5-Hydroxymethylcytosine profiles of cfDNA are highly predictive of R-CHOP treatment response in diffuse large B cell lymphoma patients

Chen, Hangyu; Zhang, Weilong; Zhang, Lei; Yang, Ping; Li, Fang; Yang, Zeruo; Wang, Jing; Hong, Yun; Yan, Changjian; Li, Wei; Liu, Jia; Xu, Nuo; Chen, Long; Xiao, Xiu-Bing; Qin, Yan; He, Xiaohong; Liu, Hui; Zhu, Haichuan; He, Chuan; Lin, Jian; Jing, Hongmei

doi:10.1186/s13148-020-00973-8

Cited by 17 publications

(13 citation statements)

References 54 publications

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“…R-DA-EPOCH (rituximab, doxorubicin, etoposide, prednisone, vincristine, cyclophosphamide) was commonly used for relapsed DLBCL patients [2]. However, existing methods maynot accurately or effectively predict therapeutic efficacy before treatment of DLBCL [9]. Therefore, understanding the potential effect mechanism of the chemotherapeutic agent acting on DLBCL is essential to improve protocols for improving patient prognosis.…”

Section: Introductionmentioning

confidence: 99%

LAG3 and PD1 Regulate CD8+ T Cell in Diffuse Large B-cell Lymphoma Patients

Liu

Zhan

et al. 2021

Computational and Mathematical Methods in Medicine

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Background. Diffuse large B-cell lymphoma (DLBCL) is a clinically and genetically heterogeneous lymphoid malignancy. The unsatisfactory outcome for refractory patients has prompted efforts to explore new therapeutic approaches for DLBCL. However, the mechanisms involved in treatment associated with immune checkpoints remain unclear. This study is aimed at investigating the potential roles of programmed cell death protein 1 (PD1) and lymphocyte activation gene 3 (LAG3) in CD8+ T cells for treatment in DLBCL. Methods. Utilizing flow cytometry, we examined the content of T cells, the levels of cytokines, and the expression of PD1 and LAG3 in patients with DLBCL as well as in healthy controls. Levels of cytokines in CD8+ T cells from DLBCL patients before and after treatment were compared by blocking of PD1 and LAG3 in magnetic bead-sorted CD8+ T cells. Results. We found that the proportion of CD4+ T cells and CD8+ T cells was increased in DLBCL patients after treatment. The levels of cytokines trended toward those of healthy controls in treatment. PD1 (+), LAG3 (+), or PD1 (+) LAG3 (+) were all expressed in lower amounts in CD4+ T cells and CD8+ T cells after treatment than in untreated DLBCL patients. In addition, blockade of PD1 and LAG3 in sorted CD8+ T cells markedly inhibited cytokine production in response to treatment. Conclusion. PD1 and LAG3 in CD8+ T cells may be important targets of therapy and play therapeutic role in patients with DLBCL.

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Section: Introductionmentioning

confidence: 99%

LAG3 and PD1 Regulate CD8+ T Cell in Diffuse Large B-cell Lymphoma Patients

Liu

Zhan

et al. 2021

Computational and Mathematical Methods in Medicine

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“…The results of both studies showed the potential of cfDNA epigenetic markers for the detection of brain gliomas. However, the direct correlation between hydroxymethylome of plasma cfDNA and transcriptome of the underlying tumor revealed in our results implies its unique advantages and future prospects in not only noninvasive molecular diagnostics, but also convenient dynamic monitoring of the tumor progression and therapeutic response 33,34 …”

Section: Discussionmentioning

confidence: 84%

Noninvasive detection of brain gliomas using plasma cell‐free DNA 5‐hydroxymethylcytosine sequencing

Zhang

Yin

et al. 2022

Intl Journal of Cancer

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Liquid biopsy techniques based on deep sequencing of plasma cell-free DNA (cfDNA) could detect the low-frequency somatic mutations and provide an accurate diagnosis for many cancers. However, for brain gliomas, reliable performance of these techniques currently requires obtaining cfDNA from patients' cerebral spinal fluid, which is cumbersome and risky. Here we report a liquid biopsy method based on sequencing of plasma cfDNA fragments carrying 5-hydroxymethylcytosine (5hmC) using selective chemical labeling (hMe-Seal). We first constructed a dataset including 180 glioma patients and 229 non-glioma controls. We found marked concordance between cfDNA hydroxymethylome and the aberrant transcriptome of the underlying gliomas. Functional analysis also revealed overrepresentation of the differentially hydroxymethylated genes (DhmGs) in oncogenic and neural pathways. After splitting our dataset into training and test cohort, we showed that a penalized logistic model constructed with training set DhmGs could distinguish glioma patients from healthy controls in both our test set (AUC = 0.962) and an independent dataset (AUC = 0.930) consisting of 111 gliomas and 111 controls. Additionally, the DhmGs between gliomas with mutant and wild-type isocitrate dehydrogenase (IDH) could be used to train a cfDNA predictor of the IDH mutation status of the underlying tumor (AUC = 0.816), and patients with predicted IDH mutant gliomas had significantly better outcome (P = .01). These results indicate that our plasma cfDNA 5hmC sequencing method could obtain glioma-specific signals, which may be used to noninvasively detect these patients and predict the aggressiveness of their tumors.

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“…Overview of study design. 5hmC library construction for all samples was consistent with previously reported (16,17). The cfDNA samples were endrepaired using the KAPA Hyper Prep Kit (KAPA Biosystems) and then ligated to sequencing adapters.…”

Section: Figurementioning

confidence: 98%

5-Hydroxymethylcytosine profiles in plasma cell-free DNA reflect molecular characteristics of diabetic kidney disease

Chu

et al. 2022

Front. Endocrinol.

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BackgroundDiabetic kidney disease (DKD), one of the main complications of diabetes mellitus (DM), has become a frequent cause of end-stage renal disease. A clinically convenient, non-invasive approach for monitoring the development of DKD would benefit the overall life quality of patients with DM and contribute to lower medical burdens through promoting preventive interventions.MethodsWe utilized 5hmC-Seal to profile genome-wide 5-hydroxymethylcytosines in plasma cell-free DNA (cfDNA). Candidate genes were identified by intersecting the differentially hydroxymethylated genes and differentially expressed genes from the GSE30528 and GSE30529. Then, a protein interaction network was constructed for the candidate genes, and the hub genes were identified by the MCODE and cytoHubba algorithm. The correlation analysis between the hydroxymethylation level of the hub genes and estimated glomerular filtration rate (eGFR) was carried out. Finally, we demonstrated differences in expression levels of the protein was verified by constructing a mouse model of DKD. In addition, we constructed a network of interactions between drugs and hub genes using the Comparative Toxicogenomics Database.ResultsThis study found that there were significant differences in the overall distribution of 5hmC in plasma of patients with DKD, and an alteration of hydroxymethylation levels in genomic regions involved in inflammatory pathways which participate in the immune response. The final 5 hub genes, including (CTNNB1, MYD88, CD28, VCAM1, CD44) were confirmed. Further analysis indicated that this 5-gene signature showed a good capacity to distinguish between DKD and DM, and was found that protein levels were increased in renal tissue of DKD mice. Correlation analysis indicated that the hydroxymethylation level of 5 hub genes were nagatively correlated with eGFR. Toxicogenomics analysis showed that a variety of drugs for the treatment of DKD can reduce the expression levels of 4 hub genes (CD44, MYD88, VCAM1, CTNNB1).ConclusionsThe 5hmC-Seal assay was successfully applied to the plasma cfDNA samples from a cohort of DM patients with or without DKD. Altered 5hmC signatures indicate that 5hmC-Seal has the potential to be a non-invasive epigenetic tool for monitoring the development of DKD and it provides new insight for the future molecularly targeted anti-inflammation therapeutic strategies of DKD.

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5-Hydroxymethylcytosine profiles of cfDNA are highly predictive of R-CHOP treatment response in diffuse large B cell lymphoma patients

Cited by 17 publications

References 54 publications

LAG3 and PD1 Regulate CD8+ T Cell in Diffuse Large B-cell Lymphoma Patients

LAG3 and PD1 Regulate CD8+ T Cell in Diffuse Large B-cell Lymphoma Patients

Noninvasive detection of brain gliomas using plasma cell‐free DNA 5‐hydroxymethylcytosine sequencing

5-Hydroxymethylcytosine profiles in plasma cell-free DNA reflect molecular characteristics of diabetic kidney disease

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