J Korean Med Sci.  2014 Jul;29(7):926-933. 10.3346/jkms.2014.29.7.926.

Clinical Significance of Previously Cryptic Copy Number Alterations and Loss of Heterozygosity in Pediatric Acute Myeloid Leukemia and Myelodysplastic Syndrome Determined Using Combined Array Comparative Genomic Hybridization plus Single-Nucleotide Polymorphism Microarray Analyses

Affiliations
  • 1Division of Pediatric Hematology/Oncology, Asan Medical Center Children's Hospital, Department of Pediatrics, University of Ulsan College of Medicine, Seoul, Korea. jjseo@amc.seoul.kr
  • 2Genome Research Center, Asan Medical Center, Seoul, Korea.
  • 3Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Abstract

The combined array comparative genomic hybridization plus single-nucleotide polymorphism microarray (CGH+SNP microarray) platform can simultaneously detect copy number alterations (CNA) and copy-neutral loss of heterozygosity (LOH). Eighteen children with acute myeloid leukemia (AML) (n=15) or myelodysplastic syndrome (MDS) (n=3) were studied using CGH+SNP microarray to evaluate the clinical significance of submicroscopic chromosomal aberrations. CGH+SNP microarray revealed CNAs at 14 regions in 9 patients, while metaphase cytogenetic (MC) analysis detected CNAs in 11 regions in 8 patients. Using CGH+SNP microarray, LOHs>10 Mb involving terminal regions or the whole chromosome were detected in 3 of 18 patients (17%). CGH+SNP microarray revealed cryptic LOHs with or without CNAs in 3 of 5 patients with normal karyotypes. CGH+SNP microarray detected additional cryptic CNAs (n=2) and LOHs (n=5) in 6 of 13 patients with abnormal MC. In total, 9 patients demonstrated additional aberrations, including CNAs (n=3) and/or LOHs (n=8). Three of 15 patients with AML and terminal LOH>10 Mb demonstrated a significantly inferior relapse-free survival rate (P=0.041). This study demonstrates that CGH+SNP microarray can simultaneously detect previously cryptic CNAs and LOH, which may demonstrate prognostic implications.

Keyword

Leukemia, Myeloid, Acute; DNA Copy Number Variations; Loss of Heterozygosity; Comparative Genomic Hybridization; Single-Nucleotide Polymorphism Microarray

MeSH Terms

Adolescent
Child
Child, Preschool
Chromosome Aberrations
*Comparative Genomic Hybridization
DNA/*analysis/metabolism
DNA Copy Number Variations
Female
Hematopoietic Stem Cell Transplantation
Humans
Infant
Kaplan-Meier Estimate
Leukemia, Myeloid, Acute/*diagnosis/*genetics/therapy
Loss of Heterozygosity
Male
Myelodysplastic Syndromes/*diagnosis/*genetics/therapy
*Oligonucleotide Array Sequence Analysis
Polymorphism, Single Nucleotide
Real-Time Polymerase Chain Reaction
Transplantation, Homologous
DNA

Figure

  • Fig. 1 Genetic aberrations detected using CGH+SNP microarray analysis. (A) Copy loss at 12p13.33-p12.3 in patient 6. (B) Large terminal LOH in 9p in patient 15. (C) Homozygous acquisition of chromosome 6 in patient 12. CGH, comparative genomic hybridization; SNP, single-nucleotide polymorphism; LOH, loss of heterozygosity.

  • Fig. 2 LOH and relapse-free survival in patients with acute myeloid leukemia. LOH, loss of heterozygosity.


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