Methylation analysis of plasma DNA informs etiologies of Epstein-Barr virus-associated diseases

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Abstract

Epstein-Barr virus (EBV) is associated with a number of diseases, including malignancies. Currently, it is not known whether patients with different EBV-associated diseases have different methylation profiles of circulating EBV DNA. Through whole-genome methylation analysis of plasma samples from patients with nasopharyngeal carcinoma (NPC), EBV-associated lymphoma and infectious mononucleosis, we demonstrate that EBV DNA methylation profiles exhibit a disease-associated pattern. This observation implies a significant potential for the development of methylation analysis of plasma EBV DNA for NPC diagnostics. We further analyse the plasma EBV DNA methylome of NPC and non-NPC subjects from a prospective screening cohort. Plasma EBV DNA fragments demonstrate differential methylation patterns between NPC and non-NPC subjects. Combining such differential methylation patterns with the fractional concentration (count) and size of plasma EBV DNA, population screening of NPC is performed with an improved positive predictive value of 35.1%, compared to a count- and size-based only protocol.

Abstract

Epstein-Barr virus (EBV) is associated with different malignant diseases and circulating EBV DNA is a biomarker for nasopharyngeal carcinoma (NPC). Here, the authors report that plasma EBV DNA methylation profiles show disease-associated patterns and can help to distinguish NPC and non-NPC subjects.

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Most cited references 34

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REporting recommendations for tumour MARKer prognostic studies (REMARK)

L M McShane, D Altman, W Sauerbrei … (2005)

Despite years of research and hundreds of reports on tumour markers in oncology, the number of markers that have emerged as clinically useful is pitifully small. Often initially reported studies of a marker show great promise, but subsequent studies on the same or related markers yield inconsistent conclusions or stand in direct contradiction to the promising results. It is imperative that we attempt to understand the reasons that multiple studies of the same marker lead to differing conclusions. A variety of methodological problems have been cited to explain these discrepancies. Unfortunately, many tumour marker studies have not been reported in a rigorous fashion, and published articles often lack sufficient information to allow adequate assessment of the quality of the study or the generalisability of the study results. The development of guidelines for the reporting of tumour marker studies was a major recommendation of the US National Cancer Institute and the European Organisation for Research and Treatment of Cancer (NCI-EORTC) First International Meeting on Cancer Diagnostics in 2000. Similar to the successful CONSORT initiative for randomised trials and the STARD statement for diagnostic studies, we suggest guidelines to provide relevant information about the study design, preplanned hypotheses, patient and specimen characteristics, assay methods, and statistical analysis methods. In addition, the guidelines suggest helpful presentations of data and important elements to include in discussions. The goal of these guidelines is to encourage transparent and complete reporting so that the relevant information will be available to others to help them to judge the usefulness of the data and understand the context in which the conclusions apply.

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Epstein-Barr virus: more than 50 years old and still providing surprises.

Lawrence S Young, Lee Yap, Paul Murray (2016)

It is more than 50 years since the Epstein-Barr virus (EBV), the first human tumour virus, was discovered. EBV has subsequently been found to be associated with a diverse range of tumours of both lymphoid and epithelial origin. Progress in the molecular analysis of EBV has revealed fundamental mechanisms of more general relevance to the oncogenic process. This Timeline article highlights key milestones in the 50-year history of EBV and discusses how this virus provides a paradigm for exploiting insights at the molecular level in the diagnosis, treatment and prevention of cancer.

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DNA sequencing of maternal plasma to detect Down syndrome: an international clinical validation study.

Glenn E. Palomaki, Edward Kloza, Geralyn M Lambert-Messerlian … (2011)

Prenatal screening for Down syndrome has improved, but the number of resulting invasive diagnostic procedures remains problematic. Measurement of circulating cell-free DNA in maternal plasma might offer improvement. A blinded, nested case-control study was designed within a cohort of 4664 pregnancies at high risk for Down syndrome. Fetal karyotyping was compared with an internally validated, laboratory-developed test based on next-generation sequencing in 212 Down syndrome and 1484 matched euploid pregnancies. None had been previously tested. Primary testing occurred at a CLIA-certified commercial laboratory, with cross validation by a CLIA-certified university laboratory. Down syndrome detection rate was 98.6% (209/212), the false-positive rate was 0.20% (3/1471), and the testing failed in 13 pregnancies (0.8%); all were euploid. Before unblinding, the primary testing laboratory also reported multiple alternative interpretations. Adjusting chromosome 21 counts for guanine cytosine base content had the largest impact on improving performance. When applied to high-risk pregnancies, measuring maternal plasma DNA detects nearly all cases of Down syndrome at a very low false-positive rate. This method can substantially reduce the need for invasive diagnostic procedures and attendant procedure-related fetal losses. Although implementation issues need to be addressed, the evidence supports introducing this testing on a clinical basis.

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Author and article information

Contributors

Y. M. Dennis Lo:

ORCID: http://orcid.org/0000-0001-8746-0293

loym@cuhk.edu.hk

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-1723

Publication date (Electronic): 22 July 2019

Publication date PMC-release: 22 July 2019

Publication date Collection: 2019

Volume: 10

Electronic Location Identifier: 3256

Affiliations

[1 ]ISNI 0000 0004 1937 0482, GRID grid.10784.3a, Li Ka Shing Institute of Health Sciences, , The Chinese University of Hong Kong, Shatin, New Territories, ; Hong Kong SAR, China

[2 ]Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China

[3 ]ISNI 0000 0004 1937 0482, GRID grid.10784.3a, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Centre for Cancer, , The Chinese University of Hong Kong, Shatin, New Territories, ; Hong Kong SAR, China

[4 ]Department of Otorhinolaryngology, Head and Neck Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China

[5 ]Department of Clinical Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China

Author information

W. K. Jacky Lam http://orcid.org/0000-0001-8922-5609

Y. M. Dennis Lo http://orcid.org/0000-0001-8746-0293

Article

Publisher ID: 11226

DOI: 10.1038/s41467-019-11226-5

PMC ID: 6646310

PubMed ID: 31332191

SO-VID: b833da47-9426-4a6f-9e9a-1668fb114653

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 24 August 2018

Date accepted : 2 July 2019

Funding

Funded by: FundRef https://doi.org/10.13039/501100004853, Chinese University of Hong Kong (CUHK);

Award ID: VCF2014021

Award Recipient : Y. M. Dennis Lo

Funded by: - Research Grants Council of the Hong Kong SAR Government under the Theme-based Research Scheme (T12-401/16-W)

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ScienceOpen disciplines: Uncategorized

Keywords: tumour biomarkers,cancer screening,dna methylation,head and neck cancer

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ScienceOpen disciplines: Uncategorized

Keywords: tumour biomarkers, cancer screening, dna methylation, head and neck cancer

Methylation analysis of plasma DNA informs etiologies of Epstein-Barr virus-associated diseases

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Core Readings in Statistical Mediation Analysis

Most cited references 34

REporting recommendations for tumour MARKer prognostic studies (REMARK)

Epstein-Barr virus: more than 50 years old and still providing surprises.

DNA sequencing of maternal plasma to detect Down syndrome: an international clinical validation study.

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