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Semimethylation is a feature of diffuse large B-cell lymphoma, and subgroups with poor prognosis are characterized by global hypomethylation and short telomere length
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Department of Diagnostics and Intervention. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
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2024 (English)In: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 16, no 1, article id 68Article in journal (Refereed) Published
Abstract [en]

Background: Large B-cell lymphoma (LBCL) is the most common lymphoma and is known to be a biologically heterogeneous disease regarding genetic, phenotypic, and clinical features. Although the prognosis is good, one-third has a primary refractory or relapsing disease which underscores the importance of developing predictive biological markers capable of identifying high- and low-risk patients. DNA methylation (DNAm) and telomere maintenance alterations are hallmarks of cancer and aging. Both these alterations may contribute to the heterogeneity of the disease, and potentially influence the prognosis of LBCL.

Results: We studied the DNAm profiles (Infinium MethylationEPIC BeadChip) and relative telomere lengths (RTL) with qPCR of 93 LBCL cases: Diffuse large B-cell lymphoma not otherwise specified (DLBCL, n = 66), High-grade B-cell lymphoma (n = 7), Primary CNS lymphoma (n = 8), and transformation of indolent B-cell lymphoma (n = 12). There was a substantial methylation heterogeneity in DLBCL and other LBCL entities compared to normal cells and other B-cell neoplasms. LBCL cases had a particularly aberrant semimethylated pattern (0.15 ≤ β ≤ 0.8) with large intertumor variation and overall low hypermethylation (β > 0.8). DNAm patterns could not be used to distinguish between germinal center B-cell-like (GC) and non-GC DLBCL cases. In cases treated with R-CHOP-like regimens, a high percentage of global hypomethylation (β < 0.15) was in multivariable analysis associated with worse disease-specific survival (DSS) (HR 6.920, 95% CI 1.499–31.943) and progression-free survival (PFS) (HR 4.923, 95% CI 1.286–18.849) in DLBCL and with worse DSS (HR 5.147, 95% CI 1.239–21.388) in LBCL. These cases with a high percentage of global hypomethylation also had a higher degree of CpG island methylation, including islands in promoter-associated regions, than the cases with less hypomethylation. Additionally, telomere length was heterogenous in LBCL, with a subset of the DLBCL-GC cases accounting for the longest RTL. Short RTL was independently associated with worse DSS (HR 6.011, 95% CI 1.319–27.397) and PFS (HR 4.689, 95% CI 1.102–19.963) in LBCL treated with R-CHOP-like regimens.

Conclusion: We hypothesize that subclones with high global hypomethylation and hypermethylated CpG islands could have advantages in tumor progression, e.g. by inactivating tumor suppressor genes or promoting treatment resistance. Our findings suggest that cases with high global hypomethylation and thus poor prognosis could be candidates for alternative treatment regimens including hypomethylating drugs.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2024. Vol. 16, no 1, article id 68
Keywords [en]
Diffuse large-B cell lymphoma, DNA methylation, High-grade B-cell lymphoma, Predictive markers, Primary CNS lymphomas, Survival, Telomere length
National Category
Hematology Cancer and Oncology
Identifiers
URN: urn:nbn:se:umu:diva-225340DOI: 10.1186/s13148-024-01680-4ISI: 001228885200001PubMedID: 38773655Scopus ID: 2-s2.0-85193701494OAI: oai:DiVA.org:umu-225340DiVA, id: diva2:1864534
Funder
The Kempe FoundationsCancerforskningsfonden i NorrlandLions Cancerforskningsfond i NorrAvailable from: 2024-06-03 Created: 2024-06-03 Last updated: 2024-06-04Bibliographically approved

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Carlund, OliviaOsterman, PiaDernstedt, AndyForsell, Mattias N. E.Erlanson, MartinLandfors, MattiasDegerman, SofieHultdin, Magnus

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Carlund, OliviaThörn, ElinaOsterman, PiaDernstedt, AndyForsell, Mattias N. E.Erlanson, MartinLandfors, MattiasDegerman, SofieHultdin, Magnus
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