title: Late recurrence of childhood T-cell acute lymphoblastic leukemia frequently represents a second leukemia rather than a relapse: first evidence for genetic predisposition.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Erasmus Medical Center, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Szczepanski
authors.forename: Vincent H J
authors.initials: VH
authors.lastname: van der Velden
authors.forename: Esmé
authors.initials: E
authors.lastname: Waanders
authors.forename: Roland P
authors.initials: RP
authors.lastname: Kuiper
authors.forename: Pieter
authors.initials: P
authors.lastname: Van Vlierberghe
authors.forename: Bernd
authors.initials: B
authors.lastname: Gruhn
authors.forename: Cornelia
authors.initials: C
authors.lastname: Eckert
authors.forename: Renate
authors.initials: R
authors.lastname: Panzer-Grümayer
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Basso
authors.forename: Hélène
authors.initials: H
authors.lastname: Cavé
authors.forename: Udo Zur
authors.initials: UZ
authors.lastname: Stadt
authors.forename: Dario
authors.initials: D
authors.lastname: Campana
authors.forename: André
authors.initials: A
authors.lastname: Schrauder
authors.forename: Rosemary
authors.initials: R
authors.lastname: Sutton
authors.forename: Elisabeth
authors.initials: E
authors.lastname: van Wering
authors.forename: Jules P P
authors.initials: JP
authors.lastname: Meijerink
authors.forename: Jacques J M
authors.initials: JJ
authors.lastname: van Dongen
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005060:Europe; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling / Q000379:methods; D015973:Gene Expression Regulation, Leukemic; D015329:Gene Rearrangement, T-Lymphocyte; D019672:Genes, T-Cell Receptor / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D008297:Male; D009154:Mutation; D016609:Neoplasms, Second Primary / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D009517:New South Wales; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000628:therapy; D051881:Receptor, Notch1 / Q000235:genetics; D012008:Recurrence; D013714:Tennessee; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: C497761:NOTCH1 protein, human; D015514:Oncogene Proteins, Fusion; D051881:Receptor, Notch1; C547584:SIL-TAL1 fusion protein, human