title: Monoallelic TP53 inactivation is associated with poor prognosis in chronic lymphocytic leukemia: results from a detailed genetic characterization with long-term follow-up.
abstract: The exact prognostic role of TP53 mutations (without 17p deletion) and any impact of the deletion without TP53 mutation in CLL are unclear. We studied 126 well-characterized CLL patients by direct sequencing and DHPLC to detect TP53 mutations (exons 2-11). Most patients with 17p deletions also had TP53 mutations (81%). Mutations in the absence of 17p deletions were found in 4.5%. We found a shorter survival for patients with TP53 mutation (n = 18; P = .002), which was more pronounced when analyzed from the time point of mutation detection (6.8 vs 69 months, P < .001). The survival was equally poor for patients with deletion 17p plus TP53 mutation (7.6 months, n = 13), TP53 mutation only (5.5 months, n = 5), and 17p deletion only (5.4 months, n = 3). The prognostic impact of TP53 mutation (HR 3.71) was shown to be independent of stage, VH status, and 11q and 17p deletion in multivariate analysis. Serial samples showed evidence of clonal evolution and increasing clone size during chemotherapy, suggesting that there may be patients where this treatment is potentially harmful. TP53 mutations are associated with poor sur-vival once they occur in CLL. The de-monstration of clonal evolution under selective pressure supports the biologic significance of TP53 mutations in CLL.
authors.affiliation: Internal Medicine III, University of Ulm, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Zenz
authors.forename: Alexander
authors.initials: A
authors.lastname: Kröber
authors.forename: Katrin
authors.initials: K
authors.lastname: Scherer
authors.forename: Sonja
authors.initials: S
authors.lastname: Häbe
authors.forename: Andreas
authors.initials: A
authors.lastname: Bühler
authors.forename: Axel
authors.initials: A
authors.lastname: Benner
authors.forename: Tina
authors.initials: T
authors.lastname: Denzel
authors.forename: Dirk
authors.initials: D
authors.lastname: Winkler
authors.forename: Jennifer
authors.initials: J
authors.lastname: Edelmann
authors.forename: Carsten
authors.initials: C
authors.lastname: Schwänen
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.forename: Stephan
authors.initials: S
authors.lastname: Stilgenbauer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002886:Chromosomes, Human, Pair 17; D015331:Cohort Studies; D005500:Follow-Up Studies; D017353:Gene Deletion; D016158:Genes, p53; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D013997:Time Factors; D016896:Treatment Outcome