Universität zu Köln

Pan, Heng, Renaud, Loic ORCID: 0000-0001-7213-9464, Chaligne, Ronan, Bloehdorn, Johannes ORCID: 0000-0003-1433-9702, Tausch, Eugen, Mertens, Daniel ORCID: 0000-0003-0227-7188, Fink, Anna Maria ORCID: 0000-0002-7669-7890, Fischer, Kirsten, Zhang, Chao, Betel, Doron ORCID: 0000-0002-8006-7752, Gnirkell, Andreas, Imielinski, Marcin, Moreaux, Jerome, Hallek, Michael, Meissner, Alexander, Stilgenbauer, Stephan, Wu, Catherine J., Elemento, Olivier and Landau, Dan A. (2021). Discovery of Candidate DNA Methylation Cancer Driver Genes. Cancer Discov., 11 (9). S. 2266 - 2282. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 2159-8290

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Abstract

Epigenetic alterations, such as promoter hypermethylation, may drive cancer through tumor suppressor gene 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 with 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. SIGNIFICANCE: MethSig provides a novel statistical framework for the analysis of DNA methylation changes in cancer, to specifically identify candidate DNA methylation driver genes of cancer progression and relapse, empowering the discovery of epigenetic mechanisms that enhance cancer cell fitness.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Pan, Heng UNSPECIFIED UNSPECIFIED UNSPECIFIED Renaud, Loic UNSPECIFIED orcid.org/0000-0001-7213-9464 UNSPECIFIED Chaligne, Ronan UNSPECIFIED UNSPECIFIED UNSPECIFIED Bloehdorn, Johannes UNSPECIFIED orcid.org/0000-0003-1433-9702 UNSPECIFIED Tausch, Eugen UNSPECIFIED UNSPECIFIED UNSPECIFIED Mertens, Daniel UNSPECIFIED orcid.org/0000-0003-0227-7188 UNSPECIFIED Fink, Anna Maria UNSPECIFIED orcid.org/0000-0002-7669-7890 UNSPECIFIED Fischer, Kirsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhang, Chao UNSPECIFIED UNSPECIFIED UNSPECIFIED Betel, Doron UNSPECIFIED orcid.org/0000-0002-8006-7752 UNSPECIFIED Gnirkell, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Imielinski, Marcin UNSPECIFIED UNSPECIFIED UNSPECIFIED Moreaux, Jerome UNSPECIFIED UNSPECIFIED UNSPECIFIED Hallek, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Meissner, Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED Stilgenbauer, Stephan UNSPECIFIED UNSPECIFIED UNSPECIFIED Wu, Catherine J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Elemento, Olivier UNSPECIFIED UNSPECIFIED UNSPECIFIED Landau, Dan A. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-602834
DOI:	10.1158/2159-8290.CD-20-1334
Journal or Publication Title:	Cancer Discov.
Volume:	11
Number:	9
Page Range:	S. 2266 - 2282
Date:	2021
Publisher:	AMER ASSOC CANCER RESEARCH
Place of Publication:	PHILADELPHIA
ISSN:	2159-8290
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CHRONIC LYMPHOCYTIC-LEUKEMIA; TUMOR-SUPPRESSOR; REGULARIZATION PATHS; IDENTIFICATION; REGIONS; MODELS; CLL Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/60283