Incidence Of TP53 Mutations Research Articles

Consistent TP53 mutations in BRCA1 and sporadic basal-like breast tumors, while infrequent in luminal BRCA1 tumors.

Abstract Abstract #4070 Breast tumors with a germline mutation of BRCA1 (BRCA1 tumors) and Basal-Like Carcinoma (BLC) have been shown to be associated with a high rate of TP53 mutations. Because it has also been shown that BRCA1 tumors frequently display a basal-like phenotype, we sought to determine whether TP53 mutations were correlated to the hereditary BRCA1 mutated status or to the particular histological type of these tumors. We first explored the status of the TP53 gene in a series of 28 BRCA1 BLCs using immunohistochemistry, direct sequencing of the coding sequence, and functional assay in yeast (FASAY), and compared it to the status of TP53 in 27 series of sporadic (non hereditary) BLCs. With this sensitive approach, TP53 was found consistently mutated in BRCA1 (28/28) and sporadic (26/27) BLCs. However, mutation spectrum was different, in particular with a much higher rate of insertion/deletion in BRCA1 BLCs (12/27) than in the sporadic group (2/25). Secondly, we analyzed the incidence of TP53 mutations in 10 BRCA1 luminal tumors, using the same strategy. Surprisingly, only 3 of these 10 tumors were mutated, a frequency similar to that found in matched sporadic luminal tumors. In conclusion, TP53 mutation is a mandatory event in BRCA1 or sporadic BLCs, but not a common feature of BRCA1 luminal tumors. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4070.

Screening for TP53 Mutations Identifies Chronic Lymphocytic Leukemia Patients with Rapid Disease Progression.

Screening for cytogenetic aberrations with a selected panel of FISH probes has identified important prognostic subgroups in chronic lymphocytic leukemia (CLL). Good prognosis CLL patients with deletions of the long arm of chromosome 13 (del13q) as sole aberration are opposed by patients with deletions of the short arm of chromosome 17 (del17p). The tumor suppressor gene TP53 is located at 17p13 and loss of TP53 is hypothesized to be at least partially responsible for the poor prognosis of del17p CLL patients. However, it is not clear, if the loss of other genes in the deleted region contributes to the poor prognosis. In addition, the degree of overlap between the patient populations defined by del17p and TP53 mutation is only poorly defined. Therefore, we characterized peripheral blood or bone marrow samples of 193 CLL patients by FISH analysis and screened for TP53 mutations by two methods, i.e. by denaturing high performance liquid chromatography (dHPLC) and by a microarray-based resequencing assay, the AmpliChip p53 Test. PCR products of exons 3–9 of TP53 were screened by dHPLC and aberrant fragments were analyzed by direct sequencing, whereas the entire coding region including the splice sites of exons 2–11 were analyzed with the AmpliChip p53 Test. The overall incidence of TP53 mutations by both methods was 13.5% (26/193), whereas the incidence of del17p by FISH was 9.3% (18/193). Interestingly, 17 out the 18 del17p samples carried a TP53 mutation suggesting that loss of TP53 does indeed play a pivotal role in the poor prognosis of del17p. At least 9 samples carried a TP53 mutation only. The AmpliChip p53 Test detected 32 mutations in 25 patients compared to 24 mutations detected in 20 patients by dHPLC/direct sequencing. The AmpliChip p53 Test, which is designed to detect single nucleotide substitutions and single nucleotide deletions, did not detect 3 mutations (1 1-bp deletion, 1 4-bp deletions, 1 single nucleotide insertion). The method of dHPLC followed by direct sequencing did not call 10 single nucleotide mutations. Of these, 1 mutation was located in exon 10 not included in the dHPLC screening. The remaining 9 mutations were detected by dHPLC analysis, but failed to be called by direct sequencing. The clinical course of patients with TP53 aberrations (n=20) (del17p and/or TP53 mutation) was compared to 113 patients lacking these abnormalities. Patients with TP53 aberration had a highly significantly decreased time to progression compared to patients without TP53 aberration (p<0.001, median 13.2 vs. 64.4 months). This difference remained significant when analysis was restricted to patient samples without prior therapy (p<0.001, median 9.2 (n=13) vs. 70.6 months (n=101)). As FISH analysis for del17p is the standard approach to detect TP53 aberrations, we compared the clinical course of patients with del17p (n=8) to patients with TP53 mutation (without del17p) (n=7) vs patients without TP53 aberration (n=113). This analysis resulted in a median time to progression of 9.2 vs 22.4 vs 63.4 month, respectively (p<0.001). The data of the present analysis suggest that TP53 mutation might be one of the factors conferring poor prognosis to CLL patients. Likewise, we identified 9 samples (4.7%) with TP53 mutation alone with poor clinical course that would have escaped detection by FISH analysis.

The Incidence of TP53 Mutations Is Low in Leukemia Overall but High in the Subgroups with Complex Aberrant Karyotypes: A Study on 309 Cases.

TP53 is the key tumor suppressor that regulates the response of the cell to DNA damage and various types of cellular stress. As a result TP53 activates signaling pathways for the induction of cell cycle arrest or apoptosis, thereby preventing the transmission of chromosomal aberrations and mutations to daughter cells. The incidence of TP53 aberrations in solid tumors like colorectal cancer is often high with 50% of patients being affected. At the same time a complex pattern of cytogenetic abnormalities is observed. However, the incidence of TP53 mutations is overall low in leukemia amounting to about 10% of patients. Oftentimes, these cases are associated with poor overall survival. To characterize TP53 aberrations in different leukemia entities, i.e. AML and CLL, in more detail, we analyzed unselected patient populations with a combination of chromosomal banding analysis and mutation screening of the TP53 gene (exons 3–9, amino acids 26-331) by denaturating high performance liquid chromatography (DHPLC) in conjunction with direct sequencing. In both disease entities, AML (n = 149) and CLL (n = 160), a comparable fraction of patients with TP53 mutations was detected with 13.4% (n = 20) and 9% (n = 14), respectively. A highly significant correlation of TP53 mutations and complex aberrant karyotypes was found in comparison to other cytogenetic subclasses in both leukemia entities (p < 0.001). Complex aberrant karyotypes were defined by the presence of 3 and more clonal abnormalities indicating an underlying mechanism for genetic instability. Of the 20 complex aberrant karyotypes in AML 17 (85%) were TP53-mutated while 10 of 22 complex aberrant CLL cases (46%) were affected. In CLL with complex aberrant karyotype there was a trend towards a significant association of a higher median age with TP53 mutations (74 y vs 69 y, p = 0.077, t-test). Comparable to other tumor types like colon cancer we find a prevalence of missense over nonsense/frameshift mutations of TP53 in AML (80%) and in CLL (86%) comprising a higher frequency of GC to AT transitions with 70% and 64%, respectively. Most TP53 mutations are selected for impaired DNA-binding and, therefore, impaired transactivation of target genes. Consistent with this in our cohort of AML samples 15/16 missense mutations were located in the DNA-binding domain of TP53 (amino acids 101–292) and all 13 missense mutations in CLL were located in this region. The location of the mutation in the different exons of TP53 was not significantly different between AML and CLL. However, there was trend towards a clustering of TP53 mutations in exon 8 (between amino acids 273 and 290) in CLL samples with 50% of mutations (n = 7) located in this region compared to only 30% (n = 6) of AML TP53 mutations in exon 8. In conclusion, we find 1.) a low overall incidence of TP53 mutations in CLL and AML but 2.) a high incidence in cases with complex aberrant karyotypes and 3.) a high incidence of TP53 missense mutations (> 80%), which are almost exclusively located in the DNA-binding domain of TP53. We hypothesize that TP53 mutations allow for genetic instability and therefore for the accumulation of mutations in leukemic cells resulting in the high incidence of these mutations in complex aberrant karyotypes. In this scenario mutant TP53 might not only play a dominant negative role, but might even act as an oncogene with different mutations conferring different phenotypes to the tumor cells.