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Homozygous deletion of the p16/MTS1 gene in pediatric acute lymphoblastic
leukemia is associated with unfavorable clinical outcome
UR Kees, PR Burton, C Lu and DL Baker
Division of Children's Leukaemia and Cancer Research, TVW Telethon
Institute for Child Health Research, Perth, Australia.
The p16 gene (MTS1, CDKN2, p16INK4A, CDKI) encoding an inhibitor of
cyclin-dependent kinase 4 (cdk4) has been found to be deleted in various
types of tumors, including leukemia, and is thought to code for a tumor
suppressor gene. Our preliminary findings on eight pediatric patients with
acute lymphoblastic leukemia (ALL) suggested that the survival of patients
carrying a homozygous p16 gene deletion was significantly inferior to that
of those without a deletion. The present study on 48 patients tested the
hypothesis that the clinical outcome for pediatric ALL patients is
correlated with the presence or absence of the p16 gene. Overall, nine of
48 children (18.3%) carried a homozygous p16 deletion. Such deletions were
significantly more common (P = .003) among T-ALL patients (five of eight,
62.5%) than among precursor-B-ALL patients (four of 40, 10.0%). Of nine
patients exhibiting p16 deletions, eight (88.9%) were classified as
high-risk patients by the recognized prognostic factors of age, white blood
cell count, and T-cell phenotype. The 4-year event-free survival in the
study population as a whole was 72.7%. Without adjustment for other risk
factors (univariate model), the presence of a homozygous p16 deletion was
associated with a markedly increased probability of both relapse (P =
.0003) and death (P = .002). These findings raise the question of whether
the p16 deletion itself confers an increased risk of relapse after
adjusting for the known risk factors. In this analysis, the estimated risk
multiplier factor for relapse in patients carrying the p16 deletion was
14.0 (P = .0004) and for the risk of death 15.6 (P = .0008). We therefore
conclude that the presence of a homozygous p16 deletion may well be an
important risk factor for both relapse and death in childhood ALL, and that
its prognostic effect is not a consequence of confounding by other factors
already known to influence outcome in this disease.
Volume 89,
Issue 11,
pp. 4161-4166,
06/01/1997
Copyright © 1997 by The American Society of Hematology
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