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PubMedDate not supplied

TP53 mutations in human meningiomas.

Overexpression of p53 has been reported to play a role in the development of neoplasms of the central nervous system. Meningiomas are generally benign intracranial tumors originating from the meninges. Overexpression of the p53 protein in meningiomas and an association with histological type and recurrence has been reported. Mutation of the TP53 gene leads to a more stable p53 protein in quantities high enough for detection by immunohistochemistry. In the search for these mutations the core domain of the TP53 gene of meningiomas has been analyzed. Only a very low incidence of mutations was reported. The apparent discordance between overexpression of p53 protein and TP53 gene mutations may be explained by mutations located outside the core domain. This issue was addressed in the present study. All 11 exons of 17 meningiomas were analyzed for DNA alterations by PCR single-strand conformation polymorphism (PCR-SSCP) analysis with subsequent sequencing. PCR-SSCP analysis showed a various number of band shifts and nucleotide alterations, caused either by alterations in the flanking introns or common polymorphisms (codon 36 and 72). The allele frequencies of the polymorphisms found in this small population of tumors resemble the frequencies reported in the literature. In addition, three nucleotide changes located in introns 2, 3 and 7 were found in 11, 3 and 4, respectively, of 17 specimens. Based on this study and on reports by others we conclude that it is not very likely that TP53 mutations are involved in the etiology of meningiomas.

Adult↗

PubMed2004

TP53 mutations in squamous-cell carcinomas of the conjunctiva: evidence for UV-induced mutagenesis.

Squamous cell carcinoma of the conjunctiva is associated with sun exposure and often occurs in HIV-positive individuals. We have analysed TP53 mutations in 21 cases of squamous cell carcinoma and 22 controls with benign conjunctival lesions from a region (Uganda, Africa) with a high prevalence of heavy sun exposure and HIV infection. TP53 mutations were detected in 11 cases (52%) and 3 controls (14%). Seven of the mutations (6 in cases and 1 in controls) were CC-->TT transitions, a molecular signature of mutagenesis by solar UV rays. A similar prevalence (56%) of TP53 mutations was found in 18 squamous cell carcinoma cases positive for epidermodysplasia verruciformis human papillomavirus types. The prevalence of CC-->TT transitions reported here is the highest observed in any cancer type and matches that of skin cancers in subjects with xeroderma pigmentosum, an inherited disease with hypersensitivity to UV damage. These results confirm at the molecular level the causal role of solar UV rays in the aetiology of squamous cell carcinoma of the conjunctiva and suggest that infection with epidermodysplasia verruciformis types of human papillomavirus may act as a cofactor to increase the sensitivity of conjunctiva cells to UV-induced mutagenesis.

Adult↗

PubMed1994

No TP53 mutations in neuroblastomas detected by PCR-SSCP analysis.

We have analysed 29 neuroblastomas for TP53 mutations in exons 5 to 8 by means of the polymerase chain reaction in combination with the single-strand conformation polymorphism technique. We could not detect any mutation. These results indicate that, in contrast to the majority of tumors so far studied, TP53 mutations do not seem to be important for the development of neuroblastomas.

DNA, Neoplasm↗

PubMed2000

TP53 mutation is an independent prognostic marker for poor outcome in both node-negative and node-positive breast cancer.

TP53 gene-mutation and protein expression of p53 are described as being of prognostic importance for the outcome of breast cancer. The present study was therefore carried out to evaluate whether TP53 mutation would be a feasible prognostic marker in the routine diagnostic evaluation of breast cancer, and, in particular, to analyse the relationship between TP53 mutation and nodal status. Tumour material was obtained from women with sporadic early breast cancer. Gene mutations in exon 2-11 were identified using denaturing gradient gel electrophoresis (DGGE) as the initial scanning procedure and characterized by sequencing. All patients were treated according to the guidelines of the Danish Breast Cancer Cooperative Group for the DBCG 89 protocols. The results were correlated with clinico-pathological parameters and the prognosis evaluated by uni- and multivariate analysis using local control, freedom from distant metastasis, disease-free survival, and overall survival as endpoints. The study included 294 patients. TP53 mutations were found in 23% of cases. Mutations were significantly more frequent in tumours from patients who were node-positive and with tumours characterized as being ductal, large of size, with a high degree of anaplasia, and oestrogen receptor negative. Using univariate analysis, it was found that distant metastasis, disease-free, and overall survival were correlated to tumour size, nodal status, degree of anaplasia, oestrogen receptor status, and TP53 mutation. In addition, overall survival was also correlated to age and menopausal status. When analysed according to nodal status, TP53 mutation was found to have a significantly poor survival probability in each of the subgroups. A Cox proportional hazard analysis, including all 294 patients, demonstrated that positive nodal status and TP53 mutation were the only parameters that had an independent poor influence on the risk of developing distant metastasis and reduced recurrence-free survival. The same factors together with postmenopausal status were found to be significantly associated with increased risk of death. TP53 mutation is a strong marker for the prediction of overall and disease-free survival in breast cancer, irrespective of nodal status. A better understanding of the role of the p53 pathway, including analysis of different types of TP53 mutations, is required in order further to investigate the prognostic potential of this marker.

Adult↗

PubMed2026

Coagulation activation is associated with genomic-instability-related features in TP53-mutated AML and MDS: routine laboratory patterns beyond classical disseminated intravascular coagulation.

BACKGROUND: Disseminated intravascular coagulation (DIC) is a serious complication of acute myeloid leukemia (AML) associated with poor prognosis. In TP53-mutated AML and myelodysplastic syndrome (MDS), however, the classical ISTH criteria rarely identify overt DIC, although bleeding and thrombotic complications are well documented in acute leukaemia. We hypothesized that these patients exhibit a lower-grade, subclinical coagulation activation that is associated with the underlying genomic-instability-related features of TP53-mutant disease. METHODS: We retrospectively analyzed 107 consecutive patients with TP53-mutated AML (n = 52) or high-risk MDS (MDS, n = 55), median age 65 years, diagnosed and initially evaluated at our centre between 2018 and 2025. Seven routine coagulation markers and 46 co-mutated genes were evaluated for associations with overall survival (OS) using univariate and multivariable Cox regression, continuous dose-response modeling, and unsupervised k-means clustering. Internal validity was assessed by 1000 bootstrap resamples. RESULTS: Overt DIC according to ISTH criteria was rare (15%). Subclinical activation was common: 50% of patients had a D-dimer ≥1 μg/mL, 41% a fibrinogen ≥4 g/L, and 29% an INR ≥1.2. In univariate analysis, D-dimer, fibrinogen, INR, prothrombin time, and activated partial thromboplastin time were each associated with OS (HR 1.33-1.38 per SD; all p < 0.05). Complex karyotype correlated with higher D-dimer (median 1.39 vs. 0.60 μg/mL, p = 0.022) and fibrinogen (3.91 vs. 2.53 g/L, p = 0.007), while TP53 variant allele frequency (VAF) showed modest positive correlations with D-dimer (ρ = 0.21), INR (ρ = 0.27), and PT (ρ = 0.27; all p < 0.05). Clustering identified three coagulation phenotypes: Silent (51%), Thrombo-inflammatory (31%), and Consumption-like (18%), showing a graded but statistically non-significant gradient in molecular features and a stepwise decline in median OS (14, 10 and 8 months; log-rank p = 0.041). After adjustment for complex karyotype, TP53 VAF, and favorable co-mutation count, the Consumption-like phenotype was associated with a non-significant increased risk (HR 1.83, 95% CI 0.92-3.65, p = 0.084), whereas favorable co-mutation pathways remained independently protective (HR 0.56, 95% CI 0.35-0.90, p = 0.016). CONCLUSION: In TP53-mutated AML/MDS, coagulation activation intensity is associated with the degree of genomic instability. The three phenotypes may add biological resolution beyond classical DIC and cytogenetic risk groups, but represent laboratory patterns rather than validated bleeding or thrombosis prediction tools. However, after accounting for genomic features, phenotypes were not independent predictors of outcome, with complex karyotype, TP53 VAF, and favorable co-mutation count driving prognosis. Because treatment intensity and other clinical confounders were not available, these survival associations are hypothesis-generating. Coagulation profiling remains inexpensive, widely accessible, and offers a practical window into disease biology that warrants prospective validation.

TP53↗

PubMed1996

Distribution of TP53 mutations among acute leukemias with MLL rearrangements.

Acute leukemias carrying MLL rearrangements are characterized by a high degree of clinical and immunologic heterogeneity, as demonstrated by variability in their immunophenotype, consistent with lymphoid or myeloid/monoblastic derivation, as well as their occurrence in distinct age groups from infancy to adulthood. Recently, it was shown that inactivation of the TP53 tumor suppressor gene occurs frequently in cases of acute lymphoblastic leukemia carrying MLL rearrangements. In order to assess the extent of TP53 inactivation throughout the immunophenotypic and clinical spectrum of MLL+ acute leukemias, we tested for TP53 mutations 29 cases of MLL+ acute leukemias displaying lymphoid (13 cases) or myeloid/monoblastic (16 cases) features and belonging to different age groups. Mutations were detected in 6/16 myeloid/monoblastic cases and in 3/13 lymphoid cases. Among myeloid/monoblastic leukemias, the TP53 mutations occurred in 3/4 infants, but only in 3/16 cases in other age groups. Overall, our data suggest that (1) TP53 inactivation is a relatively common event in leukemias with MLL rearrangements irrespective of the leukemic phenotype and of the patients' age; (2) at least two genetic lesions (i.e., MLL rearrangement and TP53 mutation) have accumulated in the short time (few weeks after the birth or conception of the child) corresponding to the development of acute leukemias of infancy.

Acute Disease↗

PubMed2006

Functional categories of TP53 mutation in colorectal cancer: results of an International Collaborative Study.

BACKGROUND: Loss of TP53 function through gene mutation is a critical event in the development and progression of many tumour types including colorectal cancer (CRC). In vitro studies have found considerable heterogeneity amongst different TP53 mutants in terms of their transactivating abilities. The aim of this work was to evaluate whether TP53 mutations classified as functionally inactive (< or=20% of wildtype transactivation ability) had different prognostic and predictive values in CRC compared with mutations that retained significant activity. MATERIALS AND METHODS: TP53 mutations within a large, international database of CRC (n = 3583) were classified according to functional status for transactivation. RESULTS: Inactive TP53 mutations were found in 29% of all CRCs and were more frequent in rectal (32%) than proximal colon (22%) tumours (P < 0.001). Higher frequencies of inactive TP53 mutations were also seen in advanced stage tumours (P = 0.0003) and in tumours with the poor prognostic features of vascular (P = 0.006) and lymphatic invasion (P = 0.002). Inactive TP53 mutations were associated with significantly worse outcome only in patients with Dukes' stage D tumours (RR = 1.71, 95%CI 1.25-2.33, P < 0.001). Patients with Dukes' C stage tumours appeared to gain a survival benefit from 5-fluorouracil-based chemotherapy regardless of TP53 functional status for transactivation ability. CONCLUSIONS: Mutations that inactivate the transactivational ability of TP53 are more frequent in advanced CRC and are associated with worse prognosis in this stage of disease.

Adenocarcinoma↗

PubMed2000

TP53 mutations and mdm2 protein overexpression in cholangiocarcinomas.

Tumor suppressor protein p53 is a positive regulator of MDM2 gene expression and the mdm2 protein can bind to p53, preventing the transactivation of p53 responsive genes, thus mimicking TP53 mutation. The authors looked for alterations that could affect, directly and indirectly, p53 function in 13 patients with extrahepatic cholangiocarcinoma. Molecular analysis by single strand conformation polymorphism and DNA sequencing revealed that TP53 gene mutations occurred in only 2 of 13 cholangiocarcinomas. High levels of mdm2 protein were found, by immunohistochemical staining, in 61% of the cholangiocarcinomas and in almost all specimens (70%) displaying stabilized p53 protein in the absence and in the presence of TP53 mutations. The finding of co-overexpressed mdm2 and p53 proteins in cholangiocarcinomas indicates that they can upregulate the expression of mdm2 protein to a level sufficient for binding and accumulating p53 in a presumably inactive complexed form. The presence of TP53 mutations or upregulation of MDM2 gene expression in 9 of the 13 cholangiocarcinomas strongly supports that the impairment of the p53 pathway is an important and specific step in cholangiocarcinoma pathogenesis. At variance with other authors, no alteration of p16ink4/CDKN2 gene was observed in all 13 cholangiocarcinomas.

Aged↗

PubMed2006

Polymorphisms in insulin-related genes predispose to specific KRAS2 and TP53 mutations in colon cancer.

Risk factors for colon cancer may not only influence the overall risk of cancer but also the risk for specific types of mutations. We evaluated the effect of polymorphisms in four insulin-related genes (G972R in IRS1, G1057D in IRS2, a CA repeat in IGFI and an A/C polymorphism at -202 of IGFBP3) on the risk of microsatellite instability and KRAS2 and TP53 mutations in a population-based set of 1788 cases of colon cancer and 1981 controls. The GR/RR IRS1 genotypes were associated with an increased risk of colon cancers with the KRAS2 G12D mutation (OR 2.3, 95% CI 1.5, 3.5 versus controls, OR 1.7, 95% CI 1.1, 2.6 versus KRAS2 wild type), the "no 192" IGFI genotype increased the risk of the KRAS2 G13D mutation (OR 2.3, 95% CI 1.2, 4.2 versus controls, OR 2.1, 95% CI 1.1, 4.0 versus wild type), and the DD IRS2 genotype increased the risk of the G12V KRAS2 mutation (OR 1.8, 95% CI 0.9, 3.5 versus controls, OR 2.0, 95% CI 1.0, 4.0 versus wild type). Polymorphisms in IRS1 and IGF1 were also associated with an approximately two-fold increased risk of specific TP53 mutations relative to controls without cancer. We conclude that polymorphisms in some insulin-related genes are associated with an increased risk of colon cancer with specific KRAS2 and TP53 mutations, implying a link between these genetic changes and specific mutational pathways in carcinogenesis.

Adult↗

PubMed2004

RAS, FLT3, and TP53 mutations in therapy-related myeloid malignancies with abnormalities of chromosomes 5 and 7.

Oncogenic mutations in the KRAS2, NRAS, or FLT3 gene are detected in more than 50% of patients with de novo acute myeloid leukemia (AML). RAS mutations are also prevalent in de novo myelodysplastic syndrome (MDS), especially chronic myelomonocytic leukemia and juvenile myelomonocytic leukemia. However, few studies have examined these genetic lesions in therapy-related myeloid malignancies. Monosomy 7/del(7q) and monosomy 5/del(5q) represent the most common cytogenetic abnormalities in therapy-related MDS and AML (t-MDS/t-AML) and are strongly associated with prior exposure to alkylating agents. Mutational analysis of bone marrow specimens from a well-characterized cohort of 26 t-MDS/t-AML patients with abnormalities of chromosomes 5 and/or 7 revealed 3 with RAS mutations. Further analyses of 23 of these cases uncovered one FLT3 internal tandem duplication and five TP53 mutations. The four patients with RAS or FLT3 mutations had monosomy 7, including one with abnormalities of chromosomes 5 and 7. One specimen demonstrated mutations in both KRAS2 and TP53. RAS and FLT3 mutations, which are thought to stimulate the proliferation of leukemia cells, appear to be less common in t-MDS/t-AML than in de novo AML, whereas TP53 mutations are more frequent.

Acute Disease↗

PubMed2005

O6-methylguanine-DNA methyltransferase methylation and TP53 mutation in malignant astrocytomas and their relationships with clinical course.

Epigenetic silencing of O(6)-methylguanine-DNA methyltransferase (MGMT) by promoter methylation can confer cancer cells with an increased sensitivity to alkylating chemotherapeutic agents and a higher susceptibility to TP53 transition mutations. The aim of our study was to assess the correlation of promoter methylation of the MGMT gene with TP53 mutations and the clinical characteristics of malignant astrocytomas. We analyzed the MGMT promoter methylation and TP53 mutations in 45 malignant astrocytomas (16 anaplastic astrocytomas and 29 glioblastomas multiforme) treated prospectively with 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-2(2-chloroethyl)-3-nitrosourea, interferon-beta and radiation therapy, and evaluated their clinical usefulness. MGMT promoter methylation was found in 17 (38%) of the 45 newly diagnosed malignant astrocytomas. A clear trend existed between MGMT methylation and G:C to A:T transition mutations of TP53 (p = 0.0596). Patients with MGMT-methylated tumors displayed a greater chance of responding to adjuvant therapy as compared with those with MGMT-unmethylated tumors (p = 0.0393). TP53 mutation was not significantly associated with the clinical response (p = 0.1310). While neither MGMT methylation nor TP53 mutation had a significant effect on prognosis of the whole population, the presence of MGMT methylation emerged as a significant predictor of a longer survival when exclusively analyzing 29 patients with glioblastomas multiforme. These findings highlight the importance of MGMT methylation as a specific predictive factor for responsiveness to nitrosourea chemotherapy.

Adult↗

PubMed1999

Isochromosome 17q in blast crisis of chronic myeloid leukemia and in other hematologic malignancies is the result of clustered breakpoints in 17p11 and is not associated with coding TP53 mutations.

An isochromosome of the long arm of chromosome 17, i(17q), is the most frequent genetic abnormality observed during the disease progression of Philadelphia chromosome-positive chronic myeloid leukemia (CML), and has been described as the sole anomaly in various other hematologic malignancies. The i(17q) hence plays a presumably important pathogenetic role both in leukemia development and progression. This notwithstanding, the molecular consequences of this abnormality have not been investigated in detail. We have analyzed 21 hematologic malignancies (8 CML in blast crisis, 8 myelodysplastic syndromes [MDS], 2 acute myeloid leukemias, 2 chronic lymphocytic leukemias, and 1 acute lymphoblastic leukemia) with i(17q) by fluorescence in situ hybridization (FISH). Using a yeast artificial chromosome (YAC) contig, derived from the short arm of chromosome 17, all cases were shown to have a breakpoint in 17p. In 12 cases, the breaks occurred within the Smith-Magenis Syndrome (SMS) common deletion region in 17p11, a gene-rich region which is genetically unstable. In 10 of these 12 cases, we were able to further map the breakpoints to specific markers localized within a single YAC clone. Six other cases showed breakpoints located proximally to the SMS common deletion region, but still within 17p11, and yet another case had a breakpoint distal to this region. Furthermore, using chromosome 17 centromere-specific probes, it could be shown that the majority of the i(17q) chromosomes (11 of 15 investigated cases) were dicentric, ie, they contained two centromeres, strongly suggesting that i(17q) is formed through an intrachromosomal recombination event, and also implicating that the i(17q), in a formal sense, should be designated idic(17)(p11). Because i(17q) formation results in loss of 17p material, potentially uncovering the effect of a tumor suppressor on the remaining 17p, the occurrence of TP53 mutations was studied in 17 cases by sequencing the entire coding region. In 16 cases, no TP53 mutations were found, whereas one MDS displayed a homozygous deletion of TP53. Thus, our data suggest that there is no association between i(17q) and coding TP53 mutations, and that another tumor suppressor gene(s), located in proximity of the SMS common deletion region, or in a more distal location, is of pathogenetic importance in i(17q)-associated leukemia.

Adolescent↗

PubMed1997

Screening for TP53 mutations in patients and tumours from 109 Swedish breast cancer families.

To estimate the prevalence of TP53 mutations in familial breast cancer, constant denaturant gel electrophoresis (CDGE) was used to screen exons 5-8 of the TP53 gene for germline mutations. Genomic DNA from 128 breast cancer patients belonging to 109 families with familial cancer were screened. No germline mutations were found in any of the patients. We also studied TP53 mutations in tumour DNA from 51 of the same individuals and found mutations in 14%. This is similar to what has been reported in sporadic breast cancer.

Breast Neoplasms↗

PubMed2004

Chromosomal comparative genomic hybridization abnormalities in early- and late-onset human breast cancers: correlation with disease progression and TP53 mutations.

Nearly 30% of the breast cancer patients in the Taiwanese community have their diseases diagnosed before the age of 40. Their 5-year survival rate is poorer than that of their late-onset breast cancer counterparts. Genomic abnormalities between these two breast cancer age groups were compared using comparative genomic hybridization (CGH) analyses. The sample set was made up of 44 early-onset (<35 years old) and 54 late-onset cases (>63 years old). Frequent CGH changes were noted, such as gains on 8q, 1q, and 17q and losses on 16q, 17p, and 8p. These were very similar for the two age groups, as well as for Taiwanese women and other ethnic populations. In contrast, several less common lesions, such as gains on 16p and 8p and losses on 11q and 9p, were significantly different between the early- and late-onset breast tumors. In addition, more profound chromosomal changes were consistently associated with the more advanced-stage tumors, and less expression of the estrogen and the progesterone receptors, and of HER-2/neu. About 19% of the breast cancers examined carried a TP53 mutation in exons 4-9. Of these, 88% (15/17) were missense point mutations and these were distributed randomly along the tested gene fragments without apparent clustering, as has been shown in certain other ethnic or regional studies. On average, patients carrying these TP53 mutations had 9.5 CGH lesions per case, compared to only 2.8 changes in samples that had no TP53 mutation. Our results indicate that certain genomic lesions, especially 11q loss, may play a role in early-onset breast tumor formation, and that combined use of genomic patterns and molecular targets may provide a useful tool for diagnostic, therapeutic, and prognostic purposes.

Adult↗

PubMed2005

FGFR3 and Tp53 mutations in T1G3 transitional bladder carcinomas: independent distribution and lack of association with prognosis.

FGFR3 and Tp53 mutations have been proposed as defining two alternative pathways in the pathogenesis of transitional bladder cancer. FGFR3 mutations are associated with low-grade tumors and a favorable prognosis. Tp53 alterations are associated with advanced tumors and, possibly, with a poor prognosis. We focus here on the subgroup of T1G3 superficial tumors because they are a major clinical challenge. Patients (n = 119) were identified from a prospective study of 1,356 cases. Mutations in FGFR3 (exons 7, 10, and 15) and Tp53 (exons 4-9) were analyzed using PCR and direct sequencing. All cases were followed for recurrence and death. Survival was analyzed using Kaplan-Meier curves and multivariable Cox regression. FGFR3 mutations were detected in 20 (16.8%) tumors; 100 mutations in Tp53 were found in tumors from 78 (65.5%) cases. Multiple alterations in Tp53 were present in 19 tumors (16%). Inactivating mutations were present in 58% of tumors. The combined mutation distribution (FGFR3/Tp53) was: wt/wt (34.5%), mut/wt (7.6%), wt/mut (48.7%), and mut/mut (9.2%), indicating that the presence of either mutation did not depend on the other (P value = 0.767). FGFR3 and Tp53 mutations were not associated with clinicopathologic characteristics of patients and did not predict, alone or in combination, recurrence or survival. Taking the risk of the wt/wt group as reference, the mutation-associated risks of cancer-specific mortality were: mut/wt 1.42 (0.15-13.75), wt/mut 0.67 (0.19-2.31), mut/mut 1.62 (0.27-9.59). These molecular features support the notion that T1G3 tumors are at the crossroads of the two main molecular pathways proposed for bladder cancer development and progression.

Aged↗

PubMed2006

BRCA1, BRCA2 and TP53 mutations in very early-onset breast cancer with associated risks to relatives.

Pathological mutations in BRCA1, BRCA2 and TP53 are associated with an increased risk of breast cancer. This study evaluated mutation frequency of these genes in early-onset breast cancer patients, and correlated this with family history and determined relative risks to family members. Patients with breast adenocarcinoma diagnosed 30 years were ascertained between 1980 and 1997. Family history was established and mutation screening of BRCA1, BRCA2 and TP53 genes was performed. Estimates of penetrance and relative risk were undertaken. DNA was obtained from 100/139 women. 17/36 familial cases had a BRCA1, BRCA2 or TP53 mutation. Of 64 non-familial cases, one BRCA2, two BRCA1 and two TP53 mutations were detected. Penetrance estimates (by age 70) for breast cancer were 84% for BRCA1 mutations and 91% for BRCA2 mutations and for ovarian cancer, 60% and 26%, respectively. Relative risks associated with mutations were consistent with previous studies. BRCA1 and BRCA2 mutations in patients with breast cancer 30 years are predicted strongly by family history. The majority of families with ovarian cancer were due to mutations in BRCA1/2 whereas these mutations only accounted for 30-50% of the excess breast cancers.

Adenocarcinoma↗

PubMed2001

TP53 mutation is related to poor prognosis after radiotherapy, but not surgery, in squamous cell carcinoma of the head and neck.

BACKGROUND AND METHODS: TP53 gene-mutation and expression of p53 have been described to influence the radiosensitivity of tumour cells from head and neck carcinomas. The present study was performed to evaluate whether TP53 mutation may influence the clinical outcome of head and neck cancer patients treated with radiotherapy or surgery. MATERIALS AND METHODS: DNA was extracted from formalin-fixed paraffin-embedded tissue sections from primary biopsies taken before radiotherapy. Gene mutations (in exons 5-9) were identified using denaturing gradient gel electrophoresis (DGGE) as the initial scanning procedure and characterized by sequencing. Patients were treated with primary radiotherapy or surgery alone. Treatment was given according to the DAHANCA schedules with 5 or 6 weekly fractions (2 Gy) of radiotherapy (66-68 Gy). Most patients were also treated with the hypoxic radiosensitizer Nimorazole. The results are reported as 5-year actuarial values, and differences estimated by log-rank analysis. RESULTS: The present analysis is based on 114 patients with squamous cell carcinoma of the larynx, pharynx and oral cavity diagnosed between March 1992 and October 1996. Ninety patients received primary radiotherapy alone and 21 were treated with surgery. TP53 mutations were found in 45 patients (39%) and in patients receiving radiotherapy, TP53 mutation was highly associated with poor prognosis. Loco-regional control rates (5-year actuarial values) for TP53 mutation was 29 vs. 54% for TP53 wildtype (P < 0.01). For disease-free survival the corresponding values were 13 and 38% (P < 0.01), respectively. The correlations were not found to be related to specific subtypes of mutations (e.g. missense mutations affecting DNA-contact or Zn-binding regions) but rather to the presence of any mutation at all. In contrast, TP53 mutation did not influence the response to surgery. CONCLUSIONS: A strong relationship was observed between TP53 mutation and poor prognosis (increased risk of loco-regional failure and death) in head and neck cancer patients given primary radiotherapy but not surgery.

Carcinoma, Squamous Cell↗

PubMed2003

Simultaneous use of DGGE and DHPLC to screen TP53 mutations in cancers of the esophagus and cardia from a European high incidence area (Lower Normandy, France).

We investigated TP53 mutation patterns in cancers of the esophagus and cardia of patients coming from Lower Normandy, a region situated in the highest incidence area in Europe. To screen tumor samples, we first used denaturing gradient gel electrophoresis (DGGE), a well-characterized technique which constituted our reference method. Then the results were compared with those obtained by denaturing high performance liquid chromatography (DHPLC), a recent and automatic screening technology. Analysis of the TP53 mutations profile showed that the detected alterations were mainly point mutations. Ninety-seven percent (33/34) of esophageal squamous cell carcinoma samples presented at least one mutation or polymorphism. The proportion of somatic, non-silent and sequence-confirmed mutations was 76% (26/34). The most common substitutions were G-->A transitions, which could be related to nitrosamines, acetaldehyde or factors prone to producing mucosal irritation, like hot beverages. G-->T transversions, which were also frequently detected, could originate from benzo[a]pyrene in tobacco smoke. A-->T transversions were not revealed in our series, which constitutes a discordance with mutational spectra already performed in north-western France. Concerning adenocarcinoma of the esophagus and cardia, the alteration frequency was 69% (11/16), with a majority of G-->A transitions at CpG dinucleotides. They are probably related to endogenous process mediated by inflammatory diseases like gastro-esophageal reflux and Barrett's esophagus. The main advantage provided by DHPLC was its ease of application. However, the optimization steps turned out to be quite critical, especially for sequences with high melting temperatures embedded in lower melting temperature fragments. Considering only the common sequences analyzed by the two techniques, four of the 46 positive samples detected by DGGE were not revealed by DHPLC. This result stresses the limited sensitivity of DHPLC compared with DGGE under the conditions described in this study.

Cardia↗