title: Characterisation of TP53 abnormalities in chronic lymphocytic leukaemia.
abstract: Abnormalities of TP53 in chronic lymphocytic leukaemia (CLL) correlate with aggressive disease and transformation. We studied 115 patients with CLL including 90 untreated, 25 with heavily pretreated/refractory CLL using fluorescent in situ hybridisation (FISH) to detect allelic loss at chromosome 17p and flow cytometry (FC) to test p53 protein overexpression. A total of 17 cases were identified with TP53 deletion and/or protein expression. Both tests correlated in 10 of 17 patients; in six, one or the other abnormality was detected and in one case, with a deletion, flow cytometry failed. Material for direct DNA sequencing was available in 14 of 17 cases. Mutations were found in seven cases. Five of 14 patients with allelic loss and seven of 13 expressing p53 protein had a mutation. These were single-base substitutions and were located in exons 5, 7 or 8. Mutations were not found in 13 of 14 other cases without deletions by FISH or protein expression. The incidence of p53 abnormalities in this series was 15%, with a significant difference between untreated patients (7%) and the pretreated/refractory group (50%; P<0.01). Abnormal p53 was predicted for shorter survival, regardless of the method used. We confirm that p53 abnormalities are more common in refractory CLL and that mutations occur at the known hot spots. Testing for TP53 deletions by FISH and protein expression by FC is an effective and simple way of screening patients who are likely to have aggressive disease. DNA sequencing adds little to these methods in identifying the population at risk.
authors.affiliation: Academic Department of Haematology and Cytogenetics, The Royal Marsden NHS Trust and Institute of Cancer Research, London, UK.
authors.forename: Patrick D
authors.initials: PD
authors.lastname: Thornton
authors.forename: Alicja M
authors.initials: AM
authors.lastname: Gruszka-Westwood
authors.forename: Rifat A
authors.initials: RA
authors.lastname: Hamoudi
authors.forename: Shayne
authors.initials: S
authors.lastname: Atkinson
authors.forename: Pawel
authors.initials: P
authors.lastname: Kaczmarek
authors.forename: Ricardo M
authors.initials: RM
authors.lastname: Morilla
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Hilditch
authors.forename: Roger
authors.initials: R
authors.lastname: A'Hern
authors.forename: Estella
authors.initials: E
authors.lastname: Matutes
authors.forename: Daniel
authors.initials: D
authors.lastname: Catovsky
mesh_terms: D004252:DNA Mutational Analysis / Q000592:standards; D004351:Drug Resistance / Q000235:genetics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D011379:Prognosis; D016016:Proportional Hazards Models; D017422:Sequence Analysis, DNA; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000235:genetics*
chemical_list: D016159:Tumor Suppressor Protein p53