Locally disordered methylation forms the basis of intratumor methylome variation in chronic lymphocytic leukemia

Dan A Landau; Kendell Clement; Michael J Ziller; Patrick Boyle; Jean Fan; Hongcang Gu; Kristen Stevenson; Carrie Sougnez; Lili Wang; Shuqiang Li; Dylan Kotliar; Wandi Zhang; Mahmoud Ghandi; Levi Garraway; Stacey M Fernandes; Kenneth J Livak; Stacey Gabriel; Andreas Gnirke; Eric S Lander; Jennifer R Brown; Donna Neuberg; Peter V Kharchenko; Nir Hacohen; Gad Getz; Alexander Meissner; Catherine J Wu

doi:10.1016/j.ccell.2014.10.012

Locally disordered methylation forms the basis of intratumor methylome variation in chronic lymphocytic leukemia

Cancer Cell. 2014 Dec 8;26(6):813-825. doi: 10.1016/j.ccell.2014.10.012.

Authors

Dan A Landau¹, Kendell Clement², Michael J Ziller³, Patrick Boyle⁴, Jean Fan⁵, Hongcang Gu⁴, Kristen Stevenson⁶, Carrie Sougnez⁴, Lili Wang⁷, Shuqiang Li⁸, Dylan Kotliar⁹, Wandi Zhang⁹, Mahmoud Ghandi⁴, Levi Garraway¹⁰, Stacey M Fernandes¹¹, Kenneth J Livak⁸, Stacey Gabriel⁴, Andreas Gnirke⁴, Eric S Lander⁴, Jennifer R Brown¹², Donna Neuberg⁶, Peter V Kharchenko¹³, Nir Hacohen¹⁴, Gad Getz¹⁵, Alexander Meissner¹⁶, Catherine J Wu¹⁷

Affiliations

¹ 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.
² 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.
³ Broad Institute, Cambridge, MA 02139, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
⁴ Broad Institute, Cambridge, MA 02139, USA.
⁵ Center for Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
⁶ Department of Biostatistics and Computational Biology, Dana Farber Cancer Institute, Boston, MA 02115, USA.
⁷ Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
⁸ Fluidigm, South San Francisco, CA 94080, USA.
⁹ Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
¹⁰ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute, Cambridge, MA 02139, USA.
¹¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
¹² 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.
¹³ Center for Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA; Division of Hematology/Oncology, Children's Hospital, Boston, MA 02115, USA.
¹⁴ Broad Institute, Cambridge, MA 02139, USA; Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02114, USA.
¹⁵ Broad Institute, Cambridge, MA 02139, USA; Cancer Center and Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
¹⁶ 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.
¹⁷ 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

B-Lymphocytes / metabolism*
CpG Islands
DNA Methylation*
Epigenesis, Genetic*
Gene Expression Regulation, Leukemic
Genetic Variation
Genome, Human
Humans
Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
Leukemia, Lymphocytic, Chronic, B-Cell / pathology
Molecular Sequence Data
Sequence Analysis, DNA
Sulfites / chemistry

Locally disordered methylation forms the basis of intratumor methylome variation in chronic lymphocytic leukemia

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