New insights into the biology and origin of mature aggressive B-cell lymphomas by combined epigenomic, genomic, and transcriptional profiling

Abstract

Lymphomas are assumed to originate at different stages of lymphocyte development through chromosomal aberrations. Thus, different lymphomas resemble lymphocytes at distinct differentiation stages and show characteristic morphologic, genetic, and transcriptional features. Here, we have performed a microarray-based DNA methylation profiling of 83 mature aggressive B-cell non-Hodgkin lymphomas (maB-NHLs) characterized for their morphologic, genetic, and transcriptional features, including molecular Burkitt lymphomas and diffuse large B-cell lymphomas. Hierarchic clustering indicated that methylation patterns in maB-NHLs were not strictly associated with morphologic, genetic, or transcriptional features. By supervised analyses, we identified 56 genes de novo methylated in all lymphoma subtypes studied and 22 methylated in a lymphoma subtype-specific manner. Remarkably, the group of genes de novo methylated in all lymphoma subtypes was significantly enriched for polycomb targets in embryonic stem cells. De novo methylated genes in all maB-NHLs studied were expressed at low levels in lymphomas and normal hematopoietic tissues but not in nonhematopoietic tissues. These findings, especially the enrichment for polycomb targets in stem cells, indicate that maB-NHLs with different morphologic, genetic, and transcriptional background share a similar stem cell-like epigenetic pattern. This suggests that maB-NHLs originate from cells with stem cell features or that stemness was acquired during lymphomagenesis by epigenetic remodeling. (Blood. 2009; 113:2488-2497 IntroductionAberrant DNA methylation is a hallmark of cancer. Virtually all cancer types are associated with alterations of the methylome. These include global DNA hypomethylation, mostly targeting DNA repeats, and hypermethylation of CpG islands located in the promoter regions of tumor suppressor genes. [1][2][3][4] It is widely accepted that tumor suppressor gene inactivation by DNA hypermethylation allows the tumor clone to obtain a selective (eg, proliferative) advantage. However, recent reports have provided evidence for an instructive mechanism behind aberrant DNA methylation in cancer, which might indicate that specific sequences are predisposed to acquire epigenetic alterations. [5][6][7][8][9] Remarkably, 3 independent reports have recently shown that a highly significant proportion of genes becoming hypermethylated in cancer were already repressed at the embryonic stem cell (ESC) stage by polycomb group (PcG) marks. 7-9 These findings are considered to support the "cancer stem cell theory" in which The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 13, 2018. by guest www.bloodjournal.org From aberrant epigenetic changes of PcG target genes occurring in a cell with stem cell features might represent the ...

Distinct DNA methylation patterns in cirrhotic liver and hepatocellular carcinoma

“…S1), which is in line with earlier studies using the BeadArray technology. 13 The median call rate on the methylation arrays was 99.99% (range 97.33-100.00%) indicating robust technical performance of the hybridization (Supporting Information Fig. S2).…”

“…13 Subsequent principal component (PCA) and herarchical cluster analyses were performed using Qlucore's Omics Explorer 2.1 (Version 2.1(25); Qlucore, Lund, Sweden) using DNA methylation values (average b values) obtained from the BeadStudio analysis. Genes were considered being differentially methylated between two data sets if the false discovery rate (FDR, t-test) was below q < 0.01.…”

“…High reproducibility of the array and good correlation with results obtained by MSP, bisulfite pyrosequencing and bisulfite sequencing has been shown before by us and others. 13 Differential methylation of loci in cirrhosis as compared to normal controls is maintained in HCC…”

“…11,12 Virtually all cancers are associated with aberrant DNA methylation, including lymphomas, colorectal, prostate and brain cancers. [13][14][15] Initially, altered methylation has been shown to be one of the silencing mechanisms for tumor-suppressor-like genes 16 but has subsequently been shown to be a phenomenon encompassing a wide array of gene types. 15,17 Among the methylation targets, polycomb repressive complexes (PRC1 and PRC2) regulate key developmental genes and play an important role in differentiation and the maintenance of cell fates.…”

Methylation of the nonhomologous end joining repair pathway genes does not explain the increase of translocations with aging

“…We found a higher number of individuals with the LIG4 promoter methylated in the group of adults (>40 years old) compared with the younger group (≤20 years old) (8.8 vs 0 %). Remarkably, LIG4 promoter was also found to be hypermethylated in different types of lymphomas (Martín-Subero et al 2009). However, no analysis on healthy individuals had been done until now.…”