Acquired Copy Number Alterations in Adult Acute Myeloid Leukemia Genomes

We performed genome-wide copy number analysis with paired normal and tumor DNA obtained from 86 adult patients with de novo AML using the Affymetrix Genome-Wide Human SNP array 6.0 containing 1.85 million features. Acquired copy number alterations (CNA) were confirmed using an independent, higher resolution, custom array comparative genomic hybridization platform.

A total of 201 somatic CNA were found in the 86 AML genomes (mean 2.34 CNA/genome), with FAB M6 and M7 AML genomes containing the most changes (10-29 CNA/genome). Twenty-four percent of AML patients with normal cytogenetics had CNA, while 40% of patients with an abnormal karyotype had additional CNA detected by SNP array, and several regions contained CNA in multiple AML genomes. The mRNA expression levels of 57 genes were significantly altered in 27 of 50 recurrent CNA regions <5 megabases in size. Array data are available online at http://www.ncbi.nlm.nih.gov/geo/ as GEO accession #GSE10358. A total of 8 uniparental disomy (UPD) segments were identified in the 86 genomes and 6/8 UPD regions occurred in samples with a normal karyotype. Collectively, 40% of AML genomes contained alterations not found with cytogenetics, and 96% of these regions contained known or novel AML associated genes. 43/86 AML genomes had no CNA or UPD at this level of resolution. The number of CNA per genome was not associated with overall survival, independent of cytogenetic classification.

In this study of 86 adult AML genomes, subcytogenetic CNAs or UPD did not add prognostic information to standard cytogenetics. However, arrays identified many somatically mutated oncogenes and tumor suppressor genes, and also genes not previously implicated in AML that may be relevant for pathogenesis.

AML CNA segments from 86 adult AML patients are available through dbVar at ftp://ftp.ncbi.nlm.nih.gov/pub/dbVar/data/Homo_sapiens/nstd11_Walter_et_al_2009.

• Study Design:
  • Tumor vs. Matched-Normal
• Study Type:
  • Tumor vs. Matched-Normal
• Total number of consented subjects: 86
• Subject Sample Telemetry Report (SSTR)

All participants are adults (>18 years) with de novo AML, bone marrow containing 30% or greater blasts, and chosen for the study based on availability of high quality, abundant, paired bone marrow (tumor) and skin (normal) DNA samples. Preference was also given to patients with 2 or fewer cytogenetic abnormalities.

• Primary Phenotype: Leukemia, Myeloid, Acute

• Principal Investigator
  • Timothy J. Ley, MD. Department of Medicine, Department of Genetics, The Genome Center, Siteman Cancer Institute, MO, USA.
• Institute
  • Washington University of Medicine, St. Louis, MO, USA.
• Funding Sources
  • P01 CA101937. National Institutes of Health, Bethesda, MD, USA.