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Noninvasive Detection of Bladder Cancer by Shallow-Depth Genome-Wide Bisulfite Sequencing of Urinary Cell-Free DNA for Methylation and Copy Number Profiling.

Abstract：

BACKGROUND:The current diagnosis and monitoring of bladder cancer are heavily reliant on cystoscopy, an invasive and costly procedure. Previous efforts in urine-based detection of bladder cancer focused on targeted approaches that are predicated on the tumor expressing specific aberrations. We aimed to noninvasively detect bladder cancer by the genome-wide assessment of methylomic and copy number aberrations (CNAs). We also investigated the size of tumor cell-free (cf)DNA fragments. METHODS:Shallow-depth paired-end genome-wide bisulfite sequencing of urinary cfDNA was done for 46 bladder cancer patients and 39 cancer-free controls with hematuria. We assessed (a) proportional contribution from different tissues by methylation deconvolution, (b) global hypomethylation, (c) CNA, and (d) cfDNA size profile. RESULTS:Methylomic and copy number approaches were synergistically combined to detect bladder cancer with a sensitivity of 93.5% (84.2% for low-grade nonmuscle-invasive disease) and a specificity of 95.8%. The prevalence of methylomic and CNAs reflected disease stage and tumor size. Sampling over multiple time points could assess residual disease and changes in tumor load. Muscle-invasive bladder cancer was associated with a higher proportion of long cfDNA, as well as longer cfDNA fragments originating from genomic regions enriched for tumor DNA. CONCLUSIONS:Bladder cancer can be detected noninvasively in urinary cfDNA by methylomic and copy number analysis without previous knowledge or assumptions of specific aberrations. Such analysis could be used as a liquid biopsy to aid diagnosis and for potential longitudinal monitoring of tumor load. Further understanding of the differential size and fragmentation of cfDNA could improve the detection of bladder cancer.

journal_name

Clin Chem

journal_title

Clinical chemistry

authors

Cheng THT,Jiang P,Teoh JYC,Heung MMS,Tam JCW,Sun X,Lee WS,Ni M,Chan RCK,Ng CF,Chan KCA,Chiu RWK,Lo YMD

doi

10.1373/clinchem.2018.301341

subject

Has Abstract

pub_date

2019-07-01 00:00:00

pages

927-936

issue

eissn

0009-9147

issn

1530-8561

pii

clinchem.2018.301341

journal_volume

pub_type

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Noninvasive Detection of Bladder Cancer by Shallow-Depth Genome-Wide Bisulfite Sequencing of Urinary Cell-Free DNA for Methylation and Copy Number Profiling.