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This article is part of our educational series on the role of circulating tumor DNA (ctDNA) in the management of patients with lymphoma.
Diffuse large B-cell lymphoma (DLBCL) accounts for ~30% of all non-Hodgkin lymphomas. The standard treatment regimen usually consists of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), however 30–50% of patients do not respond to this type of treatment. Currently the International Prognostic Index (IPI) is used to predict high-risk patients, however, it cannot accurately predict the therapeutic effect of R-CHOP in patients with DLBCL. More recently, analysis of cell-free DNA (cfDNA), which is found in the peripheral blood and emerges from the original tumor as it rapidly divides, has emerged as a novel, non-invasive tool for diagnosis and prognosis of cancers.1
Epigenetic modification of DNA, especially methylation at the fifth carbon of cytosine (5-methylcyctosine; 5mC) can influence gene expression and cancer development. 5mC in cfDNA is dynamic, reversible, and can be oxidized into 5-hydroxymethylcytosine (5hmC). 5hmC has recently been shown to be associated with DLBCL prognosis. Chen et al. have investigated whether genome-wide analyses of 5hmC profiles could be used to predict treatment response to R-CHOP in patients with DLBCL. The results of this study were published in the journal Clinical Epigenetics and are summarized below.1
5hmC profiles were analyzed by genome-wide analysis (5hmC-Seal technology) of plasma cfDNA from 86 patients with DLBCL across multicenter studies in China, before R-CHOP was administered. Baseline characteristics can be found in Table 1.
Table 1. Baseline characteristics*
Characteristic |
N = 86 |
---|---|
Mean age, years (SD) |
54.59 (15.56) |
Male/female, % |
53.5/46.5 |
Ann Arbor stage, % |
|
IPI, % |
|
Cell of origin, % |
|
Mean LDH level, U/L |
364.33 |
Mean β2M level, mg/L |
2.84 |
β2M, beta 2 macroglobulin; GCB, germinal center B cell; IPI, International Prognostic Index; LDH, lactate dehydrogenase; SD, standard deviation. |
Patients were randomly divided into the training cohort (n = 56) or the validation cohort (n = 30).
The efficacy of R-CHOP was evaluated in all patients after four treatment cycles using the Lugano 2014 criteria.
Table 2. Logistic regression coefficients of the 13 5hmC markers that predict R-CHOP response*
Gene (intercept) |
Coefficient |
SE |
Z value |
P value |
---|---|---|---|---|
THAP3 (chr1_6721489_6721898) |
0.7712 |
0.145 |
1.865 |
< 0.05 |
SMYD3 (chr1_246290825_246291238) |
0.39 |
0.149 |
1.955 |
< 0.05 |
OR2G2 (chr1_247755954_247756505) |
3.1779 |
0.108 |
1.344 |
< 0.05 |
ALKBH3 (chr11_43905400_43905804) |
3.3423 |
0.128 |
1.306 |
< 0.05 |
RNASEH2C (chr11_65511519_65512429) |
1.5211 |
0.072 |
2.061 |
< 0.05 |
ARHGEF12 (chr11_120211662_120212234) |
−3.8797 |
0.115 |
−3.225 |
< 0.001 |
ZNF280D (chr15_56982146_56982638) |
−1.2266 |
0.177 |
−3.250 |
< 0.001 |
SLC5A11 (chr16_24916341_24916920) |
0.6683 |
0.076 |
0.149 |
< 0.05 |
CTDP1 (chr18_77500908_77501376) |
−2.573 |
0.103 |
−3.182 |
< 0.001 |
GPR15 (chr3_98270705_98271079) |
0.1052 |
0.167 |
2.348 |
< 0.05 |
GOLGB1 (chr3_121430838_121431239) |
0.8526 |
0.178 |
2.982 |
< 0.01 |
FBXL4 (chr6_99461404_99461922) |
1.7188 |
0.101 |
2.165 |
< 0.05 |
LMBR1 (chr7_156700537_156701031) |
1.0942 |
0.078 |
0.579 |
< 0.05 |
SE, standard errors of coefficients; Z value, Wald z-statistic value. |
To further understand the potential associations between the 13 5hmC marker genes and R-CHOP treatment response, mRNA expression profiles of the 13 5hmC marker genes were compared to that of B-lymphocyte antigen CD20 (MS4A1), a rituximab target gene, in 48 patients with DLBCL from the TCGA dataset.
There were 13 5hmC markers derived from cfDNA that effectively distinguished responders and non-responders to R-CHOP therapy. This was superior to existing clinical indicators, such as LDH levels and staging of disease, and therefore these 5hmCs may serve as effective biomarkers of response. 5hmC of ARHGEF12 had the best prognostic score, and its expression was positively associated with genes involved in the Rho signaling pathway. This pathway is known to influence cancer initiation, proliferation, metastasis, and drug resistance.
Limitations to the study include that only Chinese patients were included, and the sample sizes were small. Therefore, the results may not fully represent all patients with DLBCL and so further studies in larger, more diverse cohorts are required.
For other articles in this theme click on the links below:
The role of ctDNA in lymphoma management
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