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Integrative DNA methylome analysis of pan-cancer biomarkers in cancer discordant monozygotic twin-pairs

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Title: Integrative DNA methylome analysis of pan-cancer biomarkers in cancer discordant monozygotic twin-pairs
Authors: Roos, L
Van Dongen, J
Bell, CG
Burri, A
Deloukas, P
Boomsma, DI
Spector, TD
Bell, JT
Item Type: Journal Article
Abstract: BACKGROUND: A key focus in cancer research is the discovery of biomarkers that accurately diagnose early lesions in non-invasive tissues. Several studies have identified malignancy-associated DNA methylation changes in blood, yet no general cancer biomarker has been identified to date. Here, we explore the potential of blood DNA methylation as a biomarker of pan-cancer (cancer of multiple different origins) in 41 female cancer discordant monozygotic (MZ) twin-pairs sampled before or after diagnosis using the Illumina HumanMethylation450 BeadChip. RESULTS: We analysed epigenome-wide DNA methylation profiles in 41 cancer discordant MZ twin-pairs with affected individuals diagnosed with tumours at different single primary sites: the breast, cervix, colon, endometrium, thyroid gland, skin (melanoma), ovary, and pancreas. No significant global differences in whole blood DNA methylation profiles were observed. Epigenome-wide analyses identified one novel pan-cancer differentially methylated position at false discovery rate (FDR) threshold of 10 % (cg02444695, P = 1.8 × 10(-7)) in an intergenic region 70 kb upstream of the SASH1 tumour suppressor gene, and three suggestive signals in COL11A2, AXL, and LINC00340. Replication of the four top-ranked signals in an independent sample of nine cancer-discordant MZ twin-pairs showed a similar direction of association at COL11A2, AXL, and LINC00340, and significantly greater methylation discordance at AXL compared to 480 healthy concordant MZ twin-pairs. The effects at cg02444695 (near SASH1), COL11A2, and LINC00340 were the most promising in biomarker potential because the DNA methylation differences were found to pre-exist in samples obtained prior to diagnosis and were limited to a 5-year period before diagnosis. Gene expression follow-up at the top-ranked signals in 283 healthy individuals showed correlation between blood methylation and gene expression in lymphoblastoid cell lines at PRL, and in the skin tissue at AXL. A significant enrichment of differential DNA methylation was observed in enhancer regions (P = 0.03). CONCLUSIONS: We identified DNA methylation signatures in blood associated with pan-cancer, at or near SASH1, COL11A2, AXL, and LINC00340. Three of these signals were present up to 5 years prior to cancer diagnosis, highlighting the potential clinical utility of whole blood DNA methylation analysis in cancer surveillance.
Issue Date: 20-Jan-2016
Date of Acceptance: 12-Jan-2016
URI: http://hdl.handle.net/10044/1/39839
DOI: http://dx.doi.org/10.1186/s13148-016-0172-y
ISSN: 1868-7083
Publisher: BioMed Central
Journal / Book Title: Clinical Epigenetics
Volume: 8
Copyright Statement: This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Keywords: Biomarker
Cancer
DNA methylation
Discordant monozygotic twins
Epigenetics
Twin study
Adult
Age Factors
Aged
Breast Neoplasms
Colonic Neoplasms
DNA Methylation
Diseases in Twins
Endometrial Neoplasms
Epigenomics
Female
Genetic Markers
Humans
Male
Melanoma
Middle Aged
Neoplasms
Ovarian Neoplasms
Pancreatic Neoplasms
Risk Factors
Skin Neoplasms
Smoking
Thyroid Neoplasms
Twins, Monozygotic
Uterine Cervical Neoplasms
Publication Status: Published
Open Access location: https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-016-0172-y
Article Number: 7
Appears in Collections:Clinical Sciences
Molecular Sciences
Faculty of Medicine



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