The p53 gene in pediatric therapy-related leukemia and myelodysplasia.
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.
Felix
C A
CA
Department of Pediatrics, Children's Hospital of Philadelphia, PA, USA.
Hosler
M R
MR
Provisor
D
D
Salhany
K
K
Sexsmith
E A
EA
Slater
D J
DJ
Cheung
N K
NK
Winick
N J
NJ
Strauss
E A
EA
Heyn
R
R
Lange
B J
BJ
Malkin
D
D
D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000627:therapeutic use; D001483:Base Sequence; D001853:Bone Marrow / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D003062:Codon / Q000235:genetics; D003131:Combined Modality Therapy; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D016158:Genes, p53; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D007938:Leukemia / Q000188:drug therapy / Q000532:radiotherapy; D007953:Leukemia, Radiation-Induced / Q000209:etiology / Q000235:genetics*; D016864:Li-Fraumeni Syndrome / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D009006:Monosomy; D009190:Myelodysplastic Syndromes / Q000209:etiology / Q000235:genetics*; D009369:Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D016609:Neoplasms, Second Primary / Q000209:etiology / Q000235:genetics*; D018807:Polymorphism, Single-Stranded Conformational; D011878:Radiotherapy / Q000009:adverse effects; D012208:Rhabdomyosarcoma / Q000188:drug therapy / Q000235:genetics / Q000532:radiotherapy; D012983:Soft Tissue Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000532:radiotherapy; D059005:Topoisomerase II Inhibitors; D014178:Translocation, Genetic
D000964:Antimetabolites, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D003062:Codon; D004273:DNA, Neoplasm; D059005:Topoisomerase II Inhibitors