title: Stratification of Wilms tumor by genetic and epigenetic analysis.
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 less than 0.001), between WT1 and pUPD 11p15 (P=0.01), and a strong negative association between WT1 and H19 epimutation (P less than 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 less than 0.001). We also identified a novel clinical association between H19 epimutation and bilateral disease (P less than 0.001). These data provide new insights into the pattern, order, interactions and clinical associations of molecular events in Wilms tumor.
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research and Royal Marsden Hospital, Sutton, UK.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Scott
authors.forename: Anne
authors.initials: A
authors.lastname: Murray
authors.forename: Linda
authors.initials: L
authors.lastname: Baskcomb
authors.forename: Clare
authors.initials: C
authors.lastname: Turnbull
authors.forename: Chey
authors.initials: C
authors.lastname: Loveday
authors.forename: Reem
authors.initials: R
authors.lastname: Al-Saadi
authors.forename: Richard
authors.initials: R
authors.lastname: Williams
authors.forename: Fin
authors.initials: F
authors.lastname: Breatnach
authors.forename: Mary
authors.initials: M
authors.lastname: Gerrard
authors.forename: Juliet
authors.initials: J
authors.lastname: Hale
authors.forename: Janice
authors.initials: J
authors.lastname: Kohler
authors.forename: Pablo
authors.initials: P
authors.lastname: Lapunzina
authors.forename: Gill A
authors.initials: GA
authors.lastname: Levitt
authors.forename: Sue
authors.initials: S
authors.lastname: Picton
authors.forename: Barry
authors.initials: B
authors.lastname: Pizer
authors.forename: Milind D
authors.initials: MD
authors.lastname: Ronghe
authors.forename: Heidi
authors.initials: H
authors.lastname: Traunecker
authors.forename: Denise
authors.initials: D
authors.lastname: Williams
authors.forename: Anna
authors.initials: A
authors.lastname: Kelsey
authors.forename: Gordan M
authors.initials: GM
authors.lastname: Vujanic
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Sebire
authors.forename: Paul
authors.initials: P
authors.lastname: Grundy
authors.forename: Charles A
authors.initials: CA
authors.lastname: Stiller
authors.forename: Kathy
authors.initials: K
authors.lastname: Pritchard-Jones
authors.forename: Jenny
authors.initials: J
authors.lastname: Douglas
authors.forename: Nazneen
authors.initials: N
authors.lastname: Rahman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000465:Algorithms; D002277:Carcinoma / Q000145:classification / Q000235:genetics* / Q000473:pathology; D002675:Child, Preschool; D002869:Chromosome Aberrations; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D016000:Cluster Analysis; D057890:Epigenomics / Q000379:methods; D005260:Female; D005787:Gene Frequency; D016162:Genes, Wilms Tumor / Q000502:physiology; D056426:Genetic Loci / Q000235:genetics / Q000502:physiology; D005821:Genetic Techniques; D006801:Humans; D007223:Infant; D007680:Kidney Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology; D008297:Male; D009154:Mutation / Q000502:physiology; D009367:Neoplasm Staging / Q000379:methods; D025521:Tumor Suppressor Proteins / Q000235:genetics; D009396:Wilms Tumor / Q000145:classification* / Q000235:genetics* / Q000473:pathology
chemical_list: C517118:AMER1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D025521:Tumor Suppressor Proteins