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  Pre-neoplastic alterations define CLL DNA methylome and persist through disease progression and therapy

Kretzmer, H., Biran, A., Purroy, N., Lemvigh, C. K., Clement, K., Gruber, M., et al. (2020). Pre-neoplastic alterations define CLL DNA methylome and persist through disease progression and therapy. Blood Cancer Discovery, 2(1): 2:1–16. doi:10.1158/2643-3230.BCD-19-0058.

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© 2020 American Association for Cancer Research
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 Creators:
Kretzmer, Helene1, Author              
Biran, Anat , Author
Purroy, Noelia , Author
Lemvigh, Camilla K. , Author
Clement, Kendell , Author
Gruber, Michaela, Author
Gu, Hongcang, Author
Rassenti, Laura , Author
Mohammad, Arman W. , Author
Lesnick, Connie , Author
Slager, Susan L., Author
Braggio, Esteban , Author
Shanafelt, Tait D. , Author
Kay, Neil E. , Author
Fernandes, Stacey M. , Author
Brown, Jennifer R. , Author
Wang, Lili, Author
Li, Shuqiang, Author
Livak, Kenneth J. , Author
Neuberg, Donna S. , Author
Klages, Sven2, Author              Timmermann, Bernd2, Author              Kipps, Thomas J. , AuthorCampo, Elias , AuthorGnirke, Andreas, AuthorWu, Catherine J., AuthorMeissner, Alexander1, Author               more..
Affiliations:
1Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2379694              
2Sequencing (Head: Bernd Timmermann), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479670              

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 Abstract: Most 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.

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Language(s): eng - English
 Dates: 2020-11-182020-12-03
 Publication Status: Published online
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 Identifiers: DOI: 10.1158/2643-3230.BCD-19-0058
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Title: Blood Cancer Discovery
Source Genre: Journal
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Pages: - Volume / Issue: 2 (1) Sequence Number: 2:1–16 Start / End Page: - Identifier: -