Inactivation of TP53 correlates with disease progression and low miR-34a expression in previously treated chronic lymphocytic leukemia patients
Annika Dufour, Giuseppe Palermo, Evelyn Zellmeier, Gudrun Mellert, Guillemette Duchateau-Nguyen, Stephanie Schneider, Tobias Benthaus, Purvi M Kakadia, Karsten Spiekermann, Wolfgang Hiddemann, Jan Braess, Sim Truong, Nancy Patten, Lin Wu, Sabine Lohmann, David Dornan, Debraj GuhaThakurta, Ru-Fang Yeh, Galina Salogub, Philippe Solal-Celigny, Anna Dmoszynska, Tadeusz Robak, Marco Montillo, John Catalano, Christian H Geisler, Martin Weisser, Stefan K Bohlander, Annika Dufour, Giuseppe Palermo, Evelyn Zellmeier, Gudrun Mellert, Guillemette Duchateau-Nguyen, Stephanie Schneider, Tobias Benthaus, Purvi M Kakadia, Karsten Spiekermann, Wolfgang Hiddemann, Jan Braess, Sim Truong, Nancy Patten, Lin Wu, Sabine Lohmann, David Dornan, Debraj GuhaThakurta, Ru-Fang Yeh, Galina Salogub, Philippe Solal-Celigny, Anna Dmoszynska, Tadeusz Robak, Marco Montillo, John Catalano, Christian H Geisler, Martin Weisser, Stefan K Bohlander
Abstract
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 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 fluorescence in situ hybridization for del17p in a phase 3 clinical trial (REACH [Rituximab in the Study of Relapsed Chronic Lymphocytic Leukemia]). 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 microRNA-34a expression levels. This trial was registered at www.clinicaltrials.gov as #NCT00090051.
Source: PubMed