This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Christiansen, D. H. Articles by Pedersen-Bjergaard, J. Search for Related Content PubMed PubMed Citation Articles by Christiansen, D. H. Articles by Pedersen-Bjergaard, J.

Mutations With Loss of Heterozygosity of p53 Are Common in Therapy-Related Myelodysplasia and Acute Myeloid Leukemia After Exposure to Alkylating Agents and Significantly Associated With Deletion or Loss of 5q, a Complex Karyotype, and a Poor Prognosis

From the Section of Hematology and Oncology, Cytogenetic Laboratory, and Department of Clinical Genetics, The Juliane Marie Center, Rigshospitalet, Copenhagen, Denmark.

Address reprint request to Debes H. Christiansen, MS, Section of Hematology/Oncology, Department of Clinical Genetics, Section 4052, The Juliane Marie Center, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark; email: Debes{at}rh.dk

PURPOSE: To study mutations and loss of heterozygosity (LOH) of p53 in therapy-related myelodysplasia (t-MDS) and acute myeloid leukemia (t-AML).

PATIENTS AND METHODS: Fifty-two unselected patients with t-MDS and 25 patients with t-AML were studied by polymerase chain reaction (PCR)–single-strand conformational polymorphism (SSCP) at the DNA level and by reverse transcriptase (RT)-PCR–SSCP at the mRNA level, and cases with aberrant SSCP patterns were sequenced.

RESULTS: Somatically acquired mutations of p53 were observed in 21 of 77 cases of t-MDS or t-AML, and 19 of these 21 patients had received alkylating agents. Single-base substitutions at A:T pairs were more common in t-MDS and t-AML, whereas single-base substitutions at G:C pairs are most common in MDS and AML de novo and in solid tumors. Six patients demonstrated a cytogenetic loss of 17p13, and these six and an additional nine patients with p53 mutations demonstrated LOH of p53 at the DNA or mRNA level. This suggests a cytogenetic loss of the normal p53 allele in these nine cases combined with duplication of the homologous chromosome 17 carrying the mutated p53 allele. Mutations of p53 were significantly associated with deletion or loss of 5q (P < .0001) and a complex karyotype (P = .0001), but surprisingly were not associated with deletion or loss of 7q (P = .73), and were infrequent in patients with balanced chromosome translocations (P = .03). Mutations of p53 were more common in older patients (P = .036) and were associated with an extremely poor prognosis (P = .014), apparently restricted to the 15 cases with LOH of p53 ( P = .046).

CONCLUSION: Mutations with loss of function of p53 are significantly associated with deletion or loss of 5q in t-MDS and t-AML after previous treatment with alkylating agents and are associated with genetic instability.

This article has been cited by other articles:

				J. M. Joslin, A. A. Fernald, T. R. Tennant, E. M. Davis, S. C. Kogan, J. Anastasi, J. D. Crispino, and M. M. Le Beau Haploinsufficiency of EGR1, a candidate gene in the del(5q), leads to the development of myeloid disorders Blood, July 15, 2007; 110(2): 719 - 726. [Abstract] [Full Text] [PDF]

				J. Suela, C. Largo, B. Ferreira, S. Alvarez, M. Robledo, A. Gonzalez-Neira, M. J. Calasanz, and J. C. Cigudosa Neurofibromatosis 1, and Not TP53, Seems to Be the Main Target of Chromosome 17 Deletions in De Novo Acute Myeloid Leukemia J. Clin. Oncol., March 20, 2007; 25(9): 1151 - 1152. [Full Text] [PDF]

				J. Pedersen-Bjergaard, M. T. Andersen, and M. K. Andersen Genetic Pathways in the Pathogenesis of Therapy-Related Myelodysplasia and Acute Myeloid Leukemia Hematology, January 1, 2007; 2007(1): 392 - 397. [Abstract] [Full Text] [PDF]

				F. R. Appelbaum, H. Gundacker, D. R. Head, M. L. Slovak, C. L. Willman, J. E. Godwin, J. E. Anderson, and S. H. Petersdorf Age and acute myeloid leukemia Blood, May 1, 2006; 107(9): 3481 - 3485. [Abstract] [Full Text] [PDF]

				D. H. Christiansen, M. K. Andersen, and J. Pedersen-Bjergaard Mutations of AML1 are common in therapy-related myelodysplasia following therapy with alkylating agents and are significantly associated with deletion or loss of chromosome arm 7q and with subsequent leukemic transformation Blood, September 1, 2004; 104(5): 1474 - 1481. [Abstract] [Full Text] [PDF]

				W. J. Bodell, N. W. Gaikwad, D. Miller, and M. S. Berger Formation of DNA Adducts and Induction of lacI Mutations in Big Blue Rat-2 Cells Treated with Temozolomide: Implications for the Treatment of Low-Grade Adult and Pediatric Brain Tumors Cancer Epidemiol. Biomarkers Prev., June 1, 2003; 12(6): 545 - 551. [Abstract] [Full Text] [PDF]

				D. T. Bowen, M. E. Frew, S. Rollinson, P. L. Roddam, A. Dring, M. T. Smith, S. E. Langabeer, and G. J. Morgan CYP1A1*2B (Val) allele is overrepresented in a subgroup of acute myeloid leukemia patients with poor-risk karyotype associated with NRAS mutation, but not associated with FLT3 internal tandem duplication Blood, April 1, 2003; 101(7): 2770 - 2774. [Abstract] [Full Text] [PDF]

				H. Harada, Y. Harada, H. Tanaka, A. Kimura, and T. Inaba Implications of somatic mutations in the AML1 gene in radiation-associated and therapy-related myelodysplastic syndrome/acute myeloid leukemia Blood, January 15, 2003; 101(2): 673 - 680. [Abstract] [Full Text] [PDF]

				J.-i. Okutsu, T. Tsunoda, Y. Kaneta, T. Katagiri, O. Kitahara, H. Zembutsu, R. Yanagawa, S. Miyawaki, K. Kuriyama, N. Kubota, et al. Prediction of Chemosensitivity for Patients with Acute Myeloid Leukemia, According to Expression Levels of 28 Genes Selected by Genome-wide Complementary DNA Microarray Analysis, Mol. Cancer Ther., October 1, 2002; 1(12): 1035 - 1042. [Abstract] [Full Text] [PDF]

				D. G. B. Leonard, L. B. Travis, K. Addya, G. M. Dores, E. J. Holowaty, K. Bergfeldt, D. Malkin, B. A. Kohler, C. F. Lynch, T. Wiklund, et al. p53 Mutations in Leukemia and Myelodysplastic Syndrome after Ovarian Cancer Clin. Cancer Res., May 1, 2002; 8(5): 973 - 985. [Abstract] [Full Text] [PDF]

				J. Pedersen-Bjergaard, M. K. Andersen, D. H. Christiansen, and C. Nerlov Genetic pathways in therapy-related myelodysplasia and acute myeloid leukemia Blood, March 15, 2002; 99(6): 1909 - 1912. [Abstract] [Full Text] [PDF]

				D. A. Sweetser, C.-S. Chen, A. A. Blomberg, D. A. Flowers, P. C. Galipeau, M. T. Barrett, N. A. Heerema, J. Buckley, W. G. Woods, I. D. Bernstein, et al. Loss of heterozygosity in childhood de novo acute myelogenous leukemia Blood, August 15, 2001; 98(4): 1188 - 1194. [Abstract] [Full Text] [PDF]