ArticleCancer cell2014
Locally disordered methylation forms the basis of intratumor methylome variation in chronic lymphocytic leukemia.
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Article in Cancer cell, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 234 papers.
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234citing papers in PubMed
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234 citing papers in PubMed, 409 citations in OpenAlex.
- Discovery of Candidate DNA Methylation Cancer Driver Genes.Cancer discovery · 2021Trial
- Decoding coupled epigenetic-fragmentomic signals in circulating cell-free DNA for interpretable cancer diagnosis.Genome medicine · 2026Article
- Pattools‑implemented methylation vector analysis reveals aberrant subtype‑specific methylation in lung cancer across tissue and plasma cfDNA.Clinical and translational medicine · 2026Article
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- Charting intratumor heterogeneity from bench to bedside.Nature cancer · 2026Review
- DNA Methylation Stochasticity Is Linked to Transcriptional Variability and Convergent Epigenetic Disruption across Genetic Subtypes of Acute Myeloid Leukemia.Cancer research · 2026Article
- Late-stage dedifferentiation and epigenetic memory of cancer stem cells in hepatocellular carcinoma.Journal of translational medicine · 2026Article
- DNA methylation heterogeneity in complex tumor microenvironment: Quantitative methods, influencing factors, and clinical implications.Genes & diseases · 2026Review
- Epigenetic Instability-Based Metrics in Cell-Free DNA for Early Cancer Detection.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Article
- MPCI: A novel metric for quantifying DNA methylation patterns in NGS data.PLoS computational biology · 2026Article
- Epigenetic reprogramming in multiple myeloma-Challenges and opportunities.International journal of cancer · 2026Review
- Skeletal muscle methylome-transcriptome disruptions during the onset and progression of colorectal cancer-induced cachexia.American journal of physiology. Cell physiology · 2026Article
- Local Promoter Methylation Disorder algorithm reveals bidirectional epigenetic disruption in DNMT3A-mutated AML and predicts azacitidine treatment response.Frontiers in oncology · 2026Article
- The Double-Edged Sword of Genomic DNA Methylation: Orchestrating Gastric Carcinogenesis and Shaping Precision Oncology.Oncology research · 2026Review
- Disordered DNA methylation leads to targetable transcriptional plasticity in ATRT.Acta neuropathologica communications · 2025Article
- Comprehensive comparison of enzymatic and bisulfite DNA methylation analysis in clinically relevant samples.Clinical epigenetics · 2025Article
- Aging by the clock and yet without a program.Nature aging · 2025Review
- Epigenetic drift score captures directional methylation variability and links aging to transcriptional, metabolic, and genetic alterations.Genome research · 2025Article
- Computational analysis of DNA methylation from long-read sequencing.Nature reviews. Genetics · 2025Review
- DNA methylation cooperates with genomic alterations during non-small cell lung cancer evolution.Nature genetics · 2025Article
174 more citing papers are in PubMed but not listed here.
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Authors and funding
26 authors at 6 institutions in 1 country.
Dan A LandauCancer 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.
Kendell ClementBroad 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.
Michael J ZillerBroad Institute, Cambridge, MA 02139, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
Patrick BoyleBroad Institute, Cambridge, MA 02139, USA.
Jean FanCenter for Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
Hongcang GuBroad Institute, Cambridge, MA 02139, USA.
Kristen StevensonDepartment of Biostatistics and Computational Biology, Dana Farber Cancer Institute, Boston, MA 02115, USA.
Carrie SougnezBroad Institute, Cambridge, MA 02139, USA.
Lili WangCancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Shuqiang LiFluidigm, South San Francisco, CA 94080, USA.
Dylan KotliarCancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Wandi ZhangCancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Mahmoud GhandiBroad Institute, Cambridge, MA 02139, USA.
Levi GarrawayDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute, Cambridge, MA 02139, USA.
Stacey M FernandesDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Kenneth J LivakFluidigm, South San Francisco, CA 94080, USA.
Stacey GabrielBroad Institute, Cambridge, MA 02139, USA.
Andreas GnirkeBroad Institute, Cambridge, MA 02139, USA.
Eric S LanderBroad Institute, Cambridge, MA 02139, USA.
Jennifer R BrownDepartment 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.
Donna NeubergDepartment of Biostatistics and Computational Biology, Dana Farber Cancer Institute, Boston, MA 02115, USA.
Peter V KharchenkoCenter for Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA; Division of Hematology/Oncology, Children's Hospital, Boston, MA 02115, USA.
Nir HacohenBroad Institute, Cambridge, MA 02139, USA; Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02114, USA.
Gad GetzBroad Institute, Cambridge, MA 02139, USA; Cancer Center and Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
Alexander MeissnerBroad Institute, Cambridge, MA 02139, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. Electronic address: alexander_meissner@harvard.edu.
Catherine J WuCancer 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.
Broad Institute · USDana-Farber Cancer Institute · USFluidigm (United States) · USCenter for Systems Biology · USHarvard University · USMassachusetts General Hospital · US
Funding
Large Scale Sequencing and Analysis of GenomesU54HG003067 · NHGRI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI GABRIEL, STACEY, LANDER, ERIC S · 2004 to 2015
$568.6MTissue CoreP01CA081534 · NCI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI REED, JOHN C · 2000 to 2016
$59.5MMedical Scientist Training ProgramT32GM007753 · NIGMS · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI WALENSKY, LOREN DAVID · 1985 to 2021
$50.0MPilot & Feasibility ProgramP30DK043351 · NIDDK · MASSACHUSETTS GENERAL HOSPITAL · PI RAYMOND T CHUNG · 1991 to 2026
$35.3MProduction sequencing of reference human epigenomesU01ES017155 · NIEHS · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI BERNSTEIN, BRADLEY EVAN, MEISSNER, ALEXANDER · 2008 to 2012
$15.4MPersonal tumor neoantigens for immunity against chronic lymphocytic leukemiaR01CA155010 · NCI · DANA-FARBER CANCER INST · PI Catherine Ju-Ying Wu · 2011 to 2026
$9.6M(PQD1) lmpact of cytotoxic and targeted therapy on clonal evolution of CLLR01CA184922 · NCI · DANA-FARBER CANCER INST · PI WU, CATHERINE JU-YING · 2014 to 2017
$2.2MDefining the impact of clonal evolution on chronic lymphocytic leukemiaR01CA182461 · NCI · DANA-FARBER CANCER INST · PI WU, CATHERINE JU-YING · 2014 to 2018
$1.8MPost-transplant vaccines to enhance graft-versus-leukemia responsesR01HL103532 · NHLBI · DANA-FARBER CANCER INST · PI WU, CATHERINE JU-YING · 2010 to 2013
$1.7MGeneration and characterization of tools for target-specific de novo DNA methylatR01DA036898 · NIDA · HARVARD UNIVERSITY · PI MEISSNER, ALEXANDER · 2013 to 2017
$1.7MThe role of epigenetic heterogeneity in CLL evolution Admin supplementK01ES025431 · NIEHS · WEILL MEDICAL COLL OF CORNELL UNIV · PI LANDAU, DAN · 2014 to 2018
$982kNCI NIH HHS 1R01CA155010-01A1NCI NIH HHS P01 CA081534NCI NIH HHS R01 CA155010NCI NIH HHS R01 CA182461NCI NIH HHS R01 CA184922NHGRI NIH HHS U54 HG003067NHGRI NIH HHS U54HG003067NHLBI NIH HHS 1R01HL103532-01NHLBI NIH HHS R01 HL103532NIDA NIH HHS 1R01DA036898NIDA NIH HHS R01 DA036898NIDDK NIH HHS P30 DK043351NIEHS NIH HHS 1K01ES025431-01NIEHS NIH HHS K01 ES025431NIEHS NIH HHS U01 ES017155NIEHS NIH HHS U01ES017155NIGMS NIH HHS T32 GM007753
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.
Indexed as
DNA MethylationEpigenesis, GeneticB-LymphocytesCpG IslandsGene Expression Regulation, LeukemicGenetic VariationGenome, HumanHumansLeukemia, Lymphocytic, Chronic, B-CellMolecular Sequence DataSequence Analysis, DNASulfiteshydrogen sulfiteSulfites
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