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
| Autor: | Jonathan C. Strefford, Nick Bown, Sarina Sulong, Helen Parker, Sarah L. Wright, Anthony V. Moorman, Marian Case, Simon Bailey, Zoe J. Konn, Lynne Minto, Christine J. Harrison, Julie Irving, Adam R. M. Stewart, Andrew G. Hall, Kerry E. Barber |
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| Rok vydání: | 2008 |
| Předmět: |
Male
medicine.medical_specialty Immunology Gene Dosage Loss of Heterozygosity Biology Biochemistry Gene dosage Polymorphism Single Nucleotide Loss of heterozygosity medicine Humans Child Childhood Acute Lymphoblastic Leukemia In Situ Hybridization Fluorescence Genetics medicine.diagnostic_test Gene Expression Regulation Leukemic Human Growth Hormone Genes p16 Incidence Cytogenetics Cell Biology Hematology Genomics DNA Methylation Precursor Cell Lymphoblastic Leukemia-Lymphoma Phenotype DNA methylation Mutation Female Hyperdiploidy Gene Deletion Fluorescence in situ hybridization Comparative genomic hybridization |
| Zdroj: | Blood. 113(1) |
| ISSN: | 1528-0020 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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