Copy number alterations in childhood acute lymphoblastic leukemia and their association with minimal residual disease.
In vivo response to initial therapy, as assessed by determination of minimal residual disease (MRD) after 5 and 12 weeks of treatment, has evolved as a strong prognostic factor in children with acute lymphoblastic leukemia (ALL) treated according to the BFM regime. Individual treatment response may be influenced by copy number alterations (CNA) leading to altered gene expression. We aimed to evaluate CNA using high-resolution array-comparative genomic hybridization (array-CGH) in different treatment-response groups. Leukemic genomic profiles of 25 standard risk (MRD-SR) and 25 high risk (MRD-HR) patients were compared. CNAs were found in 46/50 patients (92%). The most significant difference was a gain of 1q23-qter because of an unbalanced t(1;19), found in 10/25 MRD-SR patients, but in none of the MRD-HR patients (P < 0.001). The most frequent CNAs in the MRD-HR group were deletions of genomic regions harboring the immunoglobulin genes (Ig), e.g., 2p11.2 in 60% of MRD-HR compared to 28% of MRD-SR (P = 0.045). Combining all Ig loci, significantly more MRD-HR than MRD-SR patients displayed deletions (17:8 patients, P = 0.02). Frequency of other CNAs, such as loss of 9p21 or gains of 21q, did not differ strongly between the two patient groups. This is the first study evaluating the clinical significance of CNA as detected by array-CGH in childhood ALL and the first to suggest that such analyses may provide clinically important data. This article contains supplementary material available via the Internet at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.
Steinemann
Doris
D
Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany. steinemann.doris@mh-hannover.de
Cario
Gunnar
G
Stanulla
Martin
M
Karawajew
Leonid
L
Tauscher
Marcel
M
Weigmann
Anja
A
Göhring
Gudrun
G
Ludwig
Wolf-Dieter
WD
Harbott
Jochen
J
Radlwimmer
Bernhard
B
Bartram
Claus
C
Lichter
Peter
P
Schrappe
Martin
M
Schlegelberger
Brigitte
B
D016022:Case-Control Studies; D002648:Child; D002869:Chromosome Aberrations; D002877:Chromosomes, Human / Q000235:genetics / Q000648:ultrastructure; D018628:Gene Dosage; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D018365:Neoplasm, Residual / Q000235:genetics; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D012306:Risk