Frequent induction of chromosomal aberrations in in vivo skin fibroblasts after allogeneic stem cell transplantation: hints to chromosomal instability after irradiation

Abstract

BackgroundTotal body irradiation (TBI) has been part of standard conditioning regimens before allogeneic stem cell transplantation for many years. Its effect on normal tissue in these patients has not been studied extensively.MethodWe studied the in vivo cytogenetic effects of TBI and high-dose chemotherapy on skin fibroblasts from 35 allogeneic stem cell transplantation (SCT) patients. Biopsies were obtained prospectively (n = 18 patients) before, 3 and 12 months after allogeneic SCT and retrospectively (n = 17 patients) 23–65 months after SCT for G-banded chromosome analysis.ResultsChromosomal aberrations were detected in 2/18 patients (11 %) before allogeneic SCT, in 12/13 patients (92 %) after 3 months, in all patients after 12 months and in all patients in the retrospective group after allogeneic SCT. The percentage of aberrant cells was significantly higher at all times after allogeneic SCT compared to baseline analysis. Reciprocal translocations were the most common aberrations, but all other types of stable, structural chromosomal aberrations were also observed. Clonal aberrations were observed, but only in three cases they were detected in independently cultured flasks. A tendency to non-random clustering throughout the genome was observed. The percentage of aberrant cells was not different between patients with and without secondary malignancies in this study group.ConclusionHigh-dose chemotherapy and TBI leads to severe chromosomal damage in skin fibroblasts of patients after SCT. Our long-term data suggest that this damage increases with time, possibly due to in vivo radiation-induced chromosomal instability.

Clinical and treatment‐related features determining the risk of late relapse in patients with diffuse large B‐cell lymphoma

“…In accordance with some previous reports, we found patients with late reoccurrence of lymphoma after first line treatment for DLBCL to have more favourable prognostic characteristics, e.g. Radiotherapy may well play an important role in initially improving the level of remission by effectively eradicating MRD after induction chemotherapy, while it simultaneously enhances the risk of clonal instability (Massenkeil et al, 2015) and thereby the possibility of a late relapsing malignancy. However, we did not find a statistically significant difference when comparing these clinical factors of patients with late relapse to patients who stayed in CR (Table II).…”

“…This would be in keeping with our observation that radiotherapy was found to significantly lower the occurrence of early relapses, while it did not reduce the rate of late lymphoma reoccurrence. Radiotherapy may well play an important role in initially improving the level of remission by effectively eradicating MRD after induction chemotherapy, while it simultaneously enhances the risk of clonal instability (Massenkeil et al, 2015) and thereby the possibility of a late relapsing malignancy.…”

Molecular karyotyping and gene expression analysis in childhood cancer patients

“…Radiation and chemotherapeutic agents do not mechanistically distinguish a tumor cell from healthy tissue and the application of these genotoxic agents may be another source of acquired CNVs. Frequent induction of chromosomal aberrations after irradiation has been reported by Massenkeil et al [ 9 ] in skin fibroblasts in vivo .…”

Spontaneous and Radiation-Induced Chromosome Aberrations in Primary Fibroblasts of Patients With Pediatric First and Second Neoplasms

“…Another SPN donor with a rhabdomyosarcoma as the FPN and a subsequent lymphoma as the SPN displayed high rates of clonal and non-clonal translocations in 90% of metaphases detected by high-resolution mFISH. Non-clonal translocations as well as their clonal expansion have been documented in skin fibroblasts from patients with hematopoietic malignancies after high-dose CT plus total-body RT before bone marrow transplantation (58). However, such aberrations can also occur as an artifact during the in-vitro cultivation of fibroblasts from normal donors (41).…”