Focal 9p instability in hematologic neoplasias revealed by comparative genomic hybridization and single‐nucleotide polymorphism microarray analyses

Abstract

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.

Tumor suppressive microRNAs (miR-222 and miR-31) regulate molecular pathways based on microRNA expression signature in prostate cancer

“…32 Furthermore, homozygous loss of the miR-31-encoding genomic locus has been described in human urothelial carcinoma 33 and acute lymphoblastic lymphoma. 34 On the other hand, several studies showed that miR-31 is upregulated in colorectal cancer, hepatocellular cancer and most squamous cell carcinomas. To date, considerable evidence has revealed the important roles of miR-31 in cancer, but whether this miRNA functions as a tumor suppressor or an oncogene differs according to cancer type.…”

CDKN2A/BAlterations Impair Prognosis in AdultBCR-ABL1–Positive Acute Lymphoblastic Leukemia Patients

“…Deletions of p16/INK4A, p14/ARF, and p15/INK4B have been shown to frequently occur in all lymphoid malignancies (10)(11)(12)(13)(14), with homozygous deletions as the most frequent mechanism of inactivation (15). However, despite their high frequency, the prognostic importance of 9p21 alterations is still controversial in ALL (10,16).…”

Selected miRNA levels are associated with IKZF1 microdeletions in pediatric acute lymphoblastic leukemia

“…PAR1 deletions are frequently observed in patients who are positive for IKZF1 deletion (40). High expressions of miR-24 and miR-542 in patients who are positive for PAR1 deletion were detected.…”

“…This miRNA may positively regulate tumor protein 53 (p53) activity (39). The homozygous loss of the miR-31 gene is described in 9p instability in ALL (40). The 9p instability is detected in 19% of patients with ALL, and always includes the homozygous loss of CDKN2A along with loss of CDKN2B, which are associated with BCR/ABL1 and IKZF1 dysfunction (40)(41)(42)(43).…”