Monoallelic and biallelic inactivation of TP53 gene in chronic lymphocytic leukemia: selection, impact on survival, and response to DNA damage

Abstract

Deletion of TP53 gene, under routine assessment by fluorescence in situ hybridization analysis, connects with the worst prognosis in chronic lymphocytic leukemia (CLL). The presence of isolated TP53 mutation (without deletion) is associated with reduced survival in CLL patients. It is unclear how these abnormalities are selected and what their mutual proportion is. We used methodologies with similar sensitivity for the detection of deletions (interphase fluorescence in situ hybridization) and mutations (yeast functional analysis) and analyzed a large consecutive series of 400 CLL patients; a subset of p53-wild-type cases (n ‫؍‬ 132) was screened repeatedly during disease course. The most common type of TP53 inactivation, ie, mutation accompanied by deletion of the remaining allele, occurred in 42 patients (10.5%). Among additional defects, the frequency of the isolated TP53 mutation (n ‫؍‬ 20; 5%) and the combination of 2 or more mutations on separate alleles (n ‫؍‬ 5; 1.3%) greatly exceeded the sole deletion (n ‫؍‬ 3; 0.8%).Twelve patients manifested defects during repeated investigation; in all circumstances the defects involved mutation and occurred after therapy. Monoallelic defects had a negative impact on survival and impaired in vitro response to fludarabine. Mutation analysis of the TP53 should be performed before each treatment initiation because novel defects may be selected by previous therapies. (Blood. 2009;114:5307-5314)

TP53 mutation profile in chronic lymphocytic leukemia: evidence for a disease specific profile from a comprehensive analysis of 268 mutations

“…[4][5][6]8 Because of the profound clinical impact of TP53 mutation in CLL, there is a continuing interest in its further characterization not only from a clinical and diagnostic but also a mechanistic perspective. In this respect, it is important to gain insight into the mutation profile of CLL.…”

“…2,3 In addition, TP53 mutations have been associated with poor prognosis in numerous cancers including lymphomas and chronic lymphocytic leukemia (CLL). [4][5][6][7][8] Mutations of TP53 are found in 4 to 37% of patients with CLL, and unselected cohorts of untreated patients can be expected to show TP53 mutations in the order of 10%. [4][5][6][7][8][9][10] The highest incidence of TP53 mutation is seen in patients with fludarabine refractory CLL and much of the heterogeneity in mutation prevalence is explained by different patient cohorts.…”

“…[4][5][6][7][8] Mutations of TP53 are found in 4 to 37% of patients with CLL, and unselected cohorts of untreated patients can be expected to show TP53 mutations in the order of 10%. [4][5][6][7][8][9][10] The highest incidence of TP53 mutation is seen in patients with fludarabine refractory CLL and much of the heterogeneity in mutation prevalence is explained by different patient cohorts. 7 The presence of mutations in TP53 has been associated with poor prognosis in a number of retrospective studies, but the association of 17p deletion and TP53 mutation has led to the pooling of mutations with 17p deletion (usually the majority) and cases without 17p deletion.…”

“…In more recent studies, a comprehensive molecular genetic characterization with mature follow-up including fluorescence in situ hybridization and immunoglobulin heavy chain variable region (IGHV) mutation status defined the clinical impact of TP53 mutations in CLL (4-6). 8 Because of the relatively low frequency of TP53 mutations, few studies to date have assessed the particular mutation profile in CLL. The studies that have been reported included 13À46 patients with mutations and therefore these results are subject to bias.…”

Clinical impact of recurrently mutated genes on lymphoma diagnostics: state-of-the-art and beyond

“…22 Such aberrations are due to (i) deletions of chromosome 17p (covering the TP53 gene) seen in 5-10% of patients at diagnosis, which are often associated with TP53 mutations on the remaining allele; and, (ii) in a small fraction of CLL patients (3-6%), mutations within the TP53 gene only. [23][24][25] Both types of aberrations (i.e. 17p-deletions and TP53 mutations) are equally adverse in CLL, portending for refractoriness to standard chemoimmunotherapy and poor overall survival.…”