Methylome analysis identifies a Wilms tumor epigenetic biomarker detectable in blood |
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Authors: | Jocelyn Charlton Richard D Williams Mark Weeks Neil J Sebire Sergey Popov Gordan Vujanic William Mifsud Marisa Alcaide-German Lee M Butcher Stephan Beck Kathy Pritchard-Jones |
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Affiliation: | .UCL Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH UK ;.The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG UK ;.Department of Pathology, Cardiff University School of Medicine, Heath Park, Cardiff, CF14 4XN UK ;.UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6BT UK |
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Abstract: | BackgroundWilms tumor is the most common pediatric renal malignancy and there is a clinical need for a molecular biomarker to assess treatment response and predict relapse. The known mutated genes in this tumor type show low mutation frequencies, whereas aberrant methylation at 11p15 is by far the most common aberration. We therefore analyzed the epigenome, rather than the genome, to identify ubiquitous tumor-specific biomarkers.ResultsMethylome analysis of matched normal kidney and Wilms tumor identifies 309 preliminary methylation variable positions which we translate into three differentially methylated regions (DMRs) for use as tumor-specific biomarkers. Using two novel algorithms we show that these three DMRs are not confounded by cell type composition. We further show that these DMRs are not methylated in embryonic blastema but are intermediately methylated in Wilms tumor precursor lesions. We validate the biomarker DMRs using two independent sample sets of normal kidney and Wilms tumor and seven Wilms tumor histological subtypes, achieving 100% and 98% correct classification, respectively. As proof-of-principle for clinical utility, we successfully use biomarker DMR-2 in a pilot analysis of cell-free circulating DNA to monitor tumor response during treatment in ten patients.ConclusionsThese findings define the most common methylated regions in Wilms tumor known to date which are not associated with their embryonic origin or precursor stage. We show that this tumor-specific methylated DNA is released into the blood circulation where it can be detected non-invasively showing potential for clinical utility.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-014-0434-y) contains supplementary material, which is available to authorized users. |
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