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  Discovery of candidate DNA methylation cancer driver genes

Pan, H., Renaud, L., Chaligne, R., Bloehdorn, J., Tausch, E., Mertens, D., et al. (2021). Discovery of candidate DNA methylation cancer driver genes. Cancer Discovery, 2021: 20-1334. doi:10.1158/2159-8290.CD-20-1334.

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Pan, Heng, Author
Renaud, Loic , Author
Chaligne, Ronan , Author
Bloehdorn, Johannes , Author
Tausch, Eugen, Author
Mertens, Daniel, Author
Fink, Anna Maria , Author
Fischer, Kirsten, Author
Zhang, Chao , Author
Betel, Doron, Author
Gnirke, Andreas , Author
Imielinski, Marcin , Author
Moreaux, Jerome , Author
Hallek, Michael, Author
Meissner, Alexander1, Author              
Stilgenbauer, Stephan , Author
Wu, Catherine J., Author
Elemento, Olivier , Author
Landau, Dan A., Author
Affiliations:
1Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2379694              

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 Abstract: Epigenetic alterations such as promoter hypermethylation may drive cancer through tumor suppressor genes inactivation. However, we have limited ability to differentiate driver DNA methylation (DNAme) changes from passenger events. We developed DNAme driver inference - MethSig - accounting for the varying stochastic hypermethylation rate across the genome and between samples. We applied MethSig to bisulfite sequencing data of chronic lymphocytic leukemia (CLL), multiple myeloma, ductal carcinoma in situ, glioblastoma, and to methylation array data across 18 tumor types in TCGA. MethSig resulted in well-calibrated Quantile-Quantile plots and reproducible inference of likely DNAme drivers with increased sensitivity/specificity compared to benchmarked methods. CRISPR/Cas9 knockout of selected candidate CLL DNAme drivers provided a fitness advantage with and without therapeutic intervention. Notably, DNAme driver risk score was closely associated with adverse outcome in independent CLL cohorts. Collectively, MethSig represents a novel inference framework for DNAme driver discovery to chart the role of aberrant DNAme in cancer.

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Language(s): eng - English
 Dates: 2021-04-152021-05-10
 Publication Status: Published online
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 Identifiers: DOI: 10.1158/2159-8290.CD-20-1334
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Title: Cancer Discovery
Source Genre: Journal
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Pages: - Volume / Issue: 2021 Sequence Number: 20-1334 Start / End Page: - Identifier: -