Originally published as JCO Early Release 10.1200/JCO.2009.21.9840 on September 21 2009

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New Lesions Detected by Single Nucleotide Polymorphism Array–Based Chromosomal Analysis Have Important Clinical Impact in Acute Myeloid Leukemia

From the Department of Translational Hematology and Oncology Research, Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, and Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH; Department of Laboratory Medicine, Ewha Womans University, School of Medicine, Seoul, South Korea; and Division of Hematology, Department of Internal Medicine, Johns Hopkins University School of Medicine, Division of Hematological Malignancy, Sidney Kimmel Cancer Center, Baltimore, MD.

Corresponding author: Jaroslaw P. Maciejewski, MD, PhD, Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Ave, R40, Cleveland, OH 44195; e-mail: maciejj{at}ccf.org.

Purpose Cytogenetics is the primary outcome predictor in acute myeloid leukemia (AML). Metaphase cytogenetics (MC) detects an abnormal karyotype in only half of patients with AML, however. Single nucleotide polymorphism arrays (SNP-A) can detect acquired somatic uniparental disomy (UPD) and other cryptic defects, even in samples deemed normal by MC. We hypothesized that SNP-A will improve detection of chromosomal defects in AML and that this would enhance the prognostic value of MC.

Patients and Methods We performed 250K and 6.0 SNP-A analyses on 140 patients with primary (p) and secondary (s) AML and correlated the results with clinical outcomes and Flt-3/nucleophosmin (NPM-1) status.

Results SNP-A is more sensitive than MC in detecting unbalanced lesions (pAML, 65% v 39%, P = .002; and sAML, 78% v 51%, P = .003). Acquired somatic UPD, not detectable by MC, was common in our AML cohort (29% in pAML and 35% in sAML). Patients with SNP-A lesions including acquired somatic UPD exhibited worse overall survival (OS) and event-free survival (EFS) in pAML with normal MC and in pAML/sAML with abnormal MC. SNP-A improved the predictive value of Flt-3 internal tandem duplication/NPM-1 status, with inferior survival seen in patients with additional SNP-A defects. Multivariate analyses confirmed the independent predictive value of SNP-A defects for OS (hazard ratio [HR] = 2.52; 95% CI, 1.29 to 5.22; P = .006) and EFS (HR = 1.72; 95% CI, 1.12 to 3.48; P = .04).

Conclusion SNP-A analysis allows enhanced detection of chromosomal abnormalities and provides important prognostic impact in AML.

Supported by National Institutes of Health Grants No. R01 HL082983 (J.P.M.), U54 RR019391 (J.P.M. and M.A.S.), K24 HL077522 (J.P.M.), and DOD MPO48018 (M.A.M.), and a charitable donation from Robert Duggan Cancer Research Foundation.

Presented as an oral communication at the American Society of Hematology 50th Annual Meeting, December 6-9, 2008, San Francisco, CA.

The Framingham Heart Study (FHS)/Framingham SHARe (FS) project is conducted/supported by the National Heart, Lung, and Blood Institute (NHLBI)/Boston University (BU). The FS data used in this manuscript's analyses were obtained through dbGaO(phs000007.v1p1). This manuscript was not prepared in collaboration with FHS investigators and does not necessarily reflect the opinions/views of FHS, BU, or NHLBI.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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