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This study investigates a comprehensive characterization of the entire DNA methylation (DNAm) landscape of BLCA to determine the relevant biomarkers for the non\u2010invasive diagnosis of BLCA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A total of 304 samples from 224 donors were enrolled in this multi\u2010centre, prospective cohort study. BLCA\u2010specific DNAm signature discovery was carried out with genome\u2010wide bisulfite sequencing in 32 tumour tissues and 12 normal urine samples. A targeted sequencing assay for BLCA\u2010specific 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\u2010blinded manner to determine the clinical diagnosis and prognosis value of DNAm\u2010based classification models. Functions of genomic region harbouring BLCA\u2010specific DNAm signature were validated with biological assays. Concordances of pathology to urine tumour DNA (circulating tumour DNA [ctDNA]) methylation, genomic mutations or other state\u2010of\u2010the\u2010art diagnosis methods were measured.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Genome\u2010wide DNAm profile could accurately classify LG tumour from HG tumour (LG NMIBC vs. HG NMIBC: <jats:italic>p<\/jats:italic>\u00a0=\u00a0.038; LG NMIBC vs. HG MIBC, <jats:italic>p<\/jats:italic>\u00a0=\u00a0.00032; HG NMIBC vs. HG MIBC: <jats:italic>p<\/jats:italic>\u00a0=\u00a0.82; Student's <jats:italic>t<\/jats:italic>\u2010test). Overall, the DNAm profile distinguishes MIBC from NMIBC and normal urine. Targeted\u2010sequencing\u2010based 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\u2010surgery urine ctDNA methylation outperforms fluorescence in situ hybridization (FISH) assay to detect HG BLCA (<jats:italic>n<\/jats:italic>\u00a0=\u00a054) with 100% sensitivity (95% CI: 82.5%\u2013100%) and LG BLCA (<jats:italic>n<\/jats:italic>\u00a0=\u00a026) with 62% sensitivity (95% CI: 51.3%\u201372.7%), both at 100% specificity (non\u2010BLCA: <jats:italic>n<\/jats:italic>\u00a0=\u00a072; 95% CI: 84.1%\u2013100%). Pre\u2010surgery urine ctDNA methylation signature correlates with pathology and predicts recurrence and metastasis. Post\u2010surgery urine ctDNA methylation (<jats:italic>n<\/jats:italic>\u00a0=\u00a061) accurately predicts recurrence\u2010free survival within 180 days, with 100% accuracy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>With the discovery of BLCA\u2010specific DNAm signatures, targeted sequencing of ctDNA methylation outperforms FISH and DNA mutation to detect tumours, predict recurrence and make prognoses.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.1008","type":"journal-article","created":{"date-parts":[[2022,8,15]],"date-time":"2022-08-15T11:29:03Z","timestamp":1660562943000},"source":"Crossref","is-referenced-by-count":35,"title":["Non\u2010invasive diagnosis and surveillance of bladder cancer with driver and passenger DNA methylation in a prospective cohort 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