title: Inactivation of TP53 correlates with disease progression and low miR-34a expression in previously treated chronic lymphocytic leukemia patients.
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.
authors.affiliation: Laboratory for Leukemia Diagnostics, Department of Medicine III, Grosshadern Hospital, Ludwig-Maximilians-University, Munich, Germany. annika.dufour@med.uni-muenchen.de
authors.forename: Annika
authors.initials: A
authors.lastname: Dufour
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Palermo
authors.forename: Evelyn
authors.initials: E
authors.lastname: Zellmeier
authors.forename: Gudrun
authors.initials: G
authors.lastname: Mellert
authors.forename: Guillemette
authors.initials: G
authors.lastname: Duchateau-Nguyen
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schneider
authors.forename: Tobias
authors.initials: T
authors.lastname: Benthaus
authors.forename: Purvi M
authors.initials: PM
authors.lastname: Kakadia
authors.forename: Karsten
authors.initials: K
authors.lastname: Spiekermann
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hiddemann
authors.forename: Jan
authors.initials: J
authors.lastname: Braess
authors.forename: Sim
authors.initials: S
authors.lastname: Truong
authors.forename: Nancy
authors.initials: N
authors.lastname: Patten
authors.forename: Lin
authors.initials: L
authors.lastname: Wu
authors.forename: Sabine
authors.initials: S
authors.lastname: Lohmann
authors.forename: David
authors.initials: D
authors.lastname: Dornan
authors.forename: Debraj
authors.initials: D
authors.lastname: GuhaThakurta
authors.forename: Ru-Fang
authors.initials: RF
authors.lastname: Yeh
authors.forename: Galina
authors.initials: G
authors.lastname: Salogub
authors.forename: Philippe
authors.initials: P
authors.lastname: Solal-Celigny
authors.forename: Anna
authors.initials: A
authors.lastname: Dmoszynska
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Robak
authors.forename: Marco
authors.initials: M
authors.lastname: Montillo
authors.forename: John
authors.initials: J
authors.lastname: Catalano
authors.forename: Christian H
authors.initials: CH
authors.lastname: Geisler
authors.forename: Martin
authors.initials: M
authors.lastname: Weisser
authors.forename: Stefan K
authors.initials: SK
authors.lastname: Bohlander
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D018450:Disease Progression; D018572:Disease-Free Survival; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D020868:Gene Silencing / Q000502:physiology; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D011379:Prognosis; D012008:Recurrence; D017211:Treatment Failure; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53