Methylome analysis identifies a Wilms tumor epigenetic biomarker detectable in blood
| Autor: | Kathy Pritchard-Jones, Stephan Beck, Neil J. Sebire, Marisa Alcaide-German, Mark E. Weeks, Jocelyn Charlton, Lee M. Butcher, Sergey Popov, Gordan M. Vujanic, Richard D. Williams, William Mifsud |
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| Rok vydání: | 2014 |
| Předmět: |
Pilot Projects
Biology Malignancy Bioinformatics Wilms Tumor Genome Epigenesis Genetic 03 medical and health sciences 0302 clinical medicine Biomarkers Tumor medicine Humans Epigenetics 030304 developmental biology 0303 health sciences Cell-Free System Genome Human Research Wilms' tumor Epigenome DNA Methylation medicine.disease Kidney Neoplasms Human genetics 3. Good health 030220 oncology & carcinogenesis DNA methylation Biomarker (medicine) Algorithms |
| Zdroj: | Genome Biology |
| ISSN: | 1474-760X |
| DOI: | 10.1186/s13059-014-0434-y |
| Popis: | Background Wilms 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. Results Methylome 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. Conclusions These 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 material The online version of this article (doi:10.1186/s13059-014-0434-y) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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