The detection of TP53 mutations in chronic lymphocytic leukemia independently predicts rapid disease progression and is highly correlated with a complex aberrant karyotype

Abstract

The poor prognosis of chronic lymphocytic leukemia (CLL) patients with del (17p) is well established. We analyzed whether mutation of TP53 on the remaining allele adds to the poor prognosis or whether even TP53 mutation alone may be an adverse prognostic factor. We analyzed TP53 mutations in 193 CLL patients by denaturing high performance liquid chromatography in combination with direct DNA sequencing and a TP53 resequencing research microarray. Mutations were correlated to chromosomal aberrations defined by interphase fluorescent in situ hybridization and chromosome banding analyses and to the clinical course of patients. TP53 mutations were detected in 13.5% (26 of 193) of samples, whereas the incidence of del (17p) was 9.3% (18 of 193). TP53 mutations were significantly associated with del (17p) (concordance 94%, P<0.001) and complex cytogenetic abnormalities (concordance 50%, P<0.001). Among 147 patients whose clinical data were available, patients with TP53 abnormalities (n=20) had a significantly decreased time to treatment compared to patients without TP53 aberration (P<0.001). Median time to treatment was short in patients with isolated TP53 mutation (n=6, 2.0 months) and in those with del (17p) (n=14, 21.3 months) as compared to patients without TP53 aberration (n=127, 64.9 months, P<0.001). In multivariate Cox regression analysis, VH status, TP53 mutations and also isolated TP53 mutations independently predicted rapid disease progression.

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.…”

Chronic lymphocytic leukemia and treatment resistance in cancer: The role of the p53 pathway

“…23 In another study by Dicker et al, two methods of mutation detection were combined, denaturing high performance liquid chromatography (dHPLC) and a microarray-based resequencing assay, the AmpliChip p53 Test (Roche molecular systems). 24 The overall incidence of TP53 mutations by both methods in their cohort was 13.5% (26/193) and the incidence of deletion 17p by FISH was 9.3% (18/193). Interestingly, 17 out the 18 cases with 17p deletion carried a TP53 mutation suggesting again that loss of TP53 function plays a pivotal role in the poor prognosis of 17p deletion.…”

An ultra-deep sequencing strategy to detect sub-clonal TP53 mutations in presentation chronic lymphocytic leukaemia cases using multiple polymerases

“…Chronic lymphocytic leukemia (CLL) is a heterogeneous disorder, characterised by clonally expanded CD5 positive B-cells carrying a range of genetic abnormalities some of which segregate with disease severity 3,7,8 . As with many other forms of cancer, an important abnormality associated with poor overall outcome and refractoriness to DNA damaging therapy, is dysfunctional p53 [9][10][11][12][13][14][15][16] .…”