title: Evolution of DNA methylation is linked to genetic aberrations in chronic lymphocytic leukemia.
abstract: Although clonal selection by genetic driver aberrations in cancer is well documented, the ability of epigenetic alterations to promote tumor evolution is undefined. We used 450k arrays and next-generation sequencing to evaluate intratumor heterogeneity and evolution of DNA methylation and genetic aberrations in chronic lymphocytic leukemia (CLL). CLL cases exhibit vast interpatient differences in intratumor methylation heterogeneity, with genetically clonal cases maintaining low methylation heterogeneity and up to 10% of total CpGs in a monoallelically methylated state. Increasing methylation heterogeneity correlates with advanced genetic subclonal complexity. Selection of novel DNA methylation patterns is observed only in cases that undergo genetic evolution, and independent genetic evolution is uncommon and is restricted to low-risk alterations. These results reveal that although evolution of DNA methylation occurs in high-risk, clinically progressive cases, positive selection of novel methylation patterns entails coevolution of genetic alteration(s) in CLL.
authors.affiliation: Divisions of 1Epigenomics and Cancer Risk Factors, 2Theoretical Bioinformatics, 3Biostatistics, and 4Molecular Genetics; 5Department of Translational Oncology, National Center for Tumor Diseases (NCT), The German Cancer Research Center (DKFZ); 6Department of Medicine V, University of Heidelberg, Heidelberg; 7Department of Medicine, University of Freiburg Medical Center, Freiburg; 8Department of Internal Medicine III, University of Ulm, Ulm; 9The German Cancer Consortium, Germany; 10Department of Medicine, University of California at San Diego Moores Cancer Center, La Jolla, California; and 11Division of Hematology, The Ohio State University, Columbus, Ohio.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Oakes
authors.forename: Rainer
authors.initials: R
authors.lastname: Claus
authors.forename: Lei
authors.initials: L
authors.lastname: Gu
authors.forename: Yassen
authors.initials: Y
authors.lastname: Assenov
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hüllein
authors.forename: Manuela
authors.initials: M
authors.lastname: Zucknick
authors.forename: Matthias
authors.initials: M
authors.lastname: Bieg
authors.forename: David
authors.initials: D
authors.lastname: Brocks
authors.forename: Olga
authors.initials: O
authors.lastname: Bogatyrova
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Schmidt
authors.forename: Laura
authors.initials: L
authors.lastname: Rassenti
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
authors.forename: Daniel
authors.initials: D
authors.lastname: Mertens
authors.forename: Peter
authors.initials: P
authors.lastname: Lichter
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.forename: Stephan
authors.initials: S
authors.lastname: Stilgenbauer
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.forename: Thorsten
authors.initials: T
authors.lastname: Zenz
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
mesh_terms: D000368:Aged; D002877:Chromosomes, Human; D018899:CpG Islands; D019175:DNA Methylation; D018450:Disease Progression; D044127:Epigenesis, Genetic; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D018740:Genetic Heterogeneity; D015894:Genome, Human; D042822:Genomic Instability; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged