DNA damage measured in blood cells predicts overall and progression-free survival in germ cell tumour patients

Šestáková, Zuzana; Kalavska, Katarína; Smolkova, Bozena; Miškovská, Věra; Rejleková, Katarína; Syčová-Milá, Zuzana; Palacka, Patrik; Obertová, Jana; Holickova, Andrea; Hurbanova, Lenka; Jurkovičová, Dana; Roška, Jan; Goffa, Eduard; Světlovská, Daniela; Chovanec, Michal; Mardiak, Jozef; Mego, Michal; Chovanec, Miroslav

doi:10.1016/j.mrgentox.2020.503200

Cited by 3 publications

(5 citation statements)

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“…Increased levels of endogenous DNA damage in PBMCs resulting from their cocultivation with CDDP-resistant cancer cells may reflect a more aggressive disease in patients who do not respond to CDDP-based chemotherapy. These data are in accordance with our previous findings showing that endogenous DNA damage levels correlate with patient prognosis independent of the IGCCCG risk group [ 16 , 17 ]. In both studies, the DNA damage level was measured by the comet assay and expressed as the mean percentage of DNA in the tail.…”

Section: Discussionsupporting

confidence: 93%

“…PBMCs, which consisted of lymphocytes and monocytes, were isolated from EDTA- or lithium-heparin-treated blood samples using density gradient centrifugation as described previously [ 16 ]. Briefly, PB (2 mL) was diluted 1:1 with phosphate-buffered saline (PBS; 137 mM NaCl, 8 mM Na 2 HPO 4 , 2.7 mM KCl, 1.8 mM KH 2 PO 4 , pH 7.2), and the resulting mixture was carefully poured onto Histopaque-1077 (3 mL; Sigma-Aldrich, Germany).…”

Section: Methodsmentioning

confidence: 99%

“…This cutoff was calculated by receiver operator characteristic (ROC) analysis. Based on the results of ROC analysis, a value of 6.34 has a significant specificity and sensitivity to distinguish GCT patients with and those without inferior outcomes [ 16 ]. Dichotomized data were subsequently correlated with the percentage of immune cell populations by univariate analyses.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, emerging evidence has indicated an intensive interplay between DNA damage/DNA repair pathways and the TME [ 15 ]. Our previous work [ 16 , 17 ] revealed that the levels of endogenous DNA damage, measured by the comet assay in PBMCs, is an independent prognostic factor in GCTs. Chemotherapy-naïve GCT patients with % DNA in the tail above the cutoff value of 6.34 had significantly worse PFS and OS than did those patients with % DNA in the tail below or equal to the cutoff value.…”

Section: Introductionmentioning

confidence: 99%

“…Subsequently, a more comprehensive analysis of patient samples was carried out. Data obtained herein may contribute to elucidating the biological pathways underlying the prognostic value of endogenous DNA damage levels in peripheral lymphocytes in patients with chemotherapy-naïve testicular GCTs [ 16 , 17 ]. A more thorough understanding of these pathways may help to better stratify GCT patients with a high risk for relapse or poor prognosis and identify new therapeutic targets.…”

Section: Introductionmentioning

confidence: 99%

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Are Changes in the Percentage of Specific Leukocyte Subpopulations Associated with Endogenous DNA Damage Levels in Testicular Cancer Patients?

Kalavska

Šestáková

Mlcakova³

et al. 2021

IJMS

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Chemoresistance of germ cell tumors (GCTs) represents an intensively studied property of GCTs that is the result of a complicated multifactorial process. One of the driving factors in this process is the tumor microenvironment (TME). Intensive crosstalk between the DNA damage/DNA repair pathways and the TME has already been reported. This study aimed at evaluating the interplay between the immune TME and endogenous DNA damage levels in GCT patients. A cocultivation system consisting of peripheral blood mononuclear cells (PBMCs) from healthy donors and GCT cell lines was used in an in vitro study. The patient cohort included 74 chemotherapy-naïve GCT patients. Endogenous DNA damage levels were measured by comet assay. Immunophenotyping of leukocyte subpopulations was performed using flow cytometry. Statistical analysis included data assessing immunophenotypes, DNA damage levels and clinicopathological characteristics of enrolled patients. The DNA damage level in PBMCs cocultivated with cisplatin (CDDP)-resistant GCT cell lines was significantly higher than in PBMCs cocultivated with their sensitive counterparts. In GCT patients, endogenous DNA damage levels above the cutoff value were independently associated with increased percentages of natural killer cells, CD16-positive dendritic cells and regulatory T cells. The crosstalk between the endogenous DNA damage level and specific changes in the immune TME reflected in the blood of GCT patients was revealed. The obtained data contribute to a deeper understanding of ongoing interactions in the TME of GCTs.

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Section: Discussionsupporting

confidence: 93%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Are Changes in the Percentage of Specific Leukocyte Subpopulations Associated with Endogenous DNA Damage Levels in Testicular Cancer Patients?

Kalavska

Šestáková

Mlcakova³

et al. 2021

IJMS

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DNA damage in peripheral blood mononuclear cells in patients with melanoma

et al. 2022

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Introduction. The incidence and mortality of malignant melanoma have increased steadily over the last decades; therefore, the development of novel diagnostic markers for malignant melanoma is of great importance. The purpose of the study was to assess whether the development of melanoma before any treatment is accompanied by the body changes and, in particular, DNA damage in the mononuclear cells of the peripheral blood of patients. Material and Methods. In 93 patients (26 men and 67 women) admitted to the N.N. Petrov National Medical Research Center of Oncology for surgical treatment of stage T1c-2a-b-3a-b4a-bN0-1 cutaneous malignant melanoma, and in 118 healthy people as a comparison group, the level of damage to DNA in peripheral blood mononuclear cells was studied using the “comet” method. All patients were divided into two groups: group 1 included 45 patients (13 men and 32 women) who were examined before a decision on treatment was made and group 2 consisted of 48 patients (13 men and 35 women) who previously underwent excision biopsy for melanoma. Results. The level of DNA damage in peripheral blood mononuclear cells, assessed by the comet assay, was found to be signifcantly higher in patients with melanoma than in the comparison group. Moreover, the increase in the level of DNA damage was similar both in patients with a primary tumor before starting any treatment and in those who previously underwent excision biopsy for melanoma. The relationship between the level of DNA damage in peripheral blood mononuclear cells and the morphological characteristics of the tumor cells was revealed. The Spearman correlation analysis showed that all parameters that determined DNA damage positively correlated with the thickness of melanoma according to the Breslow’s depth, and the percentage of DNA in the comet and the comet tail moment correlated with the stage of the disease. Conclusion. The development of cutaneous melanoma is accompanied by an increase in the level of DNA damage in peripheral blood mononuclear cells. The level of DNA damage in peripheral blood mononuclear cells refects the changes that occur in the patient’s body under the infuence of the tumor process, which may allow using this indicator as an additional criterion for the diagnosis and aggressiveness of melanoma.

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DNA damage levels in peripheral blood mononuclear cells before and after first cycle of chemotherapy have comparable prognostic values in germ cell tumor patients

Ivovič,

Šestáková,

Roška

et al. 2024

Front. Oncol.

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BackgroundGerm cell tumors (GCTs) represent the most frequent solid malignancy in young men. This malignancy is highly curable by cisplatin (CDDP)-based chemotherapy. However, there is a proportion of patients having a poor prognosis due to refractory disease or its relapse. No reliable biomarkers being able to timely and accurately stratify poor prognosis GCT patients are currently available. Previously, we have shown that chemotherapy-naïve GCT patients with higher DNA damage levels in peripheral blood mononuclear cells (PBMCs) have significantly worse prognosis compared to patients with lower DNA damage levels.MethodsDNA damage levels in PBMCs of both chemotherapy-naïve and first cycle chemotherapy-treated GCT patients have been assessed by standard alkaline comet assay and its styrene oxide (SO)-modified version. These levels were correlated with clinico-pathological characteristics.ResultsWe re-confirm prognostic value of DNA damage level in chemotherapy-naïve GCT patients and reveal that this prognosticator is equally effective in GCT patients after first cycle of CDDP-based chemotherapy. Furthermore, we demonstrate that SO-modified comet assay is comparably sensitive as standard alkaline comet assay in case of patients who underwent first cycle of CDDP-based chemotherapy, although it appears more suitable to detect DNA cross-links.ConclusionWe propose that DNA damage levels in PBMCs before and after first cycle of CCDP-based chemotherapy are comparable independent prognosticators for progression-free and overall survivals in GCT patients. Therefore, their clinical use is highly advised to stratify GCT patients to identify those who are most at risk of developing disease recurrence or relapse, allowing tailoring therapeutic interventions to poor prognosis individuals, and optimizing their care management and treatment regimen.

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DNA damage measured in blood cells predicts overall and progression-free survival in germ cell tumour patients

Cited by 3 publications

References 45 publications

Are Changes in the Percentage of Specific Leukocyte Subpopulations Associated with Endogenous DNA Damage Levels in Testicular Cancer Patients?

Are Changes in the Percentage of Specific Leukocyte Subpopulations Associated with Endogenous DNA Damage Levels in Testicular Cancer Patients?

DNA damage in peripheral blood mononuclear cells in patients with melanoma

DNA damage levels in peripheral blood mononuclear cells before and after first cycle of chemotherapy have comparable prognostic values in germ cell tumor patients

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