Non‐invasive diagnosis and surveillance of bladder cancer with driver and passenger DNA methylation in a prospective cohort study

作者：Yu Xiao, Lingao Ju, Kaiyu Qian, Wan Jin, Gang Wang, Yan Zhao, Wei Jiang, Nan Liu, Kaichun Wu, Min‐Sheng Peng, Rui Cao, Sheng Li, Hongjie Shi, Yan Gong, Hang Zheng, Tongzu Liu, Yongwen Luo, Haoli Ma, Luyuan Chang, Gang Li, Xinyue Cao, Ye Tian, Zilin Xu, Zhonghua Yang, Liuying Shan, Zhongqiang Guo, Dongai Yao, Xianlong Zhou, Xintong Chen, Zicheng Guo, Dongmei Liu, Song Xu, Chundong Ji, Yu Fang, Xin Hong, Jun Luo, Hong Cao, Yi Zhang, Xinghuan Wang · 发表于：Clinical and Translational Medicine · 年份：2022 · DOI：10.1002/ctm2.1008 · 被引用次数：36 · 研究领域：Bladder and Urothelial Cancer Treatments、Epigenetics and DNA Methylation、Cancer Genomics and Diagnostics

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 NM...