Stratification of Wilms tumor by genetic and epigenetic analysis

Abstract

Richard H. Scott 1 , Anne Murray 1 , Linda Baskcomb 2 , Clare Turnbull 1 , Chey Loveday 1 , Reem Al-Saadi 3 , Richard Williams 3 , Fin Breatnach 4 , Mary Gerrard 5 , Juliet Hale 6 , Janice Kohler 7 , Pablo Lapunzina 8 , Gill A. Levitt 9 , Sue Picton 10 , Barry Pizer 11 , Milind D. Ronghe 12 , Heidi Traunecker 13 , Denise Williams 14 , Anna Kelsey 15 , Gordan M. Vujanic 16 , Neil J. Sebire 17 , Paul Grundy 18 , Charles A. Stiller 19 , Kathy Pritchard-Jones 3,20 , Jenny Douglas 1 and Nazneen Rahman 1   1 Division of Genetics & Epidemiology, Institute of Cancer Research and Royal Marsden Hospital, Sutton, UK 2 The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK 3 Division of Molecular Pathology, Institute of Cancer Research and Royal Marsden Hospital, Sutton, UK 4 Department of Paediatric Oncology, Our Lady’s Children’s Hospital, Dublin, Ireland 5 Department of Paediatric Oncology, Sheffield Children’s Hospital, Sheffield, UK 6 Department of Paediatric Oncology, Royal Victoria Infirmary, Newcastle Upon Tyne, UK 7 Department of Paediatric Oncology, Southampton General Hospital, Southampton, UK 8 Department of Genetics, Hospital Universitario La Paz, Madrid, Spain 9 Department of Haematology/Oncology, Great Ormond Street Hospital, London, UK 10 Regional Paediatric Oncology Unit, St James’s University Hospital, Leeds, UK 11 Department of Paediatric Oncology, Alder Hey Children’s Hospital, Liverpool, UK 12 Schiehallion Unit, Royal Hospital for Sick Children, Glasgow, UK 13 Department of Paediatric Oncology, Children’s Hospital for Wales, Cardiff, UK 14 Department of Paediatric Oncology, Addenbrooke’s NHS Trust, Cambridge, UK 15 Department of Paediatric Pathology, Royal Manchester Children’s Hospital, Manchester, UK 16 Department of Histopathology, School of Medicine, Cardiff University, Cardiff, UK 17 Department of Histopathology, Great Ormond Street Hospital, London, UK 18 Pediatric Hematology, Stollery Children’s Hospital, Edmonton, Canada 19 Childhood Cancer Research Group, Department of Paediatrics, University of Oxford, Oxford, UK 20 Molecular Haematology and Cancer Biology Unit, University College London, Institute of Child Health, London, UK Received: March 23, 2012; Accepted: March 29, 2012; Published: March  31, 2012; Keywords: Wilms tumor, WT1, WTX, CTNNB1, TP53, 11p15, somatic genetic mutation, epigenetic  Correspondence: Nazneen Rahman, email: // // Abstract Somatic defects at five loci, WT1, CTNNB1, WTX, TP53 and the imprinted 11p15 region, are implicated in Wilms tumor, the commonest childhood kidney cancer. In this study we analysed all five loci in 120 Wilms tumors. We identified epigenetic 11p15 abnormalities in 69% of tumors, 37% were H19 epimutations and 32% were paternal uniparental disomy (pUPD). We identified mutations of WTX in 32%, CTNNB1 in 15%, WT1 in 12% and TP53 in 5% of tumors. We identified several significant associations: between 11p15 and WTX (P=0.007), between WT1 and CTNNB1 (P<0.001), between WT1 and pUPD 11p15 (P=0.01), and a strong negative association between WT1 and H19 epimutation (P<0.001). We next used these data to stratify Wilms tumor into three molecular Groups, based on the status at 11p15 and WT1 . Group 1 tumors (63%) were defined as 11p15-mutant and WT1 -normal; a third also had WTX mutations. Group 2 tumors (13%) were WT1 -mutant. They either had 11p15 pUPD or were 11p15-normal. Almost all had CTNNB1 mutations but none had H19 epimutation. Group 3 tumors (25%) were defined as 11p15-normal and WT1 -normal and were typically normal at all five loci (P<0.001). We also identified a novel clinical association between H19 epimutation and bilateral disease (P<0.001). These data provide new insights into the pattern, order, interactions and clinical associations of molecular events in Wilms tumor.