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5-Hydroxymethylcytosine signatures in circulating cell-free DNA as diagnostic biomarkers for human cancers.

ABSTRACT: DNA modifications such as 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) are epigenetic marks known to affect global gene expression in mammals. Given their prevalence in the human genome, close correlation with gene expression and high chemical stability, these DNA epigenetic marks could serve as ideal biomarkers for cancer diagnosis. Taking advantage of a highly sensitive and selective chemical labeling technology, we report here the genome-wide profiling of 5hmC in circulating cell-free DNA (cfDNA) and in genomic DNA (gDNA) of paired tumor and adjacent tissues collected from a cohort of 260 patients recently diagnosed with colorectal, gastric, pancreatic, liver or thyroid cancer and normal tissues from 90 healthy individuals. 5hmC was mainly distributed in transcriptionally active regions coincident with open chromatin and permissive histone modifications. Robust cancer-associated 5hmC signatures were identified in cfDNA that were characteristic for specific cancer types. 5hmC-based biomarkers of circulating cfDNA were highly predictive of colorectal and gastric cancers and were superior to conventional biomarkers and comparable to 5hmC biomarkers from tissue biopsies. Thus, this new strategy could lead to the development of effective, minimally invasive methods for diagnosis and prognosis of cancer from the analyses of blood samples.

SUBMITTER: Li W

PROVIDER: S-EPMC5630683 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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5-Hydroxymethylcytosine signatures in circulating cell-free DNA as diagnostic biomarkers for human cancers.

Li Wenshuai W Zhang Xu X Lu Xingyu X You Lei L Song Yanqun Y Luo Zhongguang Z Zhang Jun J Nie Ji J Zheng Wanwei W Xu Diannan D Wang Yaping Y Dong Yuanqiang Y Yu Shulin S Hong Jun J Shi Jianping J Hao Hankun H Luo Fen F Hua Luchun L Wang Peng P Qian Xiaoping X Yuan Fang F Wei Lianhuan L Cui Ming M Zhang Taiping T Liao Quan Q Dai Menghua M Liu Ziwen Z Chen Ge G Meckel Katherine K Adhikari Sarbani S Jia Guifang G Bissonnette Marc B MB Zhang Xinxiang X Zhao Yupei Y Zhang Wei W He Chuan C Liu Jie J

Cell research 20170919 10

DNA modifications such as 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) are epigenetic marks known to affect global gene expression in mammals. Given their prevalence in the human genome, close correlation with gene expression and high chemical stability, these DNA epigenetic marks could serve as ideal biomarkers for cancer diagnosis. Taking advantage of a highly sensitive and selective chemical labeling technology, we report here the genome-wide profiling of 5hmC in circulating cell ...[more]

PMID: 28925386

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Project description:Approximately 85% colorectal cancers (CRCs) are thought to evolve through the adenoma-to-carcinoma sequence associated with specific molecular alterations, including the 5-hydroxymethylcytosine (5hmC) signature in circulating cell-free DNA (cfDNA). To explore colorectal disease progression and evaluate the use of cfDNA as a potential diagnostic factor for CRC screening, here, we performed genome-wide 5hmC profiling in plasma cfDNA and tissue genomic DNA (gDNA) acquired from 101 samples (63 plasma and 38 tissues), collected from 21 early-stage CRC patients, 21 AD patients, and 21 healthy controls (HC). The gDNA and cfDNA 5hmC signatures identified in gene bodies and promoter regions in CRC and AD groups were compared with those in HC group. All the differential 5hmC-modified regions (DhMRs) were gathered into four clusters: Disease-enriched, AD-enriched, Disease-lost, and AD-lost, with no overlap. AD-related clusters, AD-enriched and AD-lost, displayed the unique 5hmC signals in AD patients. Disease-enriched and Disease-lost clusters indicated the general 5hmC changes when colorectal lesions occurred. Cancer patients with a confirmable adenoma history segmentally gathered in AD-enriched clusters. KEGG functional enrichment and GO analyses determined distinct differential 5hmC-modified profiles in cfDNA of HC individuals, AD, and CRC patients. All patients had comprehensive 5hmC signatures where Disease-enriched and Disease-lost DhMR clusters demonstrated similar epigenetic modifications, while AD-enriched and AD-lost DhMR clusters indicated complicated subpopulations in adenoma. Analysis of CRC patients with adenoma history showed exclusive 5hmC-gain characteristics, consistent with the 'parallel' evolution hypothesis in adenoma, either developed through the adenoma-to-carcinoma sequence or not. These findings deepen our understanding of colorectal disease and suggest that the 5hmC modifications of different pathological subtypes (cancer patients with or without adenoma history) could be used to screen early-stage CRC and assess adenoma malignancy with large-scale follow-up studies in the future.

Dataset Information

5-Hydroxymethylcytosine signatures in circulating cell-free DNA as diagnostic biomarkers for human cancers.

Publications

5-Hydroxymethylcytosine signatures in circulating cell-free DNA as diagnostic biomarkers for human cancers.

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