A comprehensive analysis of the CDKN2A gene in childhood acute lymphoblastic leukemia reveals genomic deletion, copy number neutral loss of heterozygosity, and association with specific cytogenetic subgroups

  1. Lookup NU author(s)
  2. Sarina Sulong
  3. Professor Anthony Moorman
  4. Dr Julie Irving
  5. Marian Case
  6. Professor Simon Bailey
  7. Dr Nicholas Bown
  8. Professor Andy Hall
  9. Professor Christine Harrison
Author(s)Sulong S, Moorman AV, Irving JAE, Strefford JC, Konn ZJ, Case MC, Minto L, Barber KE, Parker H, Wright SL, Stewart ARM, Bailey S, Bown NP, Hall AG, Harrison CJ
Publication type Article
ISSN (print)0006-4971
ISSN (electronic)1528-0020
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Inactivation of the tumor suppressor gene, CDKN2A, can occur by deletion, methylation, or mutation. We assessed the principal mode of inactivation in childhood acute lymphoblastic leukemia (ALL) and frequency in biologically relevant subgroups. Mutation or methylation was rare, whereas genomic deletion occurred in 21% of B-cell precursor ALL and 50% of T-ALL patients. Single nucleotide polymorphism arrays revealed copy number neutral (CNN) loss of heterozygosity (LOH) in 8% of patients. Array-based comparative genomic hybridization demonstrated that the mean size of deletions was 14.8 Mb and biallelic deletions composed a large and small deletion (mean sizes, 23.3 Mb and 1.4 Mb). Among 86 patients, only 2 small deletions were below the resolution of detection by fluorescence in situ hybridization. Patients with high hyperdiploidy, ETV6-RUNX1, or 11q23/MLL rearrangements had low rates of deletion (11%, 15%, 13%), whereas patients with t(9;22), t(1;19), TLX3, or TLX1 rearrangements had higher frequencies (61%, 42%, 78%, and 89%). In conclusion, CDKN2A deletion is a significant secondary abnormality in childhood ALL strongly correlated with phenotype and genotype. The variation in the incidence of CDKN2A deletions by cytogenetic subgroup may explain its inconsistent association with outcome. CNN LOH without apparent CDKN2A inactivation suggests the presence of other relevant genes in this region.
PublisherAmerican Society of Hematology
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