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Acquired Copy Number Alterations in Adult Acute Myeloid Leukemia Genomes

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Acquired Copy Number Alterations in Adult Acute Myeloid Leukemia Genomes Acquired copy number alterations in adult acute myeloid leukemia genomes Matthew J. Waltera,b,c,1,2, Jacqueline E. Paytond,1, Rhonda E. Riesa,b,1, William D. Shannona, Hrishikesh Deshmukhd, Yu Zhaoa,b, Jack Batye, Sharon Heatha,b, Peter Westervelta,b,c, Mark A. Watsonc,d, Michael H. Tomassona,b,c, Rakesh Nagarajanc,d, Brian P. O’Garaa,b, Clara D. Bloomfieldf,g, Krzysztof Mro´ zekf,g, Rebecca R. Selzerh, Todd A. Richmondh, Jacob Kitzmanh, Joel Geogheganh, Peggy S. Eish, Rachel Maupini, Robert S. Fultoni, Michael McLellani, Richard K. Wilsoni, Elaine R. Mardisi, Daniel C. Linka,b,c, Timothy A. Grauberta,b,c, John F. DiPersioa,b,c, and Timothy J. Leya,b,c aDepartment of Medicine, bDivision of Oncology, cSiteman Cancer Center, dDepartment of Pathology and Immunology, and eDivision of Biostatistics, Washington University School of Medicine, St. Louis, MO 63110; fDivision of Hematology and Oncology, Department of Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210; gCancer and Leukemia Group B, Chicago, IL 60601; and hRoche NimbleGen, Inc., Madison, WI 53719; and iThe Genome Center, Washington University School of Medicine, St. Louis, MO 63110 Edited by Janet D. Rowley, University of Chicago Medical Center, Chicago, IL, and approved May 18, 2009 (received for review March 23, 2009) Cytogenetic analysis of acute myeloid leukemia (AML) cells has (CNAs) and UPD are common in AML genomes (6–12). However, accelerated the identification of genes important for AML patho- these studies used low-resolution arrays, often used reference DNA genesis. To complement cytogenetic studies and to identify genes that was not obtained from the same patient’s normal cells, and did altered in AML genomes, we performed genome-wide copy num- not routinely validate copy number changes with independent ber analysis with paired normal and tumor DNA obtained from 86 platforms. These limitations made it difficult to distinguish between adult patients with de novo AML using 1.85 million feature SNP acquired (somatic) CNA and inherited copy number variants arrays. Acquired copy number alterations (CNAs) were confirmed (CNVs) that exist in all individuals; furthermore, secondary vali- using an ultra-dense array comparative genomic hybridization dation methods are required to distinguish between true events and platform. A total of 201 somatic CNAs were found in the 86 AML false-positive findings, which are extremely common using the genomes (mean, 2.34 CNAs per genome), with French-American- current platforms. To overcome these limitations and to definitively British system M6 and M7 genomes containing the most changes identify genes that are somatically altered in AML genomes, we (10–29 CNAs per genome). Twenty-four percent of AML patients used the Affymetrix Genome-Wide Human SNP Array 6.0 plat- with normal cytogenetics had CNA, whereas 40% of patients with form (containing 1.85 million probes, median interprobe spacing an abnormal karyotype had additional CNA detected by SNP array, 680 bp) to screen paired tumor and normal DNA samples obtained and several CNA regions were recurrent. The mRNA expression from 86 adult patients with de novo AML, and validated putative levels of 57 genes were significantly altered in 27 of 50 recurrent CNA using an independent, ultra-dense custom Roche NimbleGen CNA regions <5 megabases in size. A total of 8 uniparental disomy CGH 12 ϫ 135K array (median interprobe spacing 245 bp). We (UPD) segments were identified in the 86 genomes; 6 of 8 UPD calls identified a mean of 2.34 CNAs per genome, and 76% of the CNAs occurred in samples with a normal karyotype. Collectively, 34 of 86 involved a known cancer-related gene. We identified 50 recurrent AML genomes (40%) contained alterations not found with cyto- CNAs Ͻ5 megabases (Mb) in size in the 86 genomes, and 32 of genetics, and 98% of these regions contained genes. Of 86 ge- these 50 regions contained genes not previously implicated in AML. nomes, 43 (50%) had no CNA or UPD at this level of resolution. In UPD was more common in normal karyotype samples. Fifty this study of 86 adult AML genomes, the use of an unbiased percent of the AML genomes tested in this study had no detectable high-resolution genomic screen identified many genes not previ- CNAs or UPD, indicating that other approaches, including whole- ously implicated in AML that may be relevant for pathogenesis, genome sequencing, may be required to discover the remaining along with many known oncogenes and tumor suppressor genes. genetic changes that contribute to AML pathogenesis. AML ͉ array CGH ͉ genomics ͉ SNP array Results Patient Characteristics. A total of 86 adult patients (aged Ͼ18 years) cute myeloid leukemia (AML) is a heterogeneous group of with de novo AML were chosen for study on the basis of the Adiseases currently classified by abnormalities in bone mar- availability of high-quality, abundant, paired bone marrow (tumor) row morphology, karyotype, acquired gene mutations, and al- and skin (normal) DNA samples. Paired samples allowed us to terations in gene expression (1–3). Although the identification of distinguish acquired CNA from inherited CNV. Cases were clas- specific gene mutations has resulted in improved treatments and sified in accordance with the French-American-British (FAB) outcomes for some AML patients (4), enormous clinical heter- system upon diagnosis and banking of their bone marrow speci- ogeneity exists and may reflect the presence of as-yet undetected initiating and cooperating mutations. Therefore, the discovery of somatic mutations in the genomes of AML patients with Author contributions: M.J.W., J.E.P., R.E.R., and T.J.L. designed research; M.J.W., J.E.P., normal and abnormal karyotypes will advance our understand- R.E.R., R.R.S., T.A.R., J.K., J.G., P.S.E., R.M., R.S.F., and M.M. performed research; R.R.S., ing of the genetics underlying AML and should lead to more T.A.R., J.K., J.G., P.S.E., R.M., R.S.F., and M.M. contributed new reagents/analytic tools; M.J.W., J.E.P., R.E.R., W.D.S., H.D., Y.Z., J.B., S.H., P.W., M.A.W., M.H.T., R.N., B.P.O., C.D.B., specific therapies and better patient classification schemes. K.M., R.R.S., T.A.R., J.K., J.G., P.S.E., R.M., R.S.F., M.M., R.K.W., E.R.M., D.C.L., T.A.G., J.F.D., The discovery of previously uncharacterized genes mutated in and T.J.L. analyzed data; and M.J.W., J.E.P., R.E.R., and T.J.L. wrote the paper. acute lymphoblastic leukemia (ALL) was recently reported using Conflict of interest: R.R.S., T.A.R., J.G., and J.K. are employees of Roche NimbleGen, Inc., which SNP array technology for DNA copy number analysis (5). SNP supplied the arrays and hybridization services for the research. array platforms can detect genomic amplifications, deletions, SNP Freely available online through the PNAS open access option. loss of heterozygosity (LOH), and regions of uniparental disomy 1M.J.W., J.E.P., and R.E.R. contributed equally to this work. (UPD) (copy-neutral LOH events) in cancer cells. Early studies 2To whom correspondence should be addressed. E-mail: [email protected]. using SNP arrays and array comparative genomic hybridization This article contains supporting information online at www.pnas.org/cgi/content/full/ (CGH) platforms have suggested that both copy number alterations 0903091106/DCSupplemental. 12950–12955 ͉ PNAS ͉ August 4, 2009 ͉ vol. 106 ͉ no. 31 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0903091106 Downloaded by guest on September 23, 2021 Fig. 1. Copy number and UPD heatmap for 86 AML genomes. The results of copy number and UPD (copy-neutral LOH) analysis of 86 paired tumor and normal DNA samples assayed on the Affymetrix Genome-Wide SNP 6.0 arrays are shown. For each of the 86 genomes, each genome is represented by 2 columns, copy number as the log2 ratio of tumor/normal DNA is shown on the left and UPD on the right. Copy number is designated by a color range from white (deletion) to red (amplification), with pink indicating a normal copy number. The presence of UPD is shown in blue and the normal non-UPD state in gray. The y axis represents the chromosome number, with chromosome 1 at the top and Y on the bottom. The x axis displays samples grouped by common cytogenetic abnormalities. The patient number labels correspond to the patient numbers in Table S1. See Table S2 for a complete listing of miscellaneous cytogenetics. mens. The patients include FAB M0–M7, with a median blast count CNAs that were not independently assessed on the custom array of 64% (range, 30–100%) [supporting information (SI) Table S1 CGH platform had a minimum size of 300 kb and involved at least and Table S2]. 100 probes. All putative CNAs Ͼ200 kb in size that were detected on the SNP array were validated on the custom array CGH platform Acquired CNA. We identified 201 acquired CNAs in the 86 AML (see SI Results and Fig. S1 for a complete description). genomes using the SNP arrays (Fig. 1 and Table S1 and Table S2). Of the 201 CNAs, 198 (99%) contained known genes, and 154 of The 201 CNAs occurred in 38 of 86 AML genomes, spanned from 201 loci (77%) contained at least 1 gene that had previously been associated with cancer- or AML/myelodysplastic syndromes (MDS) 35 kb (34 probes) to 250 Mb (146,524 probes) in size (median, 9.15 Ͻ Mb), and involved every chromosome at least once.
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