Hospital of Wuhan University, 
      Wuhan, China.
AD  - Euler Technology, ZGC Life Science Park, Beijing, China.
FAU - Wang, Gang
AU  - Wang G
AD  - Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of 
      Medical Sciences, Wuhan, China.
FAU - Zhao, Yan
AU  - Zhao Y
AD  - Emergency Center, Zhongnan Hospital of Wuhan University, Wuhan, China.
AD  - Hubei Clinical Research Center for Emergency and Resuscitation, Zhongnan Hospital 
      of Wuhan University, Wuhan, China.
FAU - Jiang, Wei
AU  - Jiang W
AD  - Medical Research Institute, Wuhan University, Wuhan, China.
FAU - Liu, Nan
AU  - Liu N
AD  - Human Genetic Resource Preservation Center of Hubei Province, Wuhan, China.
FAU - Wu, Kai
AU  - Wu K
AD  - Euler Technology, ZGC Life Science Park, Beijing, China.
FAU - Peng, Minsheng
AU  - Peng M
AD  - State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of 
      Zoology, Chinese Academy of Sciences, Kunming, China.
AD  - University of Academy of Sciences, Kunming College of Life Sciences, Kunming, 
      China.
FAU - Cao, Rui
AU  - Cao R
AD  - Department of Urology, Beijing Friendship Hospital, Capital Medical University, 
      Beijing, China.
FAU - Li, Sheng
AU  - Li S
AUID- ORCID: 0000-0003-4070-7345
AD  - Human Genetic Resource Preservation Center of Hubei Province, Wuhan, China.
FAU - Shi, Hongjie
AU  - Shi H
AD  - Human Genetic Resource Preservation Center of Hubei Province, Wuhan, China.
FAU - Gong, Yan
AU  - Gong Y
AUID- ORCID: 0000-0002-4805-0459
AD  - Department of Biological Repositories, Zhongnan Hospital of Wuhan University, 
      Wuhan, China.
AD  - Cancer Precision Diagnosis and Treatment and Translational Medicine Hubei 
      Engineering Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China.
FAU - Zheng, Hang
AU  - Zheng H
AD  - Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China.
FAU - Liu, Tongzu
AU  - Liu T
AD  - Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China.
FAU - Luo, Yongwen
AU  - Luo Y
AUID- ORCID: 0000-0002-8724-6550
AD  - Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China.
FAU - Ma, Haoli
AU  - Ma H
AD  - Department of Biological Repositories, Zhongnan Hospital of Wuhan University, 
      Wuhan, China.
AD  - Cancer Precision Diagnosis and Treatment and Translational Medicine Hubei 
      Engineering Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China.
FAU - Chang, Luyuan
AU  - Chang L
AD  - Euler Technology, ZGC Life Science Park, Beijing, China.
FAU - Li, Gang
AU  - Li G
AD  - Human Genetic Resource Preservation Center of Hubei Province, Wuhan, China.
FAU - Cao, Xinyue
AU  - Cao X
AD  - Clinical Trial Center, Zhongnan Hospital of Wuhan University, Wuhan, China.
FAU - Tian, Ye
AU  - Tian Y
AD  - Department of Urology, Beijing Friendship Hospital, Capital Medical University, 
      Beijing, China.
FAU - Xu, Zilin
AU  - Xu Z
AD  - Human Genetic Resource Preservation Center of Hubei Province, Wuhan, China.
FAU - Yang, Zhonghua
AU  - Yang Z
AD  - Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China.
FAU - Shan, Liuying
AU  - Shan L
AD  - Euler Technology, ZGC Life Science Park, Beijing, China.
FAU - Guo, Zhongqiang
AU  - Guo Z
AD  - Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China.
FAU - Yao, Dongai
AU  - Yao D
AD  - Physical Examination Center, Zhongnan Hospital of Wuhan University, Wuhan, China.
FAU - Zhou, Xianlong
AU  - Zhou X
AD  - Emergency Center, Zhongnan Hospital of Wuhan University, Wuhan, China.
AD  - Hubei Clinical Research Center for Emergency and Resuscitation, Zhongnan Hospital 
      of Wuhan University, Wuhan, China.
FAU - Chen, Xintong
AU  - Chen X
AD  - Euler Technology, ZGC Life Science Park, Beijing, China.
FAU - Guo, Zicheng
AU  - Guo Z
AD  - Department of Urology, The Central Hospital of Enshi Tujia and Miao Autonomous 
      Prefecture, Enshi, China.
FAU - Liu, Dongmei
AU  - Liu D
AD  - Euler Technology, ZGC Life Science Park, Beijing, China.
FAU - Xu, Song
AU  - Xu S
AD  - Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China.
FAU - Ji, Chundong
AU  - Ji C
AD  - Department of Urology, The Affiliated Hospital of Panzhihua University, 
      Panzhihua, China.
FAU - Yu, Fang
AU  - Yu F
AD  - Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, China.
FAU - Hong, Xin
AU  - Hong X
AD  - Department of Urology, Peking University International Hospital, Beijing, China.
FAU - Luo, Jun
AU  - Luo J
AD  - Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, China.
FAU - Cao, Hong
AU  - Cao H
AD  - Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, China.
FAU - Zhang, Yi
AU  - Zhang Y
AD  - Euler Technology, ZGC Life Science Park, Beijing, China.
FAU - Wang, Xinghuan
AU  - Wang X
AUID- ORCID: 0000-0003-3497-0024
AD  - Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China.
AD  - Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of 
      Medical Sciences, Wuhan, China.
AD  - Medical Research Institute, Wuhan University, Wuhan, China.
AD  - Cancer Precision Diagnosis and Treatment and Translational Medicine Hubei 
      Engineering Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China.
LA  - eng
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Clin Transl Med
JT  - Clinical and translational medicine
JID - 101597971
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Circulating Tumor DNA)
SB  - IM
MH  - Biomarkers, Tumor/genetics
MH  - *Circulating Tumor DNA
MH  - DNA Methylation/genetics
MH  - Humans
MH  - In Situ Hybridization, Fluorescence
MH  - Prospective Studies
MH  - *Urinary Bladder Neoplasms/diagnosis/genetics/pathology
PMC - PMC9377153
OTO - NOTNLM
OT  - bladder cancer
OT  - diagnosis and prognosis
OT  - methylation
OT  - non-invasive screening
OT  - prospective cohort study
OT  - urine tumour DNA
COIS- All authors declare that they have no conflict of interest or financial conflicts 
      to disclose.
EDAT- 2022/08/16 06:00
MHDA- 2022/08/17 06:00
PMCR- 2022/08/15
CRDT- 2022/08/15 07:33
PHST- 2022/07/18 00:00 [revised]
PHST- 2022/05/09 00:00 [received]
PHST- 2022/07/26 00:00 [accepted]
PHST- 2022/08/15 07:33 [entrez]
PHST- 2022/08/16 06:00 [pubmed]
PHST- 2022/08/17 06:00 [medline]
PHST- 2022/08/15 00:00 [pmc-release]
AID - CTM21008 [pii]
AID - 10.1002/ctm2.1008 [doi]
PST - ppublish
SO  - Clin Transl Med. 2022 Aug;12(8):e1008. doi: 10.1002/ctm2.1008.