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. 2009 Aug 4;106(31):12950-5.
doi: 10.1073/pnas.0903091106. Epub 2009 Jul 27.

Acquired copy number alterations in adult acute myeloid leukemia genomes

Matthew J Walter  1 , Jacqueline E Payton, Rhonda E Ries, William D Shannon, Hrishikesh Deshmukh, Yu Zhao, Jack Baty, Sharon Heath, Peter Westervelt, Mark A Watson, Michael H Tomasson, Rakesh Nagarajan, Brian P O'Gara, Clara D Bloomfield, Krzysztof Mrózek, Rebecca R Selzer, Todd A Richmond, Jacob Kitzman, Joel Geoghegan, Peggy S Eis, Rachel Maupin, Robert S Fulton, Michael McLellan, Richard K Wilson, Elaine R Mardis, Daniel C Link, Timothy A Graubert, John F DiPersio, Timothy J Ley
Affiliations

Acquired copy number alterations in adult acute myeloid leukemia genomes

Matthew J Walter et al. Proc Natl Acad Sci U S A. .

Abstract

Cytogenetic analysis of acute myeloid leukemia (AML) cells has accelerated the identification of genes important for AML pathogenesis. To complement cytogenetic studies and to identify genes altered in AML genomes, we performed genome-wide copy number analysis with paired normal and tumor DNA obtained from 86 adult patients with de novo AML using 1.85 million feature SNP arrays. Acquired copy number alterations (CNAs) were confirmed using an ultra-dense array comparative genomic hybridization platform. A total of 201 somatic CNAs were found in the 86 AML genomes (mean, 2.34 CNAs per genome), with French-American-British system M6 and M7 genomes containing the most changes (10-29 CNAs per genome). Twenty-four percent of AML patients with normal cytogenetics had CNA, whereas 40% of patients with an abnormal karyotype had additional CNA detected by SNP array, and several CNA regions were recurrent. The mRNA expression levels of 57 genes were significantly altered in 27 of 50 recurrent CNA regions <5 megabases in size. A total of 8 uniparental disomy (UPD) segments were identified in the 86 genomes; 6 of 8 UPD calls occurred in samples with a normal karyotype. Collectively, 34 of 86 AML genomes (40%) contained alterations not found with cytogenetics, and 98% of these regions contained genes. Of 86 genomes, 43 (50%) had no CNA or UPD at this level of resolution. In this study of 86 adult AML genomes, the use of an unbiased high-resolution genomic screen identified many genes not previously implicated in AML that may be relevant for pathogenesis, along with many known oncogenes and tumor suppressor genes.

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Conflict of interest statement

Conflict of interest: R.R.S., T.A.R., J.G., and J.K. are employees of Roche NimbleGen, Inc., which supplied the arrays and hybridization services for the research.

Figures

Fig. 1.
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.
Fig. 2.
Fig. 2.
CNAs (deletions and amplifications) include 1 or more genes and demonstrate significant regions of recurrence. Log2 ratio dot plots of paired tumor and normal DNA samples from the same patient were generated from data obtained from the Affymetrix Genome-Wide SNP 6.0 arrays (top plot of each panel) and custom NimbleGen CGH 12 × 135K array data (bottom plot of each panel). Solid horizontal lines indicate gene locations with selected gene names provided. The y axis is the log2 ratio of paired tumor/normal DNA, and the x axis represents the chromosomal megabase position for both array platforms. (A) Deletion of a 1.9-Mb region of chromosome 17, including the NF1 gene. (B) Deletion of a 57-kb region of chromosome X, including the STAG2 gene. (C) Partial tandem duplication of a 35.6-kb region of MLL on chromosome 11. (D) GISTIC analysis of genomic regions of deletion. Chromosome positions are indicated along the y axis and the false-discovery rate q values on the x axis, with the significance threshold indicated by the green line at 0.25. Deletion regions that surpass the significance threshold include chromosomes 3p14.1, 5q31.1, 7q31.31, 12p12.3, 16q22.1, 17p13.1, 17q11.2, and 18p11.31. (E) GISTIC analysis of genomic regions of amplification. Amplification regions that surpass the significance threshold include chromosomes 8q23.2, 11q23.3, 19q13.43, and 21q22.2.
Fig. 3.
Fig. 3.
Summary of genetic alterations in AML genomes. Pie chart demonstrates the relative proportions of AML samples with an abnormal (red, n = 50) and normal (white, n = 36) karyotype, with (+) and without (-) CNA and UPD detected by SNP arrays. (Two patients with failed cytogenetics are included with the normal karyotype data: UPN 295 had no CNAs or UPD detected by SNP arrays, and UPN 327929 had 22 CNAs detected.) The number of patients in each group is listed in parentheses. Of 36 patients with a normal karyotype (including the 2 patients with failed cytogenetics), 13 (36%) had a CNA or UPD (identified as SNP Array Specific CNA or UPD). Of 50 patients with an abnormal karyotype, 21 (42%) had an SNP array-specific CNA (not seen by cytogenetics) or UPD detected by SNP arrays (identified as SNP Array Specific CNA or UPD). Forty-three of 86 patients (50%) had no CNA or UPD detected by SNP arrays.
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