Cytogenetic studies of long‐term survivors of childhood acute lymphoblastic leukemia: A follow‐up report

Abstract

Previous series including our earlier study of survivors of childhood acute lymphoblastic leukemia have documented the presence of nonclonal chromosome abnormalities in peripheral blood lymphocytes. To investigate whether or not these abnormalities persist, we restudied nine patients, all of whom had received radiotherapy and a minimum of 3 years of systemic chemotherapy. Therapy had been discontinued a median of 3.9 years prior to study in our first report and a median of 7.2 years prior to study in this follow-up report. Thirty metaphases from short-term cultures of phytohemagglutinin-stimulated peripheral blood from each of nine patients and nine matched controls were analyzed using G-banding. Nonclonal chromosome abnormalities were present in cells from six of the nine patients and 3.0% of patients' cells overall, as compared to seven of ten patients and 3.5% of patients' cells in the earlier study. All patients studied twice had abnormalities on one or both occasions. No evidence for the development of cytogenetically abnormal clones was found. Combined data from the two evaluations indicate that all of the patients have a small population of long-lived lymphocytes with nonclonal chromosome abnormalities, the frequency of these cells appears to remain remarkably constant over time, and the proportion of cells with chromosome abnormalities is approximately threefold greater in patients than in controls. It has become apparent that survivors of acute lymphoblastic leukemia are at increased risk for development of second malignant neoplasms. The relationship between therapy-induced chromosome damage and the development of second malignant neoplasms is currently unknown. We speculate that some cells, possibly in tissues other than peripheral blood, are preneoplastic by virtue of therapy-induced chromosome rearrangements involving critical genes and, following a long latent period, may undergo subsequent genetic or cellular changes that result in malignant transformation. Unfortunately, however, estimation of genetic damage through cytogenetic studies of peripheral blood T-lymphocytes does not appear to be a useful method for prediction of second malignant neoplasms following acute lymphoblastic leukemia, since most or all of the patients have a low level of abnormal cells.

Pregnancy outcome in long-term survivors of childhood cancer

“…The most obvious of these is constitutional cytogenetics of survivors, with the idea that these would reflect mutations in germline chromosomes. The results of Rubin et al [29] suggest that this is not so; the majority of survivors of childhood ALL (who do not have abnormal children) harbor a small population of longlived lymphocytes that exhibit stable nonclonal chromosomal abnormalities. Survivors of pediatric cancer have been shown to have other markers of chromosomal injury in peripheral blood, such as sister chromatid exchanges, and mutations at the glycophorin A, HGPRT, and T-cell antigen receptor loci [30][31][32].…”

Persistence of translocation frequencies in blood lymphocytes following radiotherapy: implications for retrospective radiation biodosimetry

“…The persistence of stable aberrations in peripheral blood lymphocytes following radiation exposure has long been recognised by those studying the after effects of radiotherapy, although little has been done to quantify the frequencies in relation to the time course following exposure. A G-banding study of a group of survivors of childhood leukaemia (Rubin et al 1986) reported similar overall frequencies of chromosomally aberrant cells at 3.9 and 7.2 years post-exposure but the initial yield after treatment was not examined. A group of thyroid patients displayed similar raised frequencies of translocations 1 week and 3.5 years after treatment with radioactive iodine (Puerto et al 2000).…”

Chromosomal abnormalities in skin following total body or total lymphoid irradiation

“…Factors reported to be associated with secondary malignancies after bone marrow transplant include the presence of acute graft vs. host disease treated with either antithymocyte globulin or an anti-CD3 monoclonal antibody, T-lymphocyte depletion of the donor, HLA mismatch between donor and recipient, and use rearrangement in the causation of secondary malignancies posttransplant; however, consistent karyotypic changes have been observed in a growing number of human malignancies (Mitelman et al, 1990), including secondary neoplasms (Arthur and Bloomfield, 1984; Le Beau et al, 1986Ratain et al, 1987Pui et al, 1989Pui et al, , 1990Albain et al, 1990;Rubin et al, 1991). Given that cells with treatment-induced chromosome abnormalities can survive for long periods (Engel et al, 1964;Visfeldt, 1966Miller et al, 1978Savage and Bigger, 1978;Mouthuy and Dutrillaux, 1982;Robison et al, 1982;Rubin et al, 1986;Zaslav et al, 1988;Barrios et al, 1989), we speculate that certain of these cells with chromosome rearrangements involving critical genes are preneoplastic and may undergo subsequent genetic changes that result in malignant transformation.…”

“…Ionizing radiation and many chemotherapeutic drugs are mutagenic, with the capacity to produce detectable cytogenetic alterations, and are carcinogenic in a variety of in vitro and animal test systems. Exposure of man to certain of these agents is associated with the sustained presence of hematopoietic (Miller et al, 1978Robison et al, 1982Rubin et al, 1986;Barrios et al, 1989) and nonhematopoietic (Engel et al, 1964, Visfeldt, 1966Savage andBigger, 1978 Mouthuy andDutrillaux, 1982;Zaslav et al, 1988) cells with chromosomal abnormalities and an increased risk of secondary malignancies (reviewed by Holm, 1990). It is possible that development of secondary malignancy involves therapy-induced DNA damage in the form of gene mutation or chromosome alteration resulting in conversion of a normal cell into an initiated or preneoplastic one.…”