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.
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.
Sulong
Sarina
S
Northern Institute for Cancer Research, Newcastle University, Queen Victoria Road, Newcastle upon Tyne, UK.
Moorman
Anthony V
AV
Irving
Julie A E
JA
Strefford
Jonathan C
JC
Konn
Zoe J
ZJ
Case
Marian C
MC
Minto
Lynne
L
Barber
Kerry E
KE
Parker
Helen
H
Wright
Sarah L
SL
Stewart
Adam R M
AR
Bailey
Simon
S
Bown
Nick P
NP
Hall
Andrew G
AG
Harrison
Christine J
CJ
D002648:Child; D019175:DNA Methylation; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D015973:Gene Expression Regulation, Leukemic; D019942:Genes, p16; D023281:Genomics; D019382:Human Growth Hormone; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015994:Incidence; D019656:Loss of Heterozygosity; D008297:Male; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*
D019382:Human Growth Hormone