Journal article
Preneoplastic Alterations Define CLL DNA Methylome and Persist through Disease Progression and Therapy
Max Planck Institute for Molecular Genetics1
Universitat de Barcelona2
Dana-Farber Cancer Institute3
Department of Health Technology, Technical University of Denmark4
Bioinformatics, Department of Health Technology, Technical University of Denmark5
Broad Institute of Harvard University and Massachusetts Institute of Technology6
University of California at San Diego7
Mayo Clinic Rochester, MN8
Mayo Clinic Scottsdale, AZ9
Beckman Research Institute of City of Hope10
...and 0 moreMost human cancers converge to a deregulated methylome with reduced global levels and elevated methylation at select CpG islands. To investigate the emergence and dynamics of the cancer methylome, we characterized genome-wide DNA methylation in preneoplastic monoclonal B-cell lymphocytosis (MBL) and chronic lymphocytic leukemia (CLL), including serial samples collected across disease course.
We detected the aberrant tumor-associated methylation landscape at CLL diagnosis and found no significant differentially methylated regions in the high-count MBL-to-CLL transition. Patient methylomes showed remarkable stability with natural disease and posttherapy progression. Single CLL cells were consistently aberrantly methylated, indicating a homogeneous transition to the altered epigenetic state and a distinct expression profile together with MBL cells compared with normal B cells.
Our longitudinal analysis reveals the cancer methylome to emerge early, which may provide a platform for subsequent genetically driven growth dynamics, and, together with its persistent presence, suggests a central role in disease onset. SIGNIFICANCE: DNA methylation data from a large cohort of patients with MBL and CLL show that epigenetic transformation emerges early and persists throughout disease stages with limited subsequent changes.
Our results indicate an early role for this aberrant landscape in the normal-to-preneoplastic transition that may reflect a pan-cancer mechanism.
Language: | English |
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Year: | 2021 |
Pages: | 54-69 |
ISSN: | 26433249 , 26433230 , 21598290 and 21598274 |
Types: | Journal article |
DOI: | 10.1158/2643-3230.BCD-19-0058 |
ORCIDs: | 0000-0003-3808-0811 , 0000-0001-5263-3449 , 0000-0002-5951-5055 , 0000-0003-2566-3145 , 0000-0001-9850-9793 and 0000-0002-3348-5054 |