title: Integrative DNA methylome analysis of pan-cancer biomarkers in cancer discordant monozygotic twin-pairs.
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.
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
authors.forename: Leonie
authors.initials: L
authors.lastname: Roos
authors.affiliation: Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jenny
authors.initials: J
authors.lastname: van Dongen
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK ; MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK ; Human Development and Health Academic Unit, Institute of Developmental Sciences, University of Southampton, Southampton, UK ; Epigenomic Medicine, Centre for Biological Sciences, Faculty of Environmental and Natural Sciences, University of Southampton, Southampton, UK.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Bell
authors.affiliation: Department of Psychology, University of Zurich, Zurich, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Burri
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.affiliation: Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Dorret I
authors.initials: DI
authors.lastname: Boomsma
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
authors.forename: Jordana T
authors.initials: JT
authors.lastname: Bell
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D004200:Diseases in Twins / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000235:genetics; D057890:Epigenomics; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics; D008875:Middle Aged; D009369:Neoplasms / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics; D012307:Risk Factors; D012878:Skin Neoplasms / Q000235:genetics; D012907:Smoking / Q000009:adverse effects; D013964:Thyroid Neoplasms / Q000235:genetics; D014430:Twins, Monozygotic / Q000235:genetics*; D002583:Uterine Cervical Neoplasms / Q000235:genetics
chemical_list: D005819:Genetic Markers
keywords: Biomarker; Cancer; DNA methylation; Discordant monozygotic twins; Epigenetics; Twin study