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Radiation Oncology

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Open Access 01-12-2015 | Research

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

Authors: G. Massenkeil, P. Zschieschang, G. Thiel, P. G. Hemmati, V. Budach, B. Dörken, J. Pross, R. Arnold

Published in: Radiation Oncology | Issue 1/2015

Abstract

Background

Total 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.

Method

We 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.

Results

Chromosomal 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.

Conclusion

High-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.

Witherspoon RP, Fisher LD, Schoch G, Martin P, Sullivan KM, Sanders J, et al. Secondary cancers after bone marrow transplantation for leukemia or aplastic anemia. N Engl J Med. 1989;321(12):784–9.PubMedCrossRef

Kolb HJ, Socié G, Duell T, Van Lint MT, Tichelli A, Apperley JF, et al. Malignant neoplasms in long-term-survivors of bone marrow transplantation. Ann Intern Med. 1999;131:738–44.PubMedCrossRef

Socié G, Curtis RE, Deeg HJ, Sobocinski KA, Filipovich AH, Travis LB, et al. New malignant diseases after allogeneic marrow transplantation for childhood acute leukemia. J Clin Oncol. 2000;18(2):348–57.PubMed

Bhatia S, Louie AD, Bhatia R, O’Donnell M, Fung H, Kashyap A, et al. Solid cancers after bone marrow transplantation. J Clin Oncol. 2001;19(2):464–71.PubMed

Baker KS, DeFor TE, Burns LJ, Ramsay NK, Neglia JP, Robison LL. New malignancies after blood or marrow stem-cell transplantation in children and adults: incidence and risk factors. J Clin Oncol. 2003;21(7):1352–8. Erratum in: J Clin Oncol 2003, 21(16):3181.PubMedCrossRef

Hasegawa W, Pond GR, Rifkind JT, Messner HA, Lau A, Daly AS, et al. Long-term follow-up of secondary malignancies in adults after allogeneic bone marrow transplantation. Bone Marrow Transplant. 2005;35(1):51–5.PubMedCrossRef

Rizzo JD, Curtis RE, Socié G, Sobocinski KA, Gilbert E, Landgren O, et al. Solid cancers after allogeneic hematopoietic cell transplantation. Blood. 2009;113(5):1175–83.PubMedPubMedCentralCrossRef

Rowley JD, Golomb HM, Vardiman J. Nonrandom Chromosomal Abnormalities in Acute Nonlymphocytic Leukemia in Patients Treated for Hodgkin Disease and Non-Hodgkin Lymphomas. Blood. 1977;50(5):759–70.

Le Beau MM, Albain KS, Larson RA, Vardiman JW, Davis EM, Blough RR, et al. Clinical and Cytogenetic Correlations in 63 Patients With Therapy-Related Myelodysplastic Syndromes and Acute Nonlymphocytic Leukemia: Further Evidence for Characteristic Abnormalities of Chromosomes No. 5 and 7. J Clin Oncol. 1986;4(3):325–45.PubMed

10.

Pedersen-Bjergaard J, Andersen MT, Andersen MK, Christiansen DH. Genetics of therapy-related myelodysplasia and acute myeloid leukemia. Leukemia. 2008;22(2):240–8.PubMedCrossRef

11.

Schroeder T, Kuendgen A, Kayser S, Kröger N, Braulke F, Platzbecker U, et al. Therapy-related myeloid neoplasms following treatment with radioiodine. Haematologica. 2012;97(2):206–12.PubMedPubMedCentralCrossRef

12.

Chauveinc L, Dutrillaux AM, Validire P, Padoy E, Sabatier L, Couturier J, et al. Cytogenetic study of eight new cases of radiation-induced solid tumors. Cancer Genet Cytogenet. 1999;114(1):1–8.PubMedCrossRef

13.

Huang L, Snyder AR, Morgan WF. Radiation-induced genomic instability and its implications for radiation carcinogenesis. Oncogene. 2003;22(37):5848–54.PubMedCrossRef

14.

Niwa O. Indirect mechanisms of genomic instability and the biological significance of mutations at tandem repeat loci. Mutat Res. 2006;598(1–2):61–72.PubMedCrossRef

15.

Mouthuy M, Dutrillaux B. Cytogenetic study of skin fibroblasts in a case of accidental acute irradiation. Mutat Res. 1982;95:19–30.PubMedCrossRef

16.

Honda T, Sadamori N, Itoh M, Kusumi O. Clonal fibroblastic cell lines established from a heavily exposed atomic bomb survivor. Mutat Res. 1993;291:125–33.PubMedCrossRef

17.

Engel E, Flexner JM, Engel-de Montmollin ML, Frank HE. Blood and skin chromosomal alterations of a clonal type in a leukemic man previously irradiated for a lung carcinoma. Cytogenetics. 1964;3:228–51.PubMedCrossRef

18.

Savage JRK, Bigger TRL. Aberration distribution and chromosomally marked clones in x-irradiated skin. In: Evans HJ, Lloyd DC, editors. Mutagen-Induced Chromosome Damage in Man. Edinburgh: Edinburgh University Press; 1978. p. 155–69.

19.

Rubin CM, Nesbit Jr ME, Kim TH, Kersey JH, Arthur DC. Chromosomal abnormalities in skin following total body or total lymphoid irradiation. Genes Chrom Cancer. 1992;4(2):141–5.PubMedCrossRef

20.

Bensinger WI. High-dose preparatory regimens. In: Appelbaum RF, Forman SJ, Negrin RS, Blume KG, editors. Thomas’ Hematopoietic Cell Transplantation. 4th ed. USA: Wiley-Blackwell NY; 2011. p. 316–32.

21.

Pruniéras M, Delescluse C, Regnier M. The culture of skin. A review of theories and experimental methods. J Invest Dermatol. 1976;67(1):58–65.PubMedCrossRef

22.

Tamm I, Kikuchi T, Wang E, Pfeffer LM. Growth rate of control and beta-interferon-treated human fibroblast populations over the course of their in vitro life span. Cancer Res. 1984;44(6):2291–6.PubMed

23.

Seabright M. A rapid banding technique for human chromosomes. Lancet. 1971;2(7731):971–2.PubMedCrossRef

24.

ISCN (2013): An International System for Human Cytogenetic Nomenclature. Edited by Shaffer LG, McGowan-Jordan J, Schmid M. Basel, S. Karger 2013

25.

Visfeldt J. Clone formation in tissue culture. Acta Pathol Microbiol Scand. 1966;68:305–12.PubMed

26.

Edwards AA, Savage JRK. Is there a simple answer to the origin of complex chromosome exchanges? Int J Radiat Biol. 1999;75(1):19–22.PubMedCrossRef

27.

Kano Y, Little JB. Site specific chromosomal rearrangements induced in human diploid cells by X irradiation. Cytogenet Cell Genet. 1986;41(1):22–9.PubMedCrossRef

28.

Morton NE. Parameters of the human genome. Proc Natl Acad Sci U S A. 1991;88:7474–6.PubMedPubMedCentralCrossRef

29.

Kronenberg A. Radiation-induced genomic instability. Int J Radiat Biol. 1994;66(5):603–9.PubMedCrossRef

30.

Lee CLY, Kamra OP. The pattern of radiation induced transmissible aberrations in a human cell culture. Hum Genet. 1981;57(4):380–4.PubMedCrossRef

31.

Johnson KL, Brenner DJ, Nath J, Tucker JD, Geard CR. Radiation-induced breakpoint misrejoining in human chromosomes: random or non-random? Int J Radiat Biol. 1999;75(2):131–41.PubMedCrossRef

32.

McKinlay Gardner RJ, Sutherland GR. Chromosome Instability Syndromes. In: Chromosome Abnormalities and Genetic Counseling. Oxford Monographs on Medical Genetics No. 46. 3rd ed. New York: Oxford University Press; 2004. p. 301–8.

33.

Taylor AM. Chromosome instability syndromes. Best Pract Res Clin Haematol. 2001;14(3):631–44.PubMedCrossRef

34.

Rümenapp C, Smida J, Gonzalez-Vasconcellos I, Baumhoer D, Malfoy B, Hadj-Hamou NS, et al. Secondary Radiation-Induced Bone Tumours Demonstrate a High Degree of Genomic Instability Predictive of a Poor Prognosis. Curr Genomics. 2012;13(6):433–7.PubMedPubMedCentralCrossRef

35.

Little JB. Radiation carcinogenesis. Carcinogenesis. 2000;21(3):397–404.PubMedCrossRef

36.

Grace J, Kim GJ, Fiskum GM, Morgan WF. A Role for Mitochondrial Dysfunction in Perpetuating Radiation-Induced Genomic Instability. Cancer Res. 2006;66(21):10377–83.CrossRef

Title: Frequent induction of chromosomal aberrations in in vivo skin fibroblasts after allogeneic stem cell transplantation: hints to chromosomal instability after irradiation
Authors: G. Massenkeil
P. Zschieschang
G. Thiel
P. G. Hemmati
V. Budach
B. Dörken
J. Pross
R. Arnold
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: Radiation Oncology / Issue 1/2015
Electronic ISSN: 1748-717X
DOI: https://doi.org/10.1186/s13014-015-0576-4

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

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

Abstract

Background

Method

Results

Conclusion

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Method

Results

Conclusion

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