title: Intra-Gene DNA Methylation Variability Is a Clinically Independent Prognostic Marker in Women's Cancers.
abstract: We introduce a novel per-gene measure of intra-gene DNA methylation variability (IGV) based on the Illumina Infinium HumanMethylation450 platform, which is prognostic independently of well-known predictors of clinical outcome. Using IGV, we derive a robust gene-panel prognostic signature for ovarian cancer (OC, n = 221), which validates in two independent data sets from Mayo Clinic (n = 198) and TCGA (n = 358), with significance of p = 0.004 in both sets. The OC prognostic signature gene-panel is comprised of four gene groups, which represent distinct biological processes. We show the IGV measurements of these gene groups are most likely a reflection of a mixture of intra-tumour heterogeneity and transcription factor (TF) binding/activity. IGV can be used to predict clinical outcome in patients individually, providing a surrogate read-out of hard-to-measure disease processes.
authors.affiliation: Department of Women's Cancer, Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, United Kingdom.|Deparment of Mathematics, University College London, London, United Kingdom.|CoMPLEX, University College London, London, United Kingdom.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Bartlett
authors.affiliation: Department of Women's Cancer, Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, United Kingdom.
authors.forename: Allison
authors.initials: A
authors.lastname: Jones
authors.affiliation: Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, United States of America.
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Goode
authors.affiliation: Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS, United States of America.
authors.forename: Brooke L
authors.initials: BL
authors.lastname: Fridley
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States of America.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Cunningham
authors.affiliation: Department of Medical Oncology, Erasmus MC-Cancer Center, Rotterdam, The Netherlands.
authors.forename: Els M J J
authors.initials: EM
authors.lastname: Berns
authors.affiliation: Department of Obstetrics and Gynaecology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Wik
authors.affiliation: Department of Obstetrics and Gynaecology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Helga B
authors.initials: HB
authors.lastname: Salvesen
authors.affiliation: Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital, University of Oslo, Faculty of Medicine, Institute of Clinical Medicine, Oslo, Norway.
authors.forename: Ben
authors.initials: B
authors.lastname: Davidson
authors.affiliation: Department of Gynaecological Oncology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway.
authors.forename: Claes G
authors.initials: CG
authors.lastname: Trope
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology and Leuven Cancer Institute, University Hospitals Leuven, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Sandrina
authors.initials: S
authors.lastname: Lambrechts
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology and Leuven Cancer Institute, University Hospitals Leuven, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Ignace
authors.initials: I
authors.lastname: Vergote
authors.affiliation: Department of Women's Cancer, Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Widschwendter
mesh_terms: D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D011379:Prognosis; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D014157:Transcription Factors