Abstract
The contribution of epigenomic alterations to tumour progression and relapse is not well characterized. Here we characterize an association between disease progression and DNA methylation in diffuse large B-cell lymphoma (DLBCL). By profiling genome-wide DNA methylation at single-base pair resolution in thirteen DLBCL diagnosis–relapse sample pairs, we show that DLBCL patients exhibit heterogeneous evolution of tumour methylomes during relapse. We identify differentially methylated regulatory elements and determine a relapse-associated methylation signature converging on key pathways such as transforming growth factor-β (TGF-β) receptor activity. We also observe decreased intra-tumour methylation heterogeneity from diagnosis to relapsed tumour samples. Relapse-free patients display lower intra-tumour methylation heterogeneity at diagnosis compared with relapsed patients in an independent validation cohort. Furthermore, intra-tumour methylation heterogeneity is predictive of time to relapse. Therefore, we propose that epigenomic heterogeneity may support or drive the relapse phenotype and can be used to predict DLBCL relapse.
Highlights
The contribution of epigenomic alterations to tumour progression and relapse is not well characterized
We performed enhanced reduced representation bisulfite sequencing (ERRBS)[14] to interrogate the methylation levels at three to four million CpGs distributed in a cohort of diffuse large B-cell lymphoma (DLBCL) patients who were uniformly treated with standard chemotherapy (R-CHOP) and eventually relapsed
Several studies have shown that the DNA methylation landscape differs between primary DLBCL and normal B cells including germinal centre B cells (GCBs) and naıve B cells (NBs)[13,15,16,17]
Summary
The contribution of epigenomic alterations to tumour progression and relapse is not well characterized. We reason that characterizing the DNA methylome at single-base resolution in relapsed DLBCLs would help understand its role in disease progression and its contribution to relapse-associated phenotypes such as chemoresistance. Taking advantage of the single-nucleotide resolution provided by ERRBS14, we are able to access intra-tumour methylation heterogeneity (MH) at diagnosis and relapse in DLBCL and correlate it with disease progression. We characterize the evolution of methylome from diagnosis to relapse in DLBCL along three different axes—overall changes in DNA methylation landscape, differentially methylated regulatory elements and intra-tumour MH. Despite the heterogeneous background of DNA methylation landscape, we determine a methylation signature based on consistently differentially methylated regulatory elements between diagnosis and relapsed pairs This signature is linked with specific genes and pathways whose role in relapse may be important, for example, transforming growth factor-b (TGF-b) receptor activity pathway and apoptosis. Our data suggest that epigenetic heterogeneity in DLBCLs at diagnosis is predictive of the occurrence of relapse
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