A case of myelodysplastic syndrome with an intronic point mutation of the p53 tumour suppressor gene at the splice donor site

Kikukawa, Masayuki; Aoki, Naoto; Mori, Mayumi

doi:10.1046/j.1365-2141.1998.00599.x

Cited by 6 publications

(6 citation statements)

References 11 publications

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“…26,27 Survival of patients with a p53 mutation after the detection of monosomy 17 was significantly shorter than in patients without such a mutation (n ϭ 3, 255 Ϯ 38 days, versus n ϭ 49, 782 Ϯ 97 days, P ϭ 0.0088), which is in accordance with previous reports. 26,38 As to the relationship between karyotype abnormalities and IHC, the occurrence of monosomy 17 and a complex karyotype were higher in patients with positive IHC, which is consistent with previously reported patients.…”

Section: Discussionsupporting

confidence: 91%

“…26,38 As to the relationship between karyotype abnormalities and IHC, the occurrence of monosomy 17 and a complex karyotype were higher in patients with positive IHC, which is consistent with previously reported patients. 26,27 Our data suggest that p53 analysis is useful for predicting the occurrence of leukemic transformation in MDS. Although IHC analysis alone is useful for predicting occurrence of leukemic transformation, analysis of p53 by IHC in combination with gene analysis may provide instructive information on leukemic transformation, chemotherapy resistance, and clinical outcome.…”

Section: Discussionmentioning

confidence: 77%

“…We had previously reported two of these mutations. 26,27 All patients with a mutation had the presence of a complex karyotype with monosomy 17, occurrence of leukemic transformation, and chemotherapy resistance.…”

Section: Resultsmentioning

confidence: 99%

“…Two were missense mutations (in codon 249 26 and 237) and one was a mutation in a splice donor site. 27 The mutation in codon 249 occurred in the early phase. This mutation may have occurred in the presence of the wild-type allele and might have contributed to the onset of the second event as discussed previously.…”

Section: Discussionmentioning

confidence: 99%

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Study of p53 in Elderly Patients with Myelodysplastic Syndromes by Immunohistochemistry and DNA Analysis

Kikukawa

Aoki

Sakamoto

et al. 1999

The American Journal of Pathology

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We analyzed the tumor suppressor gene product, p53, in elderly patients with myelodysplastic syndromes (MDS) and in overt leukemia patients after transformation from MDS using immunohistochemical techniques. We examined 52 MDS patients (mean age 79 years , range 68 to 96) from the time of initial diagnosis to death or development of overt leukemia. The myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic disorders predominantly affecting the elderly and often progressing to overt leukemia. Once designated as preleukemia, MDS have been studied as a model for multistep carcinogenesis. Although recent research has revealed oncogene mutations, such as RAS and FMS, in MDS, 1,2 the roles of tumor suppressor genes have been largely unclear.p53 is a tumor suppressor gene located on the short arm of chromosome 17, 3 and p53 mutations have been found among many kinds of malignancies. 4 Normal p53 protein is a multifunctional protein that participates in cell cycle regulation, apoptosis, cell immortality, and cancer cell response to chemotherapeutic agents. 5-7 Mutations of p53 have been found in MDS patients, but not as frequently as in other malignancies, and it has been speculated that they play important roles in the progression of the disease, development of overt leukemia, and therapeutic responsiveness. 8 -21 In the present study, we examined p53 in elderly patients with MDS and leukemia arising from MDS in order to clarify its clinical significance and the molecular mechanism of the evolution of this disease. We analyzed p53 protein by immunohistochemistry (IHC) and p53 gene mutations using single-strand conformation polymorphism of polymerase chain reaction (SSCP-PCR) products. The wild-type p53 protein has a short half-life and usually cannot be detected by IHC. However, mutated p53 typically has a prolonged half-life and is detectable in tissue sections of bone marrow or in peripheral blood. 21,22 IHC of blood or bone marrow slides is a sensitive method for early detection of p53 mutations, especially in heterogeneous cell populations, such as in MDS. 23 We report the characteristics of p53 IHC and the clinical significance of p53 expression in elderly MDS patients.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 77%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Study of p53 in Elderly Patients with Myelodysplastic Syndromes by Immunohistochemistry and DNA Analysis

Kikukawa

Aoki

Sakamoto

et al. 1999

The American Journal of Pathology

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“…Although point mutations and single base insertions are the most common alterations to the p53 gene, small deletions have been reported in late‐stage B‐CLL (Gandini et al , 1994). Intronic mutations of p53 have been observed in Li–Fraumeni syndrome (Varley et al , 1998), hepatocellular carcinoma (Lai et al , 1993), lung cancer cell lines (Takahashi et al , 1990), myelodysplastic syndrome (Kikukawa et al , 1998) and a chronic myeloid leukaemia (CML) blast crisis cell line (Foti et al , 1990). These reported mutations, which affected both splice donor (four cases) and acceptor (four cases) sites, led to aberrant splicing of p53 mRNA in all cases.…”

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confidence: 99%

p53 intronic point mutation, aberrant splicing and telomeric associations in a case of B‐chronic lymphocytic leukaemia

et al. 2000

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Summary. We report a case of chronic lymphocytic leukaemia (CLL) with telomeric associations and a p53 intronic point mutation. Karyotypic analysis revealed clonal and non-clonal telomeric associations, accompanied by clonal cytogenetic abnormalities and also in isolation. The p53 mutation, which occurred at the invariant base pair 22 of the splice acceptor site in intron 7 resulted in the abolition of correct splicing of exon 7 to exon 8. Multiple aberrant splice products were characterized, all of which differed from wildtype in the DNA binding domain. Fluorescence in situ hybridization demonstrated that the clone retained two copies of the p53 gene and wild-type p53 transcript was detected on cloning of reverse transcriptase polymerase chain reaction (RT-PCR) product, indicating that one wild-type allele remained. However, a plasmid clone with correct splicing at the exon 7/8 boundary, but with a 21 bp deletion in exon 8, was also found at low frequency. This finding indicates clonal evolution, resulting in complete loss of wild-type p53. The intronic point mutation was not present in DNA extracted from cervical tissue indicating that it was a leukaemic phenomenon. This is the first case of an intronic point mutation to be reported in CLL. This mutation led to chaotic p53 expression and, interestingly, occurred in a case showing telomeric associations, a rare phenomenon in B-CLL.

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Splice mutations in the p53 gene: case report and review of the literature

et al. 2002

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Splice mutations in the p53 gene (TP53) are described as rare events that occur at a frequency of less than 1%. Using a functional assay based on the transcriptional activity of p53 and using RNA as starting material, we describe here a p53 splice mutation that could not be detected by genomic sequencing. This lack of detection is due to a deletion of the region complementary to primers commonly used for amplification. Reviewing the literature, we show that p53 splice mutations have been certainly underestimated and that careful strategy should be used for a complete mutational analysis of the p53 gene. Furthermore, some p53 gene mutations described as "neutral" due to the absence of any amino-acid change are truly deleterious, as they affect gene splicing.

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A case of myelodysplastic syndrome with an intronic point mutation of the p53 tumour suppressor gene at the splice donor site

Cited by 6 publications

References 11 publications

Study of p53 in Elderly Patients with Myelodysplastic Syndromes by Immunohistochemistry and DNA Analysis

Study of p53 in Elderly Patients with Myelodysplastic Syndromes by Immunohistochemistry and DNA Analysis

p53 intronic point mutation, aberrant splicing and telomeric associations in a case of B‐chronic lymphocytic leukaemia

Splice mutations in the p53 gene: case report and review of the literature

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