Identification of novel molecular prognostic markers for paediatric T-cell acute lymphoblastic leukaemia.
In the last four decades the survival of patients with newly diagnosed childhood T-cell acute lymphoblastic leukaemia (T-ALL) has improved dramatically. In sharp contrast, relapsed T-ALL continues to confer a dismal prognosis. We sought to determine if gene expression profiling could uncover a signature of outcome for children with T-ALL. Using 12 patient specimens obtained before therapy started, we examined the gene expression profile by oligonucleotide microarrays. We identified three genes, CFLAR, NOTCH2 and BTG3, whose expression at the time of diagnosis accurately distinguished the patients according to disease outcome. These genes are involved in the regulation of apoptosis and cellular proliferation. The prognostic value of the three predictive genes was assessed in an independent cohort of 25 paediatric T-ALL patients using quantitative real-time reverse transcription polymerase chain reaction. Patients assigned to the adverse outcome group had a significantly higher cumulative incidence of relapse compared with patients assigned to the favourable outcome group (46% vs. 8%, P = 0.029). Five-year overall survival was also significantly worse in the patients assigned to the adverse outcome group (P = 0.0039). The independent influence of the 3-gene predictor was confirmed by multivariate analysis. Our study provides proof of principle that genome-wide expression profiling can detect novel molecular prognostic markers in paediatric T-ALL.
Gottardo
Nicholas G
NG
Division of Children's Leukaemia and Cancer Research, Telethon Institute for Child Health Research and Centre for Child Health Research, University of Western Australia, Perth, WA, Australia.
Hoffmann
Katrin
K
Beesley
Alex H
AH
Freitas
Joseph R
JR
Firth
Martin J
MJ
Perera
Kanchana U
KU
de Klerk
Nicolas H
NH
Baker
David L
DL
Kees
Ursula R
UR
D000293:Adolescent; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics; D018797:Cell Cycle Proteins; D002648:Child; D002675:Child, Preschool; D005260:Female; D020869:Gene Expression Profiling; D005819:Genetic Markers; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics* / Q000401:mortality; D008297:Male; D015999:Multivariate Analysis; D020411:Oligonucleotide Array Sequence Analysis; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000401:mortality; D011237:Predictive Value of Tests; D011379:Prognosis; D011506:Proteins / Q000235:genetics; D051883:Receptor, Notch2 / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate
C424522:BTG3 protein, human; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D018797:Cell Cycle Proteins; D005819:Genetic Markers; C497764:NOTCH2 protein, human; D011506:Proteins; D051883:Receptor, Notch2