Genomic chaos in peripheral blood lymphocytes of Hodgkin's lymphoma patients one year after ABVD chemotherapy/radiotherapy

Abstract

Hodgkin's lymphoma (HL) is a lymphoid malignancy representing 5% of all cancers in children, 16% in adolescents, and 30-40% of all malignant lymphomas and has a survival rate of ~95% at 10 years. One of the most common treatment schemes uses a cocktail of genotoxic agents including adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) with or without radiotherapy. We investigated the occurrence of chromosomal damage in peripheral blood lymphocytes from five patients diagnosed with HL who provided samples before (BT), during chemotherapy (DT) and ~1 year after ABVD chemotherapy/radiotherapy (AT). Five healthy subjects served as controls. Chromosomal abnormalities were evaluated by multicolor fluorescence in situ hybridization. The average frequencies of structural chromosomal aberrations in HL samples were 0.11, 0.22, and 0.96 per cell in BT, DT, and AT samples, respectively. These frequencies were significantly different (P < 0.0001) with respect to control subjects (0.02 per cell). Interestingly, the highest frequency of structural damage, including genomic chaos and nonclonal abnormalities, was observed in the AT samples indicating that new aberrations were continuously produced. Rejoined structural chromosomal aberrations were the most common type of aberrations, although aneuploidies were also significantly increased. Finally, we found several chromosomal abnormalities linked to cancer secondary to treatment in all five HL patients. Our results show that ABVD chemotherapy plus radiotherapy is inducing genomic chaos in vivo; moreover, the persistence of genomic instability in the hematopoietic stem cells from HL patients may play a role in the occurrence of secondary cancer that is observed in 5-20% of HL patients. Environ. Mol. Mutagen. 59:755-768, 2018. © 2018 Wiley Periodicals, Inc.

Non-Clonal Chromosome Aberrations and Genome Chaos in Somatic And Germ Cells from Patients and Survivors of Hodgkin Lymphoma, Induced by Anticancer Treatment

“…Liu et al [31], found that when treating cells with chemotherapeutic agents such as those used in these patients, doxorubicin (Adriamycin) and alkylating agents, although there is a high frequency of cell death during stress, some of the chaotic genomes can survive and continue to change until the surviving genomes are selected. In fact, the observations made by Ramos et al [32], and Salas et al [17], resemble the pattern proposed by the in vitro experiments of Liu et al [31] in 2014:…”

“…It is possible that not quantifying this type of alterations, may be the reason for some unexpected data in the study conducted by Ramos et al [32], where a smaller number of classical cytogenetic alterations were found during-treatment, as compared with post-treatment samples. Duringtreatment samples represent the moment when all the cells of the whole organism were under stress, and it is during this moment when according with the results of Liu et al [31], the non-classical genomic damage could be present in a significantly high proportion, and a fraction of the highly rearranged and chaotic karyotypes could be eliminated.…”

Genomic chaos in peripheral blood lymphocytes of hodgkins lymphoma patients 1 year after ABVD chemotherapy/radiotherapy

“…In our study, we found a significant increase of chromosomal aberrations (CAs) and cells with genomic chaos 1 year after treatment and we concluded that these effects were due to the genotoxicity of the chemical and physical agents used in the anticancer therapy. The authors of the letter to the editor, while supporting our main finding, assert that that these observations are due to the reactivation of preexisting virus in the lymphocytes of the HL patients.In Ramos et al (Ramos et al 2018) the frequencies of NCCA observed in the HL samples were significantly higher than in the control samples at all three sampling times investigated: beforetreatment, during-treatment, and 1-year after treatment with ABVD (Adriamycin, Bleomycin, Vinblastine, and Dacarbazine)/ radiotherapy. Although in the study of M' Kacher et al (2003), analyses were conducted at five time points, three of these time points overlap with ours.…”

“…In Ramos et al (Ramos et al 2018) the frequencies of NCCA observed in the HL samples were significantly higher than in the control samples at all three sampling times investigated: beforetreatment, during-treatment, and 1-year after treatment with ABVD (Adriamycin, Bleomycin, Vinblastine, and Dacarbazine)/ radiotherapy. Although in the study of M' Kacher et al (2003), analyses were conducted at five time points, three of these time points overlap with ours.…”

Letter to the editor of environmental and molecular mutagenesis: In regard to Ramos et al.

“…Ramos et al (Ramos et al ) have reported an increase of chromosomal aberrations in peripheral blood lymphocytes in HL patients 1 year after treatment as compared to that observed before and during chemotherapy. Interestingly, the authors identify the presence of cells with a high frequency of chromosomal aberrations in three out of five patients (more than 10 aberrations per cell).…”