Focal 9p instability in hematologic neoplasias revealed by comparative genomic hybridization and single-nucleotide polymorphism microarray analyses.
Copy number losses in chromosome arm 9p are well-known aberrations in malignancies, including leukemias. The CDKN2A gene is suggested to play a key role in these aberrations. In this study overviewing 9p losses in hematologic neoplasias, we introduce the term focal 9p instability to indicate multiple areas of copy number loss or homozygous loss within a larger heterozygous one in 9p. We have used microarray comparative genomic hybridization to study patients with acute lymphoblastic leukemia (ALL, n = 140), acute myeloid leukemia (n = 50), chronic lymphocytic leukemia (n = 20), and myelodysplastic syndromes (n = 37). Our results show that 9p instability is restricted to ALL. In total, 58/140 (41%) patients with ALL had a loss in 9p. The 9p instability was detected in 19% of the patients with ALL and always included homozygous loss of CDKN2A along with loss of CDKN2B. Other possibly important genes included MTAP, IFN, MLLT3, JAK2, PTPLAD2, and PAX5. 13/27 (48%) patients with the instability had the BCR/ABL1 fusion gene or other oncogene-activating translocation or structural aberrations. Two patients had homozygous loss of hsa-mir -31, a microRNA known to regulate IKZF1. IKZF1 deletion at 7p12.1 was seen in 10 (37%) patients with the 9p instability. These findings suggest that, in ALL leukemogenesis, loss of CDKN2A and other target genes in the instability region is frequently associated with BCR/ABL1 and IKZF1 dysfunction. The multiple mechanisms leading to 9p instability including physical or epigenetic loss of the target genes, loss of the microRNA cluster, and the role of FRA9G fragile site are discussed.
Usvasalo
Anu
A
Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland.
Ninomiya
Shinsuke
S
Räty
Riikka
R
Hollmén
Jaakko
J
Saarinen-Pihkala
Ulla M
UM
Elonen
Erkki
E
Knuutila
Sakari
S
D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D043171:Chromosomal Instability; D002899:Chromosomes, Human, Pair 9; D055028:Comparative Genomic Hybridization / Q000379:methods; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D006801:Humans; D007938:Leukemia / Q000235:genetics*; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D020641:Polymorphism, Single Nucleotide