TY - JOUR
T1 - Late recurrence of childhood T-cell acute lymphoblastic leukemia frequently represents a second leukemia rather than a relapse
T2 - first evidence for genetic predisposition
AU - Szczepanski, Tomasz
AU - van der Velden, Vincent H J
AU - Waanders, Esmé
AU - Kuiper, Roland P
AU - Van Vlierberghe, Pieter
AU - Gruhn, Bernd
AU - Eckert, Cornelia
AU - Panzer-Grümayer, Renate
AU - Basso, Giuseppe
AU - Cavé, Hélène
AU - Stadt, Udo Zur
AU - Campana, Dario
AU - Schrauder, André
AU - Sutton, Rosemary
AU - van Wering, Elisabeth
AU - Meijerink, Jules P P
AU - van Dongen, Jacques J M
PY - 2011/4/20
Y1 - 2011/4/20
N2 - PURPOSE: Relapse of childhood T-cell acute lymphoblastic leukemia (T-ALL) often occurs during treatment, but in some cases, leukemia re-emerges off therapy. On the basis of previous analyses of T-cell receptor (TCR) gene rearrangement patterns, we hypothesized that some late recurrences of T-ALL might in fact represent second leukemias.PATIENTS AND METHODS: In 22 patients with T-ALL who had late relapses (at least 2.5 years from diagnosis), we studied TCR gene rearrangement status at first and second presentation, NOTCH1 gene mutations, and the presence of the SIL-TAL1 gene fusion. We performed genome-wide copy number and homozygosity analysis by using oligonucleotide- and single nucleotide polymorphism (SNP) -based arrays.RESULTS: We found evidence of a common clonal origin between diagnosis and relapse in 14 patients (64%). This was based on concordant TCR gene rearrangements (12 patients) or concordant genetic aberrations, as revealed by genome-wide copy number analysis (two patients). In the remaining eight patients (36%), TCR gene rearrangement sequences had completely changed between diagnosis and relapse, and gene copy number analysis showed markedly different patterns of genomic aberrations, suggesting a second T-ALL rather than a resurgence of the original clone. Moreover, NOTCH1 mutation patterns were different at diagnosis and relapse in five of these eight patients. In one patient with a second T-ALL, SNP analysis revealed a germline del(11)(p12;p13), a known recurrent aberration in T-ALL.CONCLUSION: More than one third of late T-ALL recurrences are, in fact, second leukemias. Germline genetic abnormalities might contribute to the susceptibility of some patients to develop T-ALL.
AB - PURPOSE: Relapse of childhood T-cell acute lymphoblastic leukemia (T-ALL) often occurs during treatment, but in some cases, leukemia re-emerges off therapy. On the basis of previous analyses of T-cell receptor (TCR) gene rearrangement patterns, we hypothesized that some late recurrences of T-ALL might in fact represent second leukemias.PATIENTS AND METHODS: In 22 patients with T-ALL who had late relapses (at least 2.5 years from diagnosis), we studied TCR gene rearrangement status at first and second presentation, NOTCH1 gene mutations, and the presence of the SIL-TAL1 gene fusion. We performed genome-wide copy number and homozygosity analysis by using oligonucleotide- and single nucleotide polymorphism (SNP) -based arrays.RESULTS: We found evidence of a common clonal origin between diagnosis and relapse in 14 patients (64%). This was based on concordant TCR gene rearrangements (12 patients) or concordant genetic aberrations, as revealed by genome-wide copy number analysis (two patients). In the remaining eight patients (36%), TCR gene rearrangement sequences had completely changed between diagnosis and relapse, and gene copy number analysis showed markedly different patterns of genomic aberrations, suggesting a second T-ALL rather than a resurgence of the original clone. Moreover, NOTCH1 mutation patterns were different at diagnosis and relapse in five of these eight patients. In one patient with a second T-ALL, SNP analysis revealed a germline del(11)(p12;p13), a known recurrent aberration in T-ALL.CONCLUSION: More than one third of late T-ALL recurrences are, in fact, second leukemias. Germline genetic abnormalities might contribute to the susceptibility of some patients to develop T-ALL.
KW - Adolescent
KW - Child
KW - Child, Preschool
KW - Europe
KW - Female
KW - Gene Dosage
KW - Gene Expression Profiling/methods
KW - Gene Expression Regulation, Leukemic
KW - Gene Rearrangement, T-Lymphocyte
KW - Genes, T-Cell Receptor/genetics
KW - Genetic Predisposition to Disease
KW - Homozygote
KW - Humans
KW - Male
KW - Mutation
KW - Neoplasms, Second Primary/genetics
KW - New South Wales
KW - Oligonucleotide Array Sequence Analysis
KW - Oncogene Proteins, Fusion/genetics
KW - Phenotype
KW - Polymorphism, Single Nucleotide
KW - Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics
KW - Receptor, Notch1/genetics
KW - Recurrence
KW - Tennessee
KW - Time Factors
KW - Treatment Outcome
U2 - 10.1200/JCO.2010.30.2877
DO - 10.1200/JCO.2010.30.2877
M3 - Article
C2 - 21357790
SN - 0732-183X
VL - 29
SP - 1643
EP - 1649
JO - Journal of clinical oncology : official journal of the American Society of Clinical Oncology
JF - Journal of clinical oncology : official journal of the American Society of Clinical Oncology
IS - 12
ER -