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

Full text not available from this repository.

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:
CreatorsEmailORCIDORCID Put Code
Pan, HengUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Renaud, LoicUNSPECIFIEDorcid.org/0000-0001-7213-9464UNSPECIFIED
Chaligne, RonanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bloehdorn, JohannesUNSPECIFIEDorcid.org/0000-0003-1433-9702UNSPECIFIED
Tausch, EugenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mertens, DanielUNSPECIFIEDorcid.org/0000-0003-0227-7188UNSPECIFIED
Fink, Anna MariaUNSPECIFIEDorcid.org/0000-0002-7669-7890UNSPECIFIED
Fischer, KirstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhang, ChaoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Betel, DoronUNSPECIFIEDorcid.org/0000-0002-8006-7752UNSPECIFIED
Gnirkell, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Imielinski, MarcinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moreaux, JeromeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hallek, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meissner, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stilgenbauer, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wu, Catherine J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Elemento, OlivierUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Landau, Dan A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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:
KeywordsLanguage
CHRONIC LYMPHOCYTIC-LEUKEMIA; TUMOR-SUPPRESSOR; REGULARIZATION PATHS; IDENTIFICATION; REGIONS; MODELS; CLLMultiple languages
OncologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60283

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item