DNA sequence profile of TP53 gene mutations in childhood B-cell non-Hodgkin's lymphomas: prognostic implications.
OBJECTIVE
The TP53 gene encodes a nuclear protein implicated in the regulation of the cell cycle, DNA repair, and apoptosis. TP53 mutations and other alterations have been described in numerous types of tumors, and some of these have been associated with poor prognosis. The aim of this study was to characterize TP53 mutations in childhood B non-Hodgkin's lymphoma, their correlation with clinical prognostic factors and response to therapy.


METHODS
Samples from 49 children with B non-Hodgkin's lymphoma were examined for TP53 alterations by single-strand conformation polymorphism analysis (SSCP) of exons 5-9, direct sequencing and by p53 immunohistochemistry.


RESULTS
Mutations of TP53 were detected in 11 of 49 (22.5%) patients and more specifically in 20% of Burkitt's lymphoma. The sequence analysis showed missense mutations in 10 cases and an insertion mutation in one case. Mutations of the transition type occurred more frequently than transversions (seven of 11). Analysis of the spectrum of single-nucleotide substitutions showed a 30% frequency of transition mutations in CpG dinucleotide sequences. The overall frequency of p53 immunostaining positivity was 36% (15 of 41). There was a very good agreement between protein expression and the presence of TP53 mutation (P=0.0005). No significant correlation was found regarding age, gender, clinical stage and LDH level and TP53 mutations. Comparison of EFS curves using the log-rank test were also not significant. However, the analysis of the effects of mutations on the core p53 structure identified biological and biochemical mutants with phenotypes probably related to different response to chemotherapy.


CONCLUSIONS
Our data suggest that some types of mutants can alter the protein distinctly and may be associated with a more aggressive phenotype. In addition, the impact of TP53 mutations on response to therapy may also be influenced by disruption of other genes.
Klumb
Claudete Esteves
CE
Laboratório de Hematologia Celular e Molecular, Hospital do Câncer/Instituto Nacional de Câncer, Universidade Federal do Rio de Janeiro, Brazil. cklumb@easyline.com.br
Furtado
Daniel Rodrigues
DR
de Resende
Lídia Maria Magalhães
LM
Carriço
Maria Kadma
MK
Coelho
Arthur Moellman
AM
de Meis
Ernesto
E
Maia
Raquel Ciuvalschi
RC
Rumjanek
Franklin David
FD
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D005500:Follow-Up Studies; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D007223:Infant; D016393:Lymphoma, B-Cell / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D008297:Male; D009154:Mutation / Q000235:genetics* / Q000502:physiology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016019:Survival Analysis; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000235:genetics
D016159:Tumor Suppressor Protein p53