Acquired copy number alterations in adult acute myeloid leukemia genomes

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-AmericanBritish 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. AML ͉ array CGH ͉ genomics ͉ SNP arrayA cute myeloid leukemia (AML) is a heterogeneous group of diseases currently classified by abnormalities in bone marrow morphology, karyotype, acquired gene mutations, and alterations in gene expression (1-3). Although the identification of specific gene mutations has resulted in improved treatments and outcomes for some AML patients (4), enormous clinical heterogeneity 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 normal and abnormal karyotypes will advance our understanding of the genetics underlying AML and should lead to more specific therapies and better patient classification schemes.The discovery of previously uncharacterized genes mutated in acute lymphoblastic leukemia (ALL) was recently reported using SNP array technology for DNA copy number analysis (5). SNP array platforms can detect genomic amplifications, deletions, SNP loss of heterozygosity (LOH), and regions of uniparental disomy (UPD) (copy-neutral LOH events) in cancer cells. Early studies using SNP arrays and array comparative genomic hybridization (CGH) platforms have suggested that both copy number alterations (CNAs) and UPD are common in AML genomes (6-12). However, these studies used low-resolution arrays, often used reference DNA that was not obtained from the same patient's n...

Neurofibromatosis‐1 gene deletions and mutations in de novo adult acute myeloid leukemia

“…Novel high-resolution approaches such as array-based comparative genomic hybridization (aCGH) have also been used to determine copy number (CN) alterations in AML, and candidate genes have been proposed [4,5]. Among them, heterozygous somatic deletions of the 17q11.2 region within neurofibromatosis-1 (NF1) gene have been reported in adult myeloid malignancies [6][7][8][9].…”

Genome-wide arrays in routine diagnostics of hematological malignancies

“…Recent array studies revealed acquired CNAs and regions of CNLOH that had an added independent prognostic impact on AML survival. In addition, regions of CNLOH were more often detected in patients with normal karyotypes than in aberrant karyotypes [Parkin et al, 2011;Tiu et al, 2009;Walter et al, 2009]. Furthermore, molecular karyotyping using genomic arrays has identified CNAs that are specifically detected in therapy-related AML, whereas other genomic alterations seem specific to primary AML [Itzhar et al, 2011].…”

“…The genomic CNAs identified in AML are not as common or recurrent as observed in ALL [Walter et al, 2009], but they do show, to some extent, overlap with anomalies found in MDS [Flach et al, 2011]. Interestingly, two recent studies have performed highresolution array analysis on matched, paired normal, and leukemic samples of both MDS and AML patients, determining true somatic CNAs in genomic regions where frequently benign constitutional CNVs are identified in normal control individuals [Barresi et al, 2010;Starczynowski et al, 2011].…”

Is CCDC26 a Novel Cancer-Associated Long-Chain Non-Coding RNA?

“…Genetic alterations are often observed in AML cells and the clinical heterogeneity of the disease is considered to reflect the genetic diversity of these cells (27,28). It is very important to study the genetic mutations in AML cells to fully understand the cause of the disease.…”