Letter abstract
Nature Genetics 40, 1329 - 1334 (2008)
Published online: 5 October 2008 | doi:10.1038/ng.243
Constitutional 11p15 abnormalities, including heritable imprinting center mutations, cause nonsyndromic Wilms tumor
Richard H Scott1, Jenny Douglas1, Linda Baskcomb1, Nikki Huxter1, Karen Barker1, Sandra Hanks1, Alan Craft2, Mary Gerrard3, Janice A Kohler4, Gill A Levitt5, Sue Picton6, Barry Pizer7, Milind D Ronghe8, Denise Williams9, Factors Associated with Childhood Tumours (FACT) Collaboration16, Jackie A Cook10, Pascal Pujol11, Eamonn R Maher12, Jillian M Birch13, Charles A Stiller14, Kathy Pritchard-Jones15 & Nazneen Rahman1
Constitutional abnormalities at the imprinted 11p15 growth regulatory region cause syndromes characterized by disordered growth, some of which include a risk of Wilms tumor1, 2, 3. We explored their possible contribution to nonsyndromic Wilms tumor and identified constitutional 11p15 abnormalities in genomic lymphocyte DNA from 13 of 437 individuals (3%) with sporadic Wilms tumor without features of growth disorders, including 12% of bilateral cases (P = 0.001) and in one familial Wilms tumor pedigree. No abnormality was detected in 220 controls (P = 0.006). Abnormalities identified included H19 DMR epimutations, uniparental disomy 11p15 and H19 DMR imprinting center mutations (one microinsertion and one microdeletion), thus identifying microinsertion as a new class of imprinting center mutation. Our data identify constitutional 11p15 defects as one of the most common known causes of Wilms tumor, provide mechanistic insights into imprinting disruption and reveal clinically important epigenotype-phenotype associations. The impact on clinical management dictates that constitutional 11p15 analysis should be considered in all individuals with Wilms tumor.
- Section of Cancer Genetics, Institute of Cancer Research and Royal Marsden Hospital, Sutton, Surrey, SM2 5NG, UK.
- Department of Paediatrics, Royal Victoria Infirmary, Newcastle-upon-Tyne, NE7 7DN, UK.
- Department of Paediatric Oncology, Sheffield Children's Hospital, Sheffield, S10 2TH, UK.
- Department of Paediatric Oncology, Southampton General Hospital, Southampton, SO16 6YD, UK.
- Department of Haematology/Oncology, Great Ormond Street Hospital, London, WC1N 3JH, UK.
- Regional Paediatric Oncology Unit, St James's University Hospital, Leeds, LS9 7TF, UK.
- Department of Paediatric Oncology, Alder Hey Children's Hospital, Liverpool, L12 2AP, UK.
- Schiehallion Unit, Royal Hospital for Sick Children, Glasgow, G3 8SJ, UK.
- Department of Paediatric Oncology, Addenbrooke's NHS Trust, Cambridge, CB2 0QR, UK.
- Department of Clinical Genetics, Sheffield Children's Hospital, Sheffield, S10 2TH, UK.
- Service de Génétique Médicale, Centre Hospitalier Universitaire, 34000 Montpellier, France.
- Department of Medical and Molecular Genetics, Institute of Biomedical Research, University of Birmingham, Birmingham, B15 2TT, UK.
- Cancer Research UK Paediatric and Familial Cancer Research Group, Royal Manchester Children's Hospital, Manchester, M27 4HA, UK.
- Childhood Cancer Research Group, Department of Paediatrics, University of Oxford, Oxford, OX2 6HJ, UK.
- Section of Paediatric Oncology, Institute of Cancer Research and Royal Marsden Hospital, Sutton, Surrey, SM2 5NG, UK.
- A full list of members is provided in the Supplementary Note online.
Correspondence to: Nazneen Rahman1 e-mail: nazneen.rahman@icr.ac.uk
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