Dataset Information

5-Hydroxymethylcytosine profiling from genomic and cell-free DNA for colorectal cancers patients.

ABSTRACT: 5-Hydroxymethylcytosine (5hmC) is a DNA modification that is generated by the oxidation of 5-methylcytosine (5mC) in a reaction catalyzed by the ten-eleven translocation (TET) family enzymes. It tends to mark gene activation and affects a spectrum of developmental and disease-related biological processes. In this manuscript, we present a 5hmC selective chemical labelling technology (hmC-Seal) to capture and sequence 5hmC-containing DNA fragments with low input. We tested 10 tumour/adjacent colon cancer tissues and 10 tumour/healthy plasma samples. Furthermore, we tested if this methodology could generate the 5hmC differential genes among cancer patients, healthy controls and precancerous adenoma patients from plasma. Robust cancer-specific epigenetic signatures were identified for colon cancers. The results show that 5hmC is mainly distributed in gene active regions. The results also indicate the potential application of 5hmC change signals in early stage of colon cancer, even show potential in the diagnosis of precancerous adenoma. We demonstrated the robustness of the 5hmC-Seal method in tissue and cell-free DNA (cfDNA) as potential biomarkers. Moreover, this study provides the potential value and feasibility of 5hmC-Seal approach on colorectal cancer (CRC) early detection. We believe this strategy could be an effective liquid biopsy-based diagnosis and a potential prognosis method for colon cancer using cfDNA.

SUBMITTER: Gao P

PROVIDER: S-EPMC6484304 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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5-Hydroxymethylcytosine profiling from genomic and cell-free DNA for colorectal cancers patients.

Gao Pingting P Lin Shengli S Cai Mingyan M Zhu Yan Y Song Yanqun Y Sui Yi Y Lin Jing J Liu Jiaxiuyu J Lu Xingyu X Zhong Yunshi Y Cui Yuehong Y Zhou Pinghong P

Journal of cellular and molecular medicine 20190326 5

5-Hydroxymethylcytosine (5hmC) is a DNA modification that is generated by the oxidation of 5-methylcytosine (5mC) in a reaction catalyzed by the ten-eleven translocation (TET) family enzymes. It tends to mark gene activation and affects a spectrum of developmental and disease-related biological processes. In this manuscript, we present a 5hmC selective chemical labelling technology (hmC-Seal) to capture and sequence 5hmC-containing DNA fragments with low input. We tested 10 tumour/adjacent colon ...[more]

PMID: 30912288

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Project description:Amplification (amp) of MET can be observed in cases of focal gene copy number gain, such as MET-driven amp, or with a gain of chromosome 7, such as aneuploidy. Several studies have shown that only high-level focal MET amp (MET/CEP7 ratio ≥5) is oncogenic, with such tumors responding to targeted therapy. However, there are few reports on how to distinguish between focal amplification and aneuploidy using next-generation sequencing (NGS). A total of 1025 patients with advanced solid tumors (typically pre-treated) were tested with a non-invasive comprehensive cfDNA NGS panel (Guardant360) from July 2014 to June 2019. Since bioinformatics upgrades of Guardant360 were undergoing in September 2018, focal MET amp was determined by our independent algorithm using the cohorts tested before September 2018 (291 patients), and validation was performed in the remaining cohort (734 patients). MET alterations (alts) associated with aberrant signaling were found in 110 patients (10.7%) among nine different cancer types, most commonly in non-small cell (12.2%, 62/510) and small cell (33.3%, 3/9) lung cancers, gastroesophageal cancer (19.4%, 7/36), and prostate adenocarcinoma (15.6%; 5/32). Among 291 patients tested before September 2018, 37 (12.7%) had MET alts. Among these, 24 (64.9%) had amps, 5 (13.5%) had exon 14 skipping, and 13 (35.1%) had single nucleotide variants (SNVs). Co-alterations, such as amp + SNVs, were found in four samples (10.8%). Among 24 MET amps, 29.2% (7/24) were focal according to our algorithm. MET copy number was significantly higher with focal amp compared to non-focal amp (mean copy number 3.26 vs. 2.44, respectively, p = 0.00304). In 734 patients tested after September 2018, our definition of focal MET amp was detected in 4.2% (31/734). Overall, focal amplification based on our algorithm was 3.7% (=38/1025). This study describes an approach to distinguish focal and non-focal MET amplification using comprehensive genomic profiling of cfDNA in advanced cancer patients. Focal MET amp accounted for ~30% of all MET amp, which was found in 3.7% of patients with diverse cancers and was associated with a higher plasma copy number. Clinical studies are warranted to assess the clinical utility of targeted therapies for tumors with focal MET amplification detected by NGS of cfDNA.

Project description:Background5-Hydroxymethylcytosine (5hmC) is a significant DNA epigenetic modification. However, the 5hmC modification alterations in genomic regions encoding long non-coding RNA (lncRNA) and their clinical significance remain poorly characterized.ResultsA three-phase discovery-modeling-validation study was conducted to explore the potential of the plasma-derived 5hmC modification level in genomic regions encoding lncRNAs as a superior alternative biomarker for cancer diagnosis and surveillance. Genome-wide 5hmC profiles in the plasma circulating cell-free DNA of 1632 cancer and 1379 non-cancerous control samples from different cancer types and multiple centers were repurposed and characterized. A large number of altered 5hmC modifications were distributed at genomic regions encoding lncRNAs in cancerous compared with healthy subjects. Furthermore, most 5hmC-modified lncRNA genes were cancer-specific, with only a relatively small number of 5hmC-modified lncRNA genes shared by various cancer types. A 5hmC-LncRNA diagnostic score (5hLD-score) comprising 39 tissue-shared 5hmC-modified lncRNA gene markers was developed using elastic net regularization. The 5hLD-score was able to accurately distinguish tumors from healthy controls with an area under the curve (AUC) of 0.963 [95% confidence interval (CI) 0.940-0.985] and 0.912 (95% CI 0.837-0.987) in the training and internal validation cohorts, respectively. Results from three independent validations confirmed the robustness and stability of the 5hLD-score with an AUC of 0.851 (95% CI 0.786-0.916) in Zhang's non-small cell lung cancer cohort, AUC of 0.887 (95% CI 0.852-0.922) in Tian's esophageal cancer cohort, and AUC of 0.768 (95% CI 0.746-0.790) in Cai's hepatocellular carcinoma cohort. In addition, a significant association was identified between the 5hLD-score and the progression from hepatitis to liver cancer. Finally, lncRNA genes modified by tissue-specific 5hmC alteration were again found to be capable of identifying the origin and location of tumors.ConclusionThe present study will contribute to the ongoing effort to understand the transcriptional programs of lncRNA genes, as well as facilitate the development of novel invasive genomic tools for early cancer detection and surveillance.

Dataset Information

5-Hydroxymethylcytosine profiling from genomic and cell-free DNA for colorectal cancers patients.

Publications

5-Hydroxymethylcytosine profiling from genomic and cell-free DNA for colorectal cancers patients.

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