Functional categories of TP53 mutation in colorectal cancer: results of an International Collaborative Study (original) (raw)
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Prognostic significance of TP53 gene mutation in 995 cases of colorectal carcinoma
European Journal of Cancer, 2000
Previous studies on the prognostic signi®cance of TP53 gene alterations in colorectal cancer (CRC) have led to con¯icting results. The present study investigated the prognostic signi®cance of TP53 gene mutation in a very large series of 995 Dukes' B and C CRC patients, the majority of whom did not receive chemotherapy. Mutations were found in 385 (39%) cases and were not associated with tumour stage, histological grade, patient age or sex. Signi®cantly more mutations were found in tumours from the left-sided colon compared with those from the right side (43% versus 34%, P=0.006). TP53 gene mutation had no prognostic value in the overall series or in dierent site or stage subgroups. None of the dierent types of TP53 gene mutation showed prognostic value. A trend for association with worse survival was observed in the patient subgroup that received adjuvant chemotherapy (Hazard Ratio (HR) 1.4, 95% con®dence interval (CI) 0.89±2.21, P=0.15). These results indicate that mutation of the TP53 gene is not a useful prognostic marker for CRC patients who do not receive adjuvant chemotherapy. Further study is required to determine whether dierent types of TP53 mutation might be of value in predicting the response of CRC patients to chemotherapy.
Annals of Oncology, 2005
Mutations in the Ki-ras and TP53 genes are the most frequently observed genetic alterations in colorectal cancer (CRC). Ki-ras mutations are mostly found in codons 12 and 13, and less in codon 61. The majority of the TP53 mutations occur in the core domain which contains the sequence-specific DNA binding activity of the protein, and they results in loss of DNA binding. Few centres have sufficient patients to collect detailed information in the large numbers required to determine the impact of individual ki-ras and TP53 genotypes on outcome. Moreover, it has been reported that specific genetic alterations, and not any mutation, might play a different biological role in cancer progression. For these principal reasons, two collaborative studies have been conducted (the RASCAL and the TP53-CRC Collaborative Studies) with the aim of investigating the prognostic role of any, and specific, Ki-ras and TP53 mutations in CRC progression. The results obtained from the RASCAL studies suggest that Ki-ras mutations might have an effect on the survival rate of CRC patients, and that the specific codon 12 glycine/valine mutation might play a role in the progression of this neoplasia. The results of the TP53-CRC International Collaborative Study demonstrate the importance of primary tumor site when analyzing the prognostic value of TP53 mutations in CRC. In addition, different types of TP53 mutation might play a pivotal role in determining the biological behavior of CRC from different sites and hence the prognosis of patients. This meta-analysis produced evidence for interesting tumor site differences in the predictive value of TP53 mutation for survival benefit from 5FU chemotherapy.
Journal of Cellular Physiology, 2002
p53 alterations are considered the most common genetic events in many types of neoplasms, including colorectal carcinoma (CRC). These alterations include mutations of the gene and/or overexpression of the protein. The aim of our study was to assess whether in 160 patients undergoing resective surgery for primary operable CRC there was an association between p53 mutations and protein overexpression and between these and other biological variables, such as cell DNA content (DNA-ploidy) and S-phase fraction (SPF), and the traditional clinicopathological variables. p53 mutations, identified by PCR-SSCP-sequencing analysis, were found in 68/160 patients (43%) and positive staining for p53 protein, detected with the monoclonal antibody DO-7, was present in 48% (77/160) of the cases, with agreement of 57% (91/160). In particular, a significant association was found between increased p53 expression and genetic alterations localized in the conserved regions of the gene or in the L3 DNA-binding domain and the specific type of mutation. Furthermore, both overexpression of p53 and mutations in the conserved areas of the gene were found more frequently in distal than in proximal CRCs, suggesting that they might be ''biologically different diseases.'' Although p53 mutations in conserved areas were associated with flow cytometric variables, overexpression of p53 and mutations in its L3 domain were only related respectively to DNA-aneuploidy and high SPF. These data may reflect the complex involvement of p53 in the different pathways regulating cell-cycle progression. In conclusion, the combination of the mutational status and immunohistochemistry of p53, and flow cytometric data may provide an important insight into the biological features of CRCs.
Annals of Oncology, 2005
Background: Although Ki-ras and TP53 mutations have probably been the genetic abnormalities most exhaustively implicated and studied in colorectal cancer (CRC) progression, their significance in terms of disease relapse and overall survival has not yet clearly been established. Patients and methods: A prospective study was carried out on paired tumor and normal colon tissue samples from a consecutive series of 160 previously-untreated patients, undergoing resective surgery for primary operable sporadic CRC. Mutations within the TP53 (exons 5 -8) and Ki-ras (exon 2) genes were detected by PCR-SSCP analyses following sequencing. Results: Mutation analyses of exons 5 to 8 of the TP53 gene showed mutations in 43% (68/160) of the cases, while mutation analyses of exon 2 of the Ki-ras gene showed mutations in 46% (74/160) of the cases. Multivariate analyses showed that clinical outcome were strongly associated with the presence of specific TP53 mutations in L3 domain alone (only in DFS) or in combination with specific Ki-ras mutations at codon 13. Conclusion: Specific TP53 mutations in L3 domain alone (only in DFS) or in combination with specific Ki-ras mutations at codon 13 are associated with a worse prognosis in sporadic CRC.
Role of TP53 Gene Mutations in the Pathogenesis of Colorectal Carcinoma
Journal For International Medical Graduates
Colorectal cancer (CRC) is the third most commonly diagnosed cancer in both men and women in the world. The underlying molecular mechanisms that drive colorectal carcinogenesis are not fully known. However, P53 gene mutation, the most reported somatic mutation, is observed in about 50% of colorectal cancer patients. Colorectal carcinoma is multifactorial. TP53 gene, the most novel tumor suppressor gene, acts as a major gatekeeper by preserving the genetic composition of a cell and prevents the oncogenic transformation of a cell. MDM2 and CUL-4A belong to the E3 ubiquitin ligase family, blocks P53 activation, and thus act as an oncogene. TRIM67 also has defective ligase activity, and its mutation is seen in about 80% of colorectal carcinomas. miRNA inhibits the tumor suppressor effect of TP53 and downstream signaling pathways, resulting in carcinogenesis. K RAS, WT1, IGF-1 are other markers of colorectal carcinoma. P53 antibodies produce by colorectal carcinomatous tissue are the mar...
Journal of Cellular Physiology, 2002
p53 alterations are considered the most common genetic events in many types of neoplasms, including colorectal carcinoma (CRC). These alterations include mutations of the gene and/or overexpression of the protein. The aim of our study was to assess whether in 160 patients undergoing resective surgery for primary operable CRC there was an association between p53 mutations and protein overexpression and between these and other biological variables, such as cell DNA content (DNA-ploidy) and S-phase fraction (SPF), and the traditional clinicopathological variables. p53 mutations, identified by PCR-SSCP-sequencing analysis, were found in 68/160 patients (43%) and positive staining for p53 protein, detected with the monoclonal antibody DO-7, was present in 48% (77/160) of the cases, with agreement of 57% (91/160). In particular, a significant association was found between increased p53 expression and genetic alterations localized in the conserved regions of the gene or in the L3 DNA-binding domain and the specific type of mutation. Furthermore, both overexpression of p53 and mutations in the conserved areas of the gene were found more frequently in distal than in proximal CRCs, suggesting that they might be ''biologically different diseases.'' Although p53 mutations in conserved areas were associated with flow cytometric variables, overexpression of p53 and mutations in its L3 domain were only related respectively to DNA-aneuploidy and high SPF. These data may reflect the complex involvement of p53 in the different pathways regulating cell-cycle progression. In conclusion, the combination of the mutational status and immunohistochemistry of p53, and flow cytometric data may provide an important insight into the biological features of CRCs.
Clinical outcomes and correlates of TP53 mutations and cancer
Cold Spring Harbor perspectives in biology, 2010
The initial observation that p53 accumulation might serve as a surrogate biomarker for TP53 mutation has been the cornerstone for vast translational efforts aimed at validating its clinical use for the diagnosis, prognosis, and treatment of cancer. Early on, it was realized that accurate evaluation of p53 status and function could not be achieved through protein-expression analysis only. As our understanding of the p53 pathway has evolved and more sophisticated methods for assessment of p53 functional integrity have become available, the clinical and molecular epidemiological implications of p53 abnormalities in cancers are being revealed. They include diagnostic testing for germline p53 mutations, and the assessment of selected p53 mutations as biomarkers of carcinogen exposure and cancer risk and prognosis. Here, we describe the strengths and limitations of the most frequently used techniques for determination of p53 status in tumors, as well as the most remarkable latest findings...
Molecular characterization of TP53 tumor suppressor gene in colorectal cancer
Revista Colombiana de Gastroenterologia
Introduction: Colorectal cancer (CRC) is one of the most common malignancies in the world, especially in developed countries. In Colombia, the incidence of CRC ranks fourth in men and women. CRC has great genetic heterogeneity. Purpose: The purpose of this study was to determine the presence of mutations in exons 5 to 8 of the TP53 gene in colorectal tumors by direct sequencing. Patients and Methods: Samples with histopathological diagnoses of sporadic CRC were divided into two groups. Group I included 30 tumor samples from fresh biopsies and Group II included 46 tumor tissue samples embedded in paraffi n blocks. Mutational analysis was performed for exons 5 through 8 of the TP53 gene using PCR and direct sequencing. Results: The frequency of TP53 mutations was only 4.4%, and mutations that were detected were nonsense mutations. In addition, two polymorphisms that segregate together were identifi ed. All mutations and polymorphisms were detected in samples from Group I. Most of the samples were in advanced stages of cancer. Conclusions: The low frequency of mutations in TP53 suggests the existence of alterations on other related genetic pathways in colorectal carcinogenesis. These could include MSI pathways, CIN and epigenetics. Such alterations could not be excluded in the samples tested. Molecular studies of tissue samples embedded in paraffi n are diffi cult to analyze genetically. Molecular characterization of CRC is important for determining the spectrum of mutations and molecular variants present in our population.