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The p53 gene in pediatric therapy-related leukemia and myelodysplasia
CA Felix, MR Hosler, D Provisor, K Salhany, EA Sexsmith, DJ Slater, NK Cheung, NJ Winick, EA Strauss, R Heyn, BJ Lange and D Malkin
Department of Pediatrics, Children's Hospital of Philadelphia, PA, USA.
We investigated the frequency of p53 mutations in 19 pediatric cases of
therapy-related leukemia or myelodysplastic syndrome. Eleven children
presented with acute myeloid leukemia, one with mixed-lineage leukemia, two
with acute lymphoblastic leukemia, and five with myelodysplasia at times
ranging from 11 months to 9 years after a primary cancer diagnosis. The
primary cancers, which included 11 solid tumors and eight leukemias, were
treated with various combinations of DNA topoisomerase II inhibitors,
alkylating agents, or irradiation. Leukemic or myelodysplastic marrows were
screened for possible mutations by single-strand conformation polymorphism
(SSCP) analysis of p53 exons 4 to 8. The only observed mutation was an
inherited 2- basepair deletion at codon 209 in exon 6 that would shift the
open reading frame, create a premature termination codon, and foreshorten
the resultant protein. Prior therapy in this patient included DNA
topoisomerase II inhibitors, alkylating agents, and irradiation. The
secondary leukemia presented as myelodysplasia with monosomies of
chromosomes 5 and 7 and abnormalities of chromosome 17. Although the
primary cancer was an embryonal rhabdomyosarcoma and there was a family
history of cancer, the case did not fulfill the clinical criteria for
Li-Fraumeni syndrome. This study suggests that germline p53 mutations may
predispose some children to therapy-related leukemia and myelodysplasia,
but that p53 mutations otherwise are infrequent in this setting.
Volume 87,
Issue 10,
pp. 4376-4381,
05/15/1996
Copyright © 1996 by The American Society of Hematology
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