Two new papers on epigenetic biomarker assays

Bock C*, Halbritter F, Carmona FJ, Tierling S, Datlinger P, Assenov Y, Berdasco M, Bergmann AK, Booher K, Busato F, Campan M, Dahl C, Dahmcke CM, Diep D, Fernández AF, Gerhauser C, Haake A, Heilmann K, Holcomb T, Hussmann D, Ito M, Kreutz M, Kulis M, Lopez V, Nair SS, Paul DS, Plongthongkum N, Qu W, Queirós AC, Sauter G, Schlomm T, Stirzaker C, Statham A, Strogantsev R, Urdinguio RG, Walter K, Weichenhan D, Weisenberger DJ, Beck S, Clark SJ, Esteller M, Ferguson-Smith AC, Fraga MF, Guldberg P, Hansen LL, Laird PW, Martin-Subero JI, Nygren AOH, Peist R, Plass C, Shames DS, Siebert R, Sun X, Tost J, Walter J, Zhang K, for the BLUEPRINT consortium (2016). Quantitative comparison of DNA methylation assays for large-scale validation and epigenetic biomarker development. Nature Biotechnology, doi:10.1038/nbt.3605.

Abstract: DNA methylation patterns are altered in numerous diseases and often correlate with clinically relevant information such as disease subtypes, prognosis and drug response. With suitable assays and after validation in large cohorts, such associations can be exploited for clinical diagnostics and personalized treatment decisions. Here we describe the results of a community-wide benchmarking study comparing the performance of all widely used methods for DNA methylation analysis that are compatible with routine clinical use. We shipped 32 reference samples to 18 laboratories in seven different countries. Researchers in those laboratories collectively contributed 21 locus-specific assays for an average of 27 predefined genomic regions, as well as six global assays. We evaluated assay sensitivity on low-input samples and assessed the assays’ ability to discriminate between cell types. Good agreement was observed across all tested methods, with amplicon bisulfite sequencing and bisulfite pyrosequencing showing the best all-round performance. Our technology comparison can inform the selection, optimization and use of DNA methylation assays in large-scale validation studies, biomarker development and clinical diagnostics. (PDF)

-> In this project, which was coordinated by our lab, 18 research groups from three continents compared all promising methods for analyzing DNA methylation in the clinic. This multicenter benchmarking study identifies the most accurate methods and shows that epigenetic tests based on DNA methylation are a mature technology ready for broad clinical use.


Rendeiro AF, Schmidl C#, Strefford JC#, Walewska R, Davis Z, Farlik M, Oscier D, Bock C* (2016). Chromatin accessibility maps of chronic lymphocytic leukemia identify subtype-specific epigenome signatures and transcription regulatory networks. Nature Communications, doi:10.1038/ncomms11938.

Abstract: Chronic lymphocytic leukaemia (CLL) is characterized by substantial clinical heterogeneity, despite relatively few genetic alterations. To provide a basis for studying epigenome deregulation in CLL, here we present genome-wide chromatin accessibility maps for 88 CLL samples from 55 patients measured by the ATAC-seq assay. We also performed ChIPmentation and RNA-seq profiling for ten representative samples. Based on the resulting data set, we devised and applied a bioinformatic method that links chromatin profiles to clinical annotations. Our analysis identified sample-specific variation on top of a shared core of CLL regulatory regions. IGHV mutation status—which distinguishes the two major subtypes of CLL—was accurately predicted by the chromatin profiles and gene regulatory networks inferred for IGHV-mutated versus IGHV-unmutated samples identified characteristic differences between these two disease subtypes. In summary, we discovered widespread heterogeneity in the chromatin landscape of CLL, established a community resource for studying epigenome deregulation in leukaemia and demonstrated the feasibility of large-scale chromatin accessibility mapping in cancer cohorts and clinical research. (PDF)

-> This paper demonstrates the use of chromatin mapping for identifying disease subtypes and predicting prognosis in chronic lymphocytic leukemia. Moreover, it highlights the clinical utility of epigenetic biomarkers especially for diseases with widespread heterogeneity between individual patients.

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