PMID- 26669438 OWN - NLM STAT- MEDLINE DCOM- 20161005 LR - 20220129 IS - 1756-994X (Electronic) IS - 1756-994X (Linking) VI - 7 DP - 2015 Dec 15 TI - A donor-specific epigenetic classifier for acute graft-versus-host disease severity in hematopoietic stem cell transplantation. PG - 128 LID - 10.1186/s13073-015-0246-z [doi] LID - 128 AB - BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for many hematological conditions. Acute graft-versus-host disease (aGVHD) is a prevalent immune-mediated complication following HSCT. Current diagnostic biomarkers that correlate with aGVHD severity, progression, and therapy response in graft recipients are insufficient. Here, we investigated whether epigenetic marks measured in peripheral blood of healthy graft donors stratify aGVHD severity in human leukocyte antigen (HLA)-matched sibling recipients prior to T cell-depleted HSCT. METHODS: We measured DNA methylation levels genome-wide at single-nucleotide resolution in peripheral blood of 85 HSCT donors, matched to recipients with various transplant outcomes, with Illumina Infinium HumanMethylation450 BeadChips. RESULTS: Using genome-wide DNA methylation profiling, we showed that epigenetic signatures underlying aGVHD severity in recipients correspond to immune pathways relevant to aGVHD etiology. We discovered 31 DNA methylation marks in donors that associated with aGVHD severity status in recipients, and demonstrated strong predictive performance of these markers in internal cross-validation experiments (AUC = 0.98, 95% CI = 0.96-0.99). We replicated the top-ranked CpG classifier using an alternative, clinical DNA methylation assay (P = 0.039). In an independent cohort of 32 HSCT donors, we demonstrated the utility of the epigenetic classifier in the context of a T cell-replete conditioning regimen (P = 0.050). CONCLUSIONS: Our findings suggest that epigenetic typing of HSCT donors in a clinical setting may be used in conjunction with HLA genotyping to inform both donor selection and transplantation strategy, with the ultimate aim of improving patient outcome. FAU - Paul, Dirk S AU - Paul DS AD - UCL Cancer Institute, University College London, London, UK. d.paul@ucl.ac.uk. FAU - Jones, Allison AU - Jones A AD - Department of Women's Cancer, UCL Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, UK. FAU - Sellar, Rob S AU - Sellar RS AD - UCL Cancer Institute, University College London, London, UK. AD - Department of Haematology, University College London, University College London Hospital, London, UK. FAU - Mayor, Neema P AU - Mayor NP AD - UCL Cancer Institute, University College London, London, UK. AD - Anthony Nolan Research Institute, Royal Free Hospital, London, UK. FAU - Feber, Andrew AU - Feber A AD - UCL Cancer Institute, University College London, London, UK. FAU - Webster, Amy P AU - Webster AP AD - UCL Cancer Institute, University College London, London, UK. FAU - Afonso, Neuza AU - Afonso N AD - Department of Haematology, University College London, Royal Free Hospital, London, UK. FAU - Sergeant, Ruhena AU - Sergeant R AD - Clinical Immunology, Imperial NHS Trust Hammersmith Hospital, London, UK. FAU - Szydlo, Richard M AU - Szydlo RM AD - Centre for Haematology, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, UK. AD - Department of Clinical Haematology, Imperial College Healthcare NHS Trust, Hammersmith Hospital, London, UK. FAU - Apperley, Jane F AU - Apperley JF AD - Centre for Haematology, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, UK. AD - Department of Clinical Haematology, Imperial College Healthcare NHS Trust, Hammersmith Hospital, London, UK. FAU - Widschwendter, Martin AU - Widschwendter M AD - Department of Women's Cancer, UCL Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, UK. FAU - Mackinnon, Stephen AU - Mackinnon S AD - UCL Cancer Institute, University College London, London, UK. AD - Department of Haematology, University College London, Royal Free Hospital, London, UK. FAU - Marsh, Steven G E AU - Marsh SG AD - UCL Cancer Institute, University College London, London, UK. AD - Anthony Nolan Research Institute, Royal Free Hospital, London, UK. FAU - Madrigal, J Alejandro AU - Madrigal JA AD - UCL Cancer Institute, University College London, London, UK. AD - Anthony Nolan Research Institute, Royal Free Hospital, London, UK. FAU - Rakyan, Vardhman K AU - Rakyan VK AD - Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. v.rakyan@qmul.ac.uk. FAU - Peggs, Karl S AU - Peggs KS AD - UCL Cancer Institute, University College London, London, UK. karl.peggs@ucl.ac.uk. AD - Department of Haematology, University College London, University College London Hospital, London, UK. karl.peggs@ucl.ac.uk. FAU - Beck, Stephan AU - Beck S AD - UCL Cancer Institute, University College London, London, UK. s.beck@ucl.ac.uk. LA - eng GR - MR/L003120/1/MRC_/Medical Research Council/United Kingdom GR - Department of Health/United Kingdom GR - 99148/Wellcome Trust/United Kingdom GR - Cancer Research UK/United Kingdom GR - RG/08/014/24067/BHF_/British Heart Foundation/United Kingdom PT - Journal Article DEP - 20151215 PL - England TA - Genome Med JT - Genome medicine JID - 101475844 RN - 0 (HLA Antigens) SB - IM MH - Adolescent MH - Adult MH - Aged MH - DNA Methylation MH - Epigenomics MH - Female MH - Genotype MH - Graft vs Host Disease/blood/etiology/*genetics/immunology MH - HLA Antigens/genetics/immunology MH - Hematopoietic Stem Cell Transplantation/*adverse effects MH - Humans MH - Male MH - Middle Aged MH - Siblings MH - T-Lymphocytes/immunology MH - *Tissue Donors MH - Transplantation Conditioning/adverse effects MH - Young Adult PMC - PMC4681168 EDAT- 2015/12/17 06:00 MHDA- 2016/10/07 06:00 PMCR- 2015/12/15 CRDT- 2015/12/17 06:00 PHST- 2015/07/26 00:00 [received] PHST- 2015/11/12 00:00 [accepted] PHST- 2015/12/17 06:00 [entrez] PHST- 2015/12/17 06:00 [pubmed] PHST- 2016/10/07 06:00 [medline] PHST- 2015/12/15 00:00 [pmc-release] AID - 10.1186/s13073-015-0246-z [pii] AID - 246 [pii] AID - 10.1186/s13073-015-0246-z [doi] PST - epublish SO - Genome Med. 2015 Dec 15;7:128. doi: 10.1186/s13073-015-0246-z.