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Journal of Clinical Oncology, Vol 25, No 9 (March 20), 2007: pp. 1151-1152 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.3013
Neurofibromatosis 1, and Not TP53, Seems to Be the Main Target of Chromosome 17 Deletions in De Novo Acute Myeloid LeukemiaMolecular Cytogenetics Group, Centro Nacional Investigaciones Oncológicas, Madrid, Spain
Endrocrine Cancer Group, Centro Nacional Investigaciones Oncológicas, Madrid, Spain
Centro Nacional de Genotipado, Centro Nacional Investigaciones Oncológicas, Madrid, Spain
Department of Genetics, University of Navarra, Navarra, Spain
Molecular Cytogenetics Group, Centro Nacional Investigaciones Oncológicas, Madrid, Spain To the Editor: We read with great interest the article by Rucker et al1 about array comparative genomic hybridization (CGH) profiling on acute myeloid leukemia (AML) complex karyotype patients, which included therapy-related, post-myelodysplastic syndrome, and de novo AML samples. Among the pattern of most frequent aberrations, they found that a discrete loss at 17p13, which contains the TP53 gene, is one of the most recurrent deletions in these patients (55% of recurrence). They also described another deleted region in chromosome 17 (6.4 Mb) that is located around the centromeric area (17p11 to 17q11) and contains the neurofibromatosis 1 (NF1) gene. They found this second deletion in 18 samples. Interestingly, in 17 of these18 patients, this deletion was concomitant with the loss of the TP53 region. Only in one patient the deletion encompassed NF1 without involving TP53. Among a series of 120 de novo AML, on which we have conducted DNA profiling analysis using a high density oligonucleotide-based array CGH (more than 44,000 probes) from Agilent Technologies (Santa Clara, CA),2 we detected seven patients of AML that showed DNA copy number aberrations involving chromosome 17 (Table 1). Aberrations in chromosome 17 were cryptic deletions affecting the regions 17p13.1 (including TP53 gene) or 17q11.2 (including NF1 gene). We observed that all our seven samples displayed losses involving NF1, but in contrast with the data reported by Rucker et al,1 only two of them showed concomitant loss of TP53 (both patients also displayed complex karyotype). We validated the array data with fluorescence in situ hybridization (FISH) assays. The TP53 FISH probe was commercial (LSI p53, Vysis, Abbott Molecular Inc, Des Plaines, IL) and the NF1 FISH probe was prepared from BAC clone RP11-518B17 (CHORI Collection, Oakland, CA). In all samples, FISH data confirmed array CGH copy number values.
Two more approaches were used to better characterize the genomic and genetic features of the rearranged chromosome 17. The presence of loss of hetorozigosity (LOH) was studied with the Illumina Infinium 300K SNP platform (Illumina Inc, San Diego, CA).3 This genomic platform, in addition to detect LOH in a chromosome region that is deleted due to an actual genetic loss, allows the detection of uniparental isodisomy (UPiD) LOH regions without actual loss of genetic material. In AML, UPiD LOH has been shown to be associated with mutations in relevant oncogenes (ie, CEBPA) located within the affected region.4 Only patient 2 showed LOH affecting the TP53 genomic region. Finally, TP53 mutation analysis was performed by complete sequencing of exons 4 to 9 in all patients (ABI PRISM 310 Genetic Analyzer [Applied Biosystems, Foster City, CA]). Patients 3 and 4 harbored mutations in exons 8 and 9, respectively. Patient 3 had lost the wild-type allele of TP53 and patient 4 was heterozygous for the mutation. In conclusion, we confirmed the existence of recurrent cryptic deletions in the area of 17q11.2, targeting the gene NF1, as suggested previously by Rucker et al.1 By using a high density array CGH, the minimum deleted region in 17q11 was reduced down to approximately 1.5 Mb. Although previous reports described that deletions of 17q11.2 were tightly associated with deletions in 17p13.1, including the TP53 gene, we report here that less than 50% of our de novo AML samples with deletions in 17q11.2 showed either deletion or UPiD LOH among the TP53 locus (none of the noncomplex patients and three of the five complex karyotype patients). Only one patient with deletion or UPiD in TP53 showed mutations in the gene, suggesting that TP53 may not be the principal target in de novo AML, although its role has been demonstrated to be more relevant in secondary AML.5,6 Therefore, we think our genetic data support the proposed role of NF1 as the main target in rearrangements of chromosome 17 in de novo AML, based on previous reports, which set NF1 as a leukemogenic agent when mutated or haploinsufficient.7,8 AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The authors indicated no potential conflicts of interest.
ACKNOWLEDGMENTS Financial support from Grants No. PI 040555 and G03/136 from the Ministerio de Sanidad y Consumo to JCC. We thank Fatima Mercadillo and Emilio A. González for their technical assistance. REFERENCES
1. Rücker FG, Bullinger L, Schwaenen C, et al: Disclosure of candidate genes in acute myeloid leukemia with complex karyotypes using microarray-based molecular characterization. J Clin Oncol 24:3887-3894, 2006 2. Barrett MT, Scheffer A, Ben-Dor A, et al: Comparative genomic hybridization using oligonucleotide microarrays and total genomic DNA. Proc Natl Acad Sci U S A 101:17765-17770, 2004 3. Peiffer DA, Le JM, Steemers FJ, et al: High-resolution genomic profiling of chromosomal aberrations using Infinium whole-genome genotyping. Genome Res 16:1136-1148, 2006 4. Raghavan M, Lillington DM, Skoulakis S, et al: Genome-wide single nucleotide polymorphism analysis reveals frequent partial uniparental disomy due to somatic recombination in acute myeloid leukemias. Cancer Res 65:375-378, 2005 5. Christiansen DH, Andersen MK, 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. J Clin Oncol 19:1405-1413, 2001 6. Herzog G, Lu-Hesselmann J, Zimmermann Y, et al: Microsatellite instability and p53 mutations are characteristic of subgroups of acute myeloid leukemia but independent events. Haematologica 90:693-695, 2005 7. Stephens K, Weaver M, Leppig KA, et al: Interstitial uniparental isodisomy at clustered breakpoint intervals is a frequent mechanism of NF1 inactivation in myeloid malignancies. Blood 108:1684-1689, 2006 8. Birnbaum RA, O'Marcaigh A, Wardak Z, et al: NF1 and GMCSF interact in myeloid leukemogenesis. Mol Cell 5:189-195, 2000[CrossRef][Medline]
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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