title: Noninvasive detection of cancer-associated genome-wide hypomethylation and copy number aberrations by plasma DNA bisulfite sequencing.
abstract: We explored the detection of genome-wide hypomethylation in plasma using shotgun massively parallel bisulfite sequencing as a marker for cancer. Tumor-associated copy number aberrations (CNAs) could also be observed from the bisulfite DNA sequencing data. Hypomethylation and CNAs were detected in the plasma DNA of patients with hepatocellular carcinoma, breast cancer, lung cancer, nasopharyngeal cancer, smooth muscle sarcoma, and neuroendocrine tumor. For the detection of nonmetastatic cancer cases, plasma hypomethylation gave a sensitivity and specificity of 74% and 94%, respectively, when a mean of 93 million reads per case were obtained. Reducing the sequencing depth to 10 million reads per case was found to have no adverse effect on the sensitivity and specificity for cancer detection, giving respective figures of 68% and 94%. This characteristic thus indicates that analysis of plasma hypomethylation by this sequencing-based method may be a relatively cost-effective approach for cancer detection. We also demonstrated that plasma hypomethylation had utility for monitoring hepatocellular carcinoma patients following tumor resection and for detecting residual disease. Plasma hypomethylation can be combined with plasma CNA analysis for further enhancement of the detection sensitivity or specificity using different diagnostic algorithms. Using the detection of at least one type of aberration to define an abnormality, a sensitivity of 87% could be achieved with a specificity of 88%. These developments have thus expanded the applications of plasma DNA analysis for cancer detection and monitoring.
authors.affiliation: Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, China.
authors.forename: K C Allen
authors.initials: KC
authors.lastname: Chan
authors.forename: Peiyong
authors.initials: P
authors.lastname: Jiang
authors.forename: Carol W M
authors.initials: CW
authors.lastname: Chan
authors.forename: Kun
authors.initials: K
authors.lastname: Sun
authors.forename: John
authors.initials: J
authors.lastname: Wong
authors.forename: Edwin P
authors.initials: EP
authors.lastname: Hui
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Chan
authors.forename: Wing Cheong
authors.initials: WC
authors.lastname: Chan
authors.forename: David S C
authors.initials: DS
authors.lastname: Hui
authors.forename: Simon S M
authors.initials: SS
authors.lastname: Ng
authors.forename: Henry L Y
authors.initials: HL
authors.lastname: Chan
authors.forename: Cesar S C
authors.initials: CS
authors.lastname: Wong
authors.forename: Brigette B Y
authors.initials: BB
authors.lastname: Ma
authors.forename: Anthony T C
authors.initials: AT
authors.lastname: Chan
authors.forename: Paul B S
authors.initials: PB
authors.lastname: Lai
authors.forename: Hao
authors.initials: H
authors.lastname: Sun
authors.forename: Rossa W K
authors.initials: RW
authors.lastname: Chiu
authors.forename: Y M Dennis
authors.initials: YM
authors.lastname: Lo
mesh_terms: D056915:DNA Copy Number Variations / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D057890:Epigenomics / Q000379:methods; D015723:Gene Library; D015894:Genome, Human / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006723:Hong Kong; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D010949:Plasma / Q000737:chemistry; D017422:Sequence Analysis, DNA / Q000379:methods*
keywords: epigenetics; epigenomics; global hypomethylation; next-generation sequencing; tumor markers