Abstract
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.
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Acknowledgements
We thank the affected individuals and families involved in the research. We thank the many physicians and nurses who referred families and provided samples and clinical information. The following members of the FACT Collaboration provided familial Wilms tumor pedigrees analyzed in this study: L. Arbour, C. Bonaïti-Pellié, L. Cannon-Albright, A. Chompret, T. Cole, C. Dhooge, W. Dupuis, A. Foot, W. Foulkes, H. Galvin, A. Gnekow, N. Graf, D. King, J. Kingston, I. Lewis, A. O'Meara, F. Millot, H. Price, B. Royer-Pokora, V. Schumacher, C. Schwartz, R. Shannon, E. Sheridan, J. Skeen, P. Tonin and A. Weirich. We thank B. Messahel, R. Al-Saadi, M. Cohen, N. Coleman and M. Malone for providing Wilms tumor specimens. We thank M. Stratton and C. Turnbull for their comments on the manuscript. The research was carried out as part of the Investigation of Familial Wilms Tumour Genes and the Factors Associated with Childhood Tumours (FACT) study, which are UK Children's Cancer and Leukaemia Group (CCLG) studies. The Childhood Cancer Research Group receives funding from the Department of Health and the Scottish Ministers. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health and the Scottish Ministers. R.H.S. is supported by the Michael and Betty Kadoorie Cancer Genetics Research Programme. This work was supported by grants from Medical Research Council (UK), Cancer Research UK and the Institute of Cancer Research (UK).
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The study was designed by R.H.S. and N.R. The molecular analyses were performed by R.H.S., J.D., L.B., K.B. and S.H. Samples and clinical information were provided by members of the FACT Collaboration, R.H.S., A.C., M.G., J.A.K., G.A.L., S.P., B.P., M.D.R., D.W., J.A.C., P.P., E.R.M., J.M.B., C.A.S., K.P.-J. and N.R. and coordinated by N.H. The manuscript was written by R.H.S. and N.R., with input from the other authors.
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Scott, R., Douglas, J., Baskcomb, L. et al. Constitutional 11p15 abnormalities, including heritable imprinting center mutations, cause nonsyndromic Wilms tumor. Nat Genet 40, 1329–1334 (2008). https://doi.org/10.1038/ng.243
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DOI: https://doi.org/10.1038/ng.243
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