Inactivation of TP53 correlates with disease progression and low miR-34a expression in previously treated chronic lymphocytic leukemia patients
Menée sur 457 patients atteints d'une leucémie lymphocytaire chronique et inclus dans un essai clinique de phase III (REACH), cette étude analyse les effets de mutations du gène TP53, d'une délétion du locus 17p13 et d'une faible expression du micro-ARN 34a sur la survie de patients dont la maladie a récidivé
In chronic lymphocytic leukemia (CLL) patients, disruptions of the TP53 tumor suppressor pathway by 17p13 deletion (del17p), somatic TP53 mutations or downregulation of microRNA-34a (miR-34a), a direct downstream target of TP53, have been associated with a poor prognosis. So far, the impact of the various TP53 defects has not been evaluated in a large cohort of previously treated and relapsed CLL patients. Here we present the results of TP53 gene sequencing and FISH for del17p in a phase III clinical trial (REACH). Of the 457 patients, 52 had TP53 mutations, and 37 had del17p. In 24 (46%) of the TP53 mutated patients, no del17p was found and in 9 of the del17p patients, no TP53 mutation was identified. Based on a predicted proportion of TP53 disruption, a complete disruption of TP53 function, either by a combination of point mutations and/or del17p, was associated with a high risk for disease progression. Progression-free survival of patients with a heterozygous TP53 mutation was not significantly different from patients with a completely intact TP53 locus. In addition, only a complete loss of TP53 function correlated with low miR-34a expression levels. MiR-34a expression levels did not show prognostic significance in CLL patients without TP53 mutations. (ClinicalTrials.gov identifier: NCT00090051)
Blood , résumé, 2013