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Genomic Analysis Reveals Few Genetic Alterations in Pediatric Acute Myeloid Leukemia

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Genomic Analysis Reveals Few Genetic Alterations in Pediatric Acute Myeloid Leukemia Genomic analysis reveals few genetic alterations in pediatric acute myeloid leukemia Ina Radtkea, Charles G. Mullighana, Masami Ishiia, Xiaoping Sua, Jinjun Chenga, Jing Mab, Ramapriya Gantia, Zhongling Caia, Salil Goorhaa, Stanley B. Poundsc, Xueyuan Caoc, Caroline Obertb, Jianling Armstrongb, Jinghui Zhangd, Guangchun Songa, Raul C. Ribeiroe, Jeffrey E. Rubnitze, Susana C. Raimondia, Sheila A. Shurtleffa, and James R. Downinga,1 Departments of aPathology, cBiostatistics, and eOncology, and the bHartwell Center for Bioinformatics and Biotechnology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105; and dCenter for Biomedical Informatics and Information Technology, National Cancer Institute, National Institutes of Health, 2115 E. Jefferson Street, Rockville, MD 20892 Edited by Janet D. Rowley, University of Chicago Medical Center, Chicago, IL, and approved June 11, 2009 (received for review March 20, 2009) Pediatric de novo acute myeloid leukemia (AML) is an aggressive disease with an inferior treatment outcome compared to ALL. malignancy with current therapy resulting in cure rates of only 60%. Despite the introduction of new drugs and allogeneic bone marrow To better understand the cause of the marked heterogeneity in transplantation, overall cure rates in most contemporary treatment therapeutic response and to identify new prognostic markers and protocols remain below 60% (10–12). therapeutic targets a comprehensive list of the genetic mutations that Like pediatric ALL, de novo AML is a heterogeneous disease underlie the pathogenesis of AML is needed. To approach this goal, composed of different genetic subtypes with distinct clinical fea- we examined diagnostic leukemic samples from a cohort of 111 tures and responses to contemporary therapies. The best charac- children with de novo AML using single-nucleotide-polymorphism terized subtypes include the core-binding factor leukemias microarrays and candidate gene resequencing. Our data demonstrate (t(8;21)[RUNX1(AML1)-RUNX1T1(ETO)] and inv(16)/ that, in contrast to pediatric acute lymphoblastic leukemia (ALL), de t(16;16)[CBF␤-MYH11]), cases with rearrangements of the MLL novo AML is characterized by a very low burden of genomic alter- gene on chromosome 11q23, cases with distinct morphology in- ations, with a mean of only 2.38 somatic copy-number alterations per cluding acute promyeloctic leukemia with t(15;17)[PML-RARA] leukemia, and less than 1 nonsynonymous point mutation per leu- and acute megakaryoblastic leukemia (FAB-M7), and cases with kemia in the 25 genes analyzed. Even more surprising was the normal cytogenetics. Although some cooperating lesions have been observation that 34% of the leukemias lacked any identifiable copy- identified in AMLs, including point mutations or CNAs of NRAS, number alterations, and 28% of the leukemias with recurrent trans- KRAS, FLT3, KIT, PTPN11, RUNX1, MLL, NPM1, CEBPA, and locations lacked any identifiable sequence or numerical abnormali- TP53 (13–17), the full complement of cooperating lesions remains ties. The only exception to the presence of few mutations was acute to be defined. The identification of the complete complement of megakaryocytic leukemias, with the majority of these leukemias genetic lesions within AML will not only improve our understand- being characterized by a high number of copy-number alterations but ing of the molecular pathology of acute leukemia, but should also rare point mutations. Despite the low overall number of lesions across directly impact diagnosis and risk stratification, and may lead to the the patient cohort, novel recurring regions of genetic alteration were identification of new targets against which novel therapies can be identified that harbor known, and potential new cancer genes. These developed. data reflect a remarkably low burden of genomic alterations within We report the results of a study of genome-wide DNA CNAs, pediatric de novo AML, which is in stark contrast to most other human LOH, and targeted gene resequencing analyses on primary leuke- malignancies. mic blasts from 111 pediatric AML patients. Our data demonstrate that, in contrast to pediatric ALL, de novo AML is characterized copy number alterations ͉ single-nucleotide-polymorphism (SNP) ͉ by a very low burden of genomic alterations. Despite the low microarray ͉ candidate gene resequencing ͉ loss-of-heterozygosity (LOH) number of lesions, however, unique recurring regions of genetic alteration were identified that harbor known, and potential new eukemia results from multiple genetic and epigenetic alterations cancer genes. Moreover, the spectrum of CNAs and sequence Lwithin hematopoietic stem cells (HSCs) or progenitors that alter mutations was found to vary significantly across the different their normal self-renewal, proliferation, differentiation, and apop- genetic subtypes of AML. totic pathways (1–3). These alterations include point mutations, Results gene rearrangements, deletions, amplifications, and a diverse array of epigenetic changes that influence gene expression. For most AML Leukemic Cells Contain Few Copy-Number Alterations. As an initial leukemias the full complement of oncogenic lesions remains to be approach to define the total complement of genetic lesions in defined. pediatric de novo AML, we performed high resolution genome- To define the lesions in acute leukemia, we recently used wide analysis on leukemic blasts from diagnostic bone marrow single-nucleotide-polymorphism (SNP) microarrays to perform aspirates from 111 patients using both Affymetrix 100K and 500K genome-wide DNA copy-number and loss-of-heterozygosity SNP microarrays (combined resolution of 615K). The leukemias (LOH) analyses on primary leukemic blasts from pediatric patients with acute lymphoblastic leukemia (ALL) (4, 5). These studies Author contributions: I.R., C.G.M., S.A.S., and J.R.D. designed research; I.R., C.G.M., M.I., identified a high frequency of genetic alterations of key regulators X.S., J.C., R.G., Z.C., S.G., J.A., and S.C.R. performed research; X.S., S.B.P., and J.Z. contributed of B lymphoid development and cell cycle in B-progenitor ALL. new reagents/analytic tools; I.R., C.G.M., M.I., X.S., J.C., J.M., S.G., S.B.P., X.C., C.O., J.Z., G.S., More recently, similar approaches have been used to explore the R.C.R., J.E.R., S.C.R., and S.A.S. analyzed data; and I.R. and J.R.D. wrote the paper. type of copy-number alterations (CNAs) in adult myeloid malig- The authors declare no conflict of interest. nancies (6–9), although these studies have used relatively low This article is a PNAS Direct Submission. resolution platforms. Freely available online through the PNAS open access option. We have now extended these analyses to pediatric de novo acute 1To whom correspondence should be addressed. E-mail: [email protected]. myeloid leukemia (AML). AML comprises 15–20% of the acute This article contains supporting information online at www.pnas.org/cgi/content/full/ leukemias diagnosed in this age group and remains a challenging 0903142106/DCSupplemental. 12944–12949 ͉ PNAS ͉ August 4, 2009 ͉ vol. 106 ͉ no. 31 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0903142106 Downloaded by guest on September 30, 2021 A t(8;21) inv(16) MLL t(15;17) M7 Miscellaneous Normal 1 2 3 4 5 6 7 8 9 10 11 SNPs by chromosome 12 13 14 15-16 17-19 20-22 X patients -2 0 +2 log2ratio B Amplifications C Deletions Deletions 3 genes 4 genes 22 genes RUNX1T1 CCDC26 12 genes (*CDKN2A) TUSC1 13 genes (*XPA) 7 genes 4 genes (*MLL) 31 genes ABCC4 5 genes (*MYH11) 88 genes 17 genes (*CBFB) 81 genes No gene (*ERG, *TMPRSS2) 410 genes -0.85 -1.1 -1.6 -2.6 -4.7 -8.8 10 10 10 10 10 10 10-0.810-110-1.4 10-2.2 10-3.8 10-7 0.25 False Discovery Rate 0.25 False Discovery Rate Fig. 1. DNA copy-number abnormalities in pediatric de novo AML. (A) Summary of CNA (log2 ratio) from a combined 100K and 500K Affymetrix SNP array analysis of diagnostic leukemia cells from 111 pediatric de novo AML patients. Each column represents a case and the 615K SNPs are arranged in rows according to chromosomal location. Cases are arranged by subgroup. Diploid regions are white. Blue represents deletion, red amplification (see color scale). Gross changes can be observed for example in chromosome 8 (10 cases with trisomy 8). (B) GISTIC (18) analysis of copy-number gains. (C) GISTIC analysis of copy-number losses. False discovery rate q values are plotted along the x axis with chromosomal position along the y axis. Altered regions with significance levels exceeding 0.25 (marked by vertical green line) are deemed significant. Five significant regions of amplification and 13 significant regions of deletion were identified. Chromosomal position and relevant genes are shown for each significant region on the right side of the plots. Genes indicated in blue are associated with known translocations, genes marked with * are cancer census genes (19). included a representation of the different genetic subtypes of the Gene Targets of Recurrent Copy-Number Alterations. Recurrent CNAs pediatric de novo AML (in SI Appendix, Tables S1 and S2). Germ within a patient cohort can be used to identify alterations of line DNA was available for 65 of the patients allowing a definitive potential biological significance (driver versus passenger muta- identification of somatically acquired CNAs. Two-hundred seven tions). Surprisingly, when large regions (whole chromosomes or CNAs were detected across the cohort with a mean number of chromosome arms) of gains or losses were excluded the majority of CNAs/patient of 2.38 (range 0–45), with no significant difference the remaining lesions were nonrecurrent, being identified in only a in the average number of gains (1.32, range 0–41) and losses (1.06, single patient (SI Appendix, Table S2). Using the genomic identi- range 0–12) (Fig.
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