title: Locally disordered methylation forms the basis of intratumor methylome variation in chronic lymphocytic leukemia.
abstract: Intratumoral heterogeneity plays a critical role in tumor evolution. To define the contribution of DNA methylation to heterogeneity within tumors, we performed genome-scale bisulfite sequencing of 104 primary chronic lymphocytic leukemias (CLLs). Compared with 26 normal B cell samples, CLLs consistently displayed higher intrasample variability of DNA methylation patterns across the genome, which appears to arise from stochastically disordered methylation in malignant cells. Transcriptome analysis of bulk and single CLL cells revealed that methylation disorder was linked to low-level expression. Disordered methylation was further associated with adverse clinical outcome. We therefore propose that disordered methylation plays a similar role to that of genetic instability, enhancing the ability of cancer cells to search for superior evolutionary trajectories.
authors.affiliation: Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute, Cambridge, MA 02139, USA.
authors.forename: Dan A
authors.initials: DA
authors.lastname: Landau
authors.affiliation: Broad Institute, Cambridge, MA 02139, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139, USA.
authors.forename: Kendell
authors.initials: K
authors.lastname: Clement
authors.affiliation: Broad Institute, Cambridge, MA 02139, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ziller
authors.affiliation: Broad Institute, Cambridge, MA 02139, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Boyle
authors.affiliation: Center for Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jean
authors.initials: J
authors.lastname: Fan
authors.affiliation: Broad Institute, Cambridge, MA 02139, USA.
authors.forename: Hongcang
authors.initials: H
authors.lastname: Gu
authors.affiliation: Department of Biostatistics and Computational Biology, Dana Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Stevenson
authors.affiliation: Broad Institute, Cambridge, MA 02139, USA.
authors.forename: Carrie
authors.initials: C
authors.lastname: Sougnez
authors.affiliation: Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.affiliation: Fluidigm, South San Francisco, CA 94080, USA.
authors.forename: Shuqiang
authors.initials: S
authors.lastname: Li
authors.affiliation: Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Dylan
authors.initials: D
authors.lastname: Kotliar
authors.affiliation: Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Wandi
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Broad Institute, Cambridge, MA 02139, USA.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Ghandi
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute, Cambridge, MA 02139, USA.
authors.forename: Levi
authors.initials: L
authors.lastname: Garraway
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Stacey M
authors.initials: SM
authors.lastname: Fernandes
authors.affiliation: Fluidigm, South San Francisco, CA 94080, USA.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Livak
authors.affiliation: Broad Institute, Cambridge, MA 02139, USA.
authors.forename: Stacey
authors.initials: S
authors.lastname: Gabriel
authors.affiliation: Broad Institute, Cambridge, MA 02139, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Gnirke
authors.affiliation: Broad Institute, Cambridge, MA 02139, USA.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Lander
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Brown
authors.affiliation: Department of Biostatistics and Computational Biology, Dana Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.affiliation: Center for Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA; Division of Hematology/Oncology, Children's Hospital, Boston, MA 02115, USA.
authors.forename: Peter V
authors.initials: PV
authors.lastname: Kharchenko
authors.affiliation: Broad Institute, Cambridge, MA 02139, USA; Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Nir
authors.initials: N
authors.lastname: Hacohen
authors.affiliation: Broad Institute, Cambridge, MA 02139, USA; Cancer Center and Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.affiliation: Broad Institute, Cambridge, MA 02139, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. Electronic address: alexander_meissner@harvard.edu.
authors.forename: Alexander
authors.initials: A
authors.lastname: Meissner
authors.affiliation: Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Division of Hematology/Oncology, Children's Hospital, Boston, MA 02115, USA. Electronic address: cwu@partners.org.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Wu
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism*; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015973:Gene Expression Regulation, Leukemic; D014644:Genetic Variation; D015894:Genome, Human; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D017422:Sequence Analysis, DNA; D013447:Sulfites / Q000737:chemistry
chemical_list: D013447:Sulfites; C042345:hydrogen sulfite