Locally disordered methylation forms the basis of intratumor methylome variation in chronic lymphocytic leukemia.
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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. |
Year of Publication | 2014
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Journal | Cancer Cell
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Volume | 26
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Issue | 6
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Pages | 813-25
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Date Published | 2014 Dec 08
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ISSN | 1878-3686
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URL | |
DOI | 10.1016/j.ccell.2014.10.012
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PubMed ID | 25490447
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PubMed Central ID | PMC4302418
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Grant list | 1R01HL103532-01 / HL / NHLBI NIH HHS / United States
R01 CA182461 / CA / NCI NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
P30 DK043351 / DK / NIDDK NIH HHS / United States
1K01ES025431-01 / ES / NIEHS NIH HHS / United States
U01ES017155 / ES / NIEHS NIH HHS / United States
1R01DA036898 / DA / NIDA NIH HHS / United States
R01 HL103532 / HL / NHLBI NIH HHS / United States
U54HG003067 / HG / NHGRI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
K01 ES025431 / ES / NIEHS NIH HHS / United States
R01 CA184922 / CA / NCI NIH HHS / United States
R01 CA155010 / CA / NCI NIH HHS / United States
1R01CA155010-01A1 / CA / NCI NIH HHS / United States
U01 ES017155 / ES / NIEHS NIH HHS / United States
R01 DA036898 / DA / NIDA NIH HHS / United States
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