title: Deducing the stage of origin of Wilms' tumours from a developmental series of Wt1-mutant mice.
abstract: Wilms' tumours, paediatric kidney cancers, are the archetypal example of tumours caused through the disruption of normal development. The genetically best-defined subgroup of Wilms' tumours is the group caused by biallelic loss of the WT1 tumour suppressor gene. Here, we describe a developmental series of mouse models with conditional loss of Wt1 in different stages of nephron development before and after the mesenchymal-to-epithelial transition (MET). We demonstrate that Wt1 is essential for normal development at all kidney developmental stages under study. Comparison of genome-wide expression data from the mutant mouse models with human tumour material of mutant or wild-type WT1 datasets identified the stage of origin of human WT1-mutant tumours, and emphasizes fundamental differences between the two human tumour groups due to different developmental stages of origin.
authors.affiliation: MRC Human Genetics Unit, MRC Institute for Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Berry
authors.affiliation: MRC Human Genetics Unit, MRC Institute for Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK The Roslin Institute, University of Edinburgh, Easter Bush Campus, Midlothian, EH25 9RG, UK.
authors.forename: Derya D
authors.initials: DD
authors.lastname: Ozdemir
authors.affiliation: Department of Biomedical Informatics and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Aronow
authors.affiliation: MRC Human Genetics Unit, MRC Institute for Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK The Roslin Institute, University of Edinburgh, Easter Bush Campus, Midlothian, EH25 9RG, UK.
authors.forename: Nils O
authors.initials: NO
authors.lastname: Lindström
authors.affiliation: MRC Human Genetics Unit, MRC Institute for Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Dudnakova
authors.affiliation: MRC Human Genetics Unit, MRC Institute for Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Thornburn
authors.affiliation: MRC Human Genetics Unit, MRC Institute for Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Perry
authors.affiliation: MRC Human Genetics Unit, MRC Institute for Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Baldock
authors.affiliation: MRC Human Genetics Unit, MRC Institute for Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Armit
authors.affiliation: The Roslin Institute, University of Edinburgh, Easter Bush Campus, Midlothian, EH25 9RG, UK.
authors.forename: Anagha
authors.initials: A
authors.lastname: Joshi
authors.affiliation: INSERM, UMR 1163, Laboratory of Inherited Kidney Diseases, Paris 75015, France Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Paris 75015, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Jeanpierre
authors.affiliation: Biocenter Oulu, InfoTech Oulu, Faculty of Biochemistry and Molecular Medicine, Aapistie 5A, University of Oulu, PO Box 5000, Oulu 90014, Finland.
authors.forename: Jingdong
authors.initials: J
authors.lastname: Shan
authors.affiliation: Biocenter Oulu, InfoTech Oulu, Faculty of Biochemistry and Molecular Medicine, Aapistie 5A, University of Oulu, PO Box 5000, Oulu 90014, Finland.
authors.forename: Seppo
authors.initials: S
authors.lastname: Vainio
authors.affiliation: Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.
authors.forename: James
authors.initials: J
authors.lastname: Baily
authors.affiliation: Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.
authors.forename: David
authors.initials: D
authors.lastname: Brownstein
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, 15 George Square, Edinburgh, EH8 9XD, UK.
authors.forename: Jamie
authors.initials: J
authors.lastname: Davies
authors.affiliation: MRC Human Genetics Unit, MRC Institute for Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Hastie
authors.affiliation: MRC Human Genetics Unit, MRC Institute for Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK The Roslin Institute, University of Edinburgh, Easter Bush Campus, Midlothian, EH25 9RG, UK peter.hohenstein@roslin.ed.ac.uk.
authors.forename: Peter
authors.initials: P
authors.lastname: Hohenstein
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D019070:Cell Lineage; D015972:Gene Expression Regulation, Neoplastic; D016678:Genome; D019426:Integrases / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009367:Neoplasm Staging; D009399:Nephrons / Q000254:growth & development* / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D059008:Time-Lapse Imaging; D025721:WT1 Proteins / Q000235:genetics / Q000378:metabolism*; D009396:Wilms Tumor / Q000235:genetics / Q000473:pathology*
chemical_list: D015415:Biomarkers; D025721:WT1 Proteins; C045073:Cre recombinase; D019426:Integrases
keywords: Kidney development; Mouse model; WT1; Wilms’ tumour