Global hypomethylation is an independent prognostic factor in diffuse large B cell lymphoma

Abstract

Global hypomethylation has been linked to disease progression in several cancers, but has not been reported for Diffuse Large B Cell Lymphoma (DLBCL). This study aimed to assess global methylation in DLBCL and describe its prognostic value. Mean LINE1 methylation, a validated surrogate measure for global methylation, was measured in DNA from 67 tumor biopsies. Additionally, cell-free circulating DNA (cfDNA) in plasma samples from 74 patients was tested to assess the feasibility of global hypomethylation as a biomarker in liquid biopsies. LINE1 methylation was assessed using a commercially available kit, based on pyrosequencing of PCR amplified bisulfite-treated DNA. Global hypomethylation was detected in a subset of cases and was associated with poor overall survival in both tumor biopsies (P = .001) and cfDNA (P = .009). It was the strongest risk factor in multivariate analysis in both biopsies (HR: 10.65, CI: 2.03-55.81, P = .005) and cfDNA (HR: 11.87, CI: 2.80-50.20, P = .001), outperforming conventional clinical risk factors. Finally, hierarchical cluster analyses were performed for the cfDNA samples using previously published gene-specific methylation data. This analysis shows that global hypomethylation co-occurs with other epigenetic abnormalities, including DAPK1 promoter hypermethylation. In conclusion, we have shown that global hypomethylation is strongly associated with poor survival in DLBCL both when present in tumor biopsy DNA and when detected in plasma cfDNA, and has potential for clinical application as a prognostic biomarker.

Insight into origins, mechanisms, and utility of DNA methylation in B-cell malignancies

“…8,9 Global DNA methylation loss is highly prevalent in B-cell malignancies An immediate obvious feature of DNA methylation in B-cell malignancies is the overall global reduction in DNA methylation levels observed in most tumor types investigated, with the exception of acute lymphocytic leukemia (ALL) ( Figure 2). 8,[10][11][12][13][14] The majority of this loss can be attributed to partial loss of methylation in heterochromatic, intergenic DNA sequences. Global methylation loss is not unique to B-cell tumors per se, as it is also observed in Epstein-Barr virus-transformed lymphoblastoid cell lines 15,16 and is observed in some solid tumors.…”

50‐Hz MF does not affect global DNA methylation of SH‐SY5Y cells treated with the neurotoxin MPP+

“…For the abundance and widespread location of these regions, their CpG methylation percentage has been proposed and validated as a good estimate for global DNA methylation level [Bollati et al, ; Consales et al, ]. Significant associations of these biomarkers with human diseases have also been found [Bollati et al, ; Matsuda et al, ; Wedge et al, ].…”

Long interspersed nuclear element 1 hypomethylation has novel prognostic value and potential utility in liquid biopsy for oral cavity cancer

“…At present, several studies have investigated the relationship between ctDNA hypomethylation transitions of LINE-1 and clinical features in cancer patients. LINE-1 hypomethylation in ctDNA was linked to poor overall survival in diffuse large B cell lymphoma and to surrogate biomarkers for neuroblastoma tumor burden (28,29). As further evidence of its clinical bene t, LINE-1 hypomethylation is described as a blood biomarker to detect colorectal cancer, particularly in the early stages of the disease (30).…”