Genome-wide profiling identifies a DNA methylation signature that associates with TET2 mutations in diffuse large B-cell lymphoma

Abstract

The discovery that the Ten-Eleven Translocation (TET) hydroxylases cause DNA demethylation has fundamentally changed the notion of how DNA methylation is regulated. Clonal analysis of the hematopoetic stem cell compartment suggests that TET2 mutations can be early events in hematologic cancers and recent investigations have shown TET2 mutations in diffuse large B-cell lymphoma. However, the detection rates and the types of TET2 mutations vary, and the relation to global methylation patterns has not been investigated. Here, we show TET2 mutations in 12 of 100 diffuse large B-cell lymphomas with 7% carrying loss-of-function and 5% carrying missense mutations. Genome-wide methylation profiling using 450K Illumina arrays identified 315 differentially methylated genes between TET2 mutated and TET2 wild-type cases. TET2 mutations are primarily associated with hypermethylation within CpG islands (70%; P<0.0001), and at CpG-rich promoters (60%; P<0.0001) of genes involved in hematopoietic differentiation and cellular development. Hypermethylated loci in TET2 muta ted samples overlap with the bivalent (H3K27me3/H3K4me3) silencing mark in human embryonic stem cells (P=1.5x10 -30 ). Surprisingly, gene expression profiling showed that only 11% of the hypermethylated genes were down-regulated, among which there were several genes previously suggested to be tumor suppressors. A metaanalysis suggested that the 35 hypermethylated and down-regulated genes are associated with the activated B-celllike type of diffuse large B-cell lymphoma in other studies. In conclusion, our data suggest that TET2 mutations may cause aberrant methylation mainly of genes involved in hematopoietic development, which are silenced but poised for activation in human embryonic stem cells.Genome-wide profiling identifies a DNA methylation signature that associates with TET2 mutations in diffuse large B-cell lymphoma

B-cell tumor development in Tet2-deficient mice

“…10 Those DLBCLs are associated with the activated B-cell subtype and a specific DNA-methylation signature. 10 This lymphoma subtype is highly sensitive to ibrutinib.…”

“…10 Those DLBCLs are associated with the activated B-cell subtype and a specific DNA-methylation signature. 10 This lymphoma subtype is highly sensitive to ibrutinib. 46 We show that a Tet2-deficient gene signature may separate human FL samples from CLL and DLBCL (supplemental Figure 3C).…”

“…Intriguingly, although TET2 mutations are very rare in human CLL, 31 they are found in at least 5% of diffuse large B-cell lymphoma (DLBCL) samples. 10,11,32 Tet2-deficient tumors harbor AID-mediated somatic mutations…”

“…5 The TET proteins are a-ketoglutarate (a-KG)-dependent dioxygenases able to oxidize 5-methylated cytosine (mC) into hydroxymethylated C (hmC), which represent a step toward active or passive DNA demethylation, or both. The TET2 gene is mutated in 15% of all types of human myeloid neoplasms, [7][8][9] 2% to 10% of B-cell lymphomas, 10,11 and 10% of T-cell lymphomas, particularly of the angioimmunoblastic subtype. 8 However, no major member of the DNA methylation control pathway was recurrently found mutated in CLL and malignant B-cell differentiation.…”

Clinical impact of recurrently mutated genes on lymphoma diagnostics: state-of-the-art and beyond

“…For instance, germinal center derived B-cell malignancies, such as DLBCL of the germinal center B-cell-like type (GCB DLBCL) and FL, appear to have higher frequencies of aberrations in epigenetic-related genes (e.g. EZH2, CREPPB, TET2, IDH2), 61,62 while other B-cell lymphomas demonstrate common mutations of members in the NOTCH, B-cell receptor (BcR), and NF-κB signaling pathways (Table 1). 63,64 Similarly, different PTCL subtypes, such as mycosis fungoides and Sézary syndrome, AITL and other T FH -derived PTCL, and adult T-cell leukemia/lymphoma (ATLL) share frequent alterations affecting both epigenetic regulation and T-cell receptor NGS-based diagnostics in lymphomas haematologica | 2016; 101 (9) 1005 Table 1B.…”