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PubMed2002

A region close to Tp53 shows LOH in familial breast cancer.

The proportions of mutation of BRCA1 and BRCA2 detected in familial breast cancer vary in different regions. Most breast cancer families in Sweden cannot be explained by mutations in the known major susceptibility genes. Our previous studies have found a high frequency of LOH in the Tp53 region in familial breast cancer suggesting a putative tumor suppressor gene in this region, and the Tp53 gene was excluded as predisposing gene in these families by mutation screening. In order to identify other candidate tumor suppressor genes responsible for familial breast cancer, we performed LOH analysis in 98 paired tumor and blood samples from 91 breast cancer families using 11 microsatellite markers on chromosome 17p. Two loci with high frequency of LOH were found. One spanned the Tp53 gene, the other was distal to Tp53. Linkage studies were performed on 17p with 11 microsatellite markers in 102 breast cancer families with no detectable mutations in the BRCA1 and BRCA2 gene. The linkage analysis did not further support any of the regions suggested by the LOH study. However, since the Tp53 gene is already known to predispose to breast cancer as well as being involved in tumor progression, it is possible that also this region, close but distal to Tp53 contains a gene involved in familial and/or sporadic breast cancer development similar to Tp53.

Adult↗

PubMed2003

Selection pressures of TP53 mutation and microenvironmental location influence epidermal growth factor receptor gene amplification in human glioblastomas.

Epidermal growth factor receptor (EGFR) gene amplification occurs in glioblastomas as so-called double minutes. Because double minutes are extrachromosomal fragments, selection pressures must operate to maintain high EGFR copy number over multiple cell divisions. In analyses of glioblastoma lysates, EGFR amplification has been observed almost exclusively in glioblastomas harboring wild-type TP53 genes, which raises the alternative hypotheses that TP53 mutation either prevents amplification or selects against maintenance of EGFR-amplified cells. To address these possibilities at the cellular level, we studied 14 glioblastomas for TP53 mutation and EGFR gene amplification status, using fluorescence in situ hybridization (FISH) for the latter. Remarkably, four of the six cases with TP53 mutation had isolated EGFR-amplified cells in different regions, demonstrating that EGFR amplification occurs frequently at the cellular level in TP53-mutant glioblastomas. Thus, TP53 mutation does not prevent EGFR amplification but does not facilitate selection of EGFR-amplified cells. Of the eight cases without TP53 mutation, five had widespread EGFR amplification. In four of these five cases, multiple regions of the tumor were available for examination; FISH demonstrated a gradation of EGFR amplification, with highly amplified cells, primarily at the invading edges rather than the relatively solid tumor centers, suggesting that EGFR overexpression, when selected for in vivo, may be related to tumor invasion.

ErbB Receptors↗

PubMed2004

DSCP1, a novel TP53-inducible gene, is upregulated by strong genotoxic stresses and its overexpression inhibits tumor cell growth in vitro.

TP53-inducible genes play crucial roles from many biological aspects including cell cycle control, DNA repair, and apoptosis. Herein we report the identification and characterization of a novel TP53-inducible gene, DSCP1 (damage stimulated cytoplasmic protein 1), localized at 17q11. The gene was expressed ubiquitously in normal adult tissues; its protein product was localized mainly in the cytoplasm with anchoring on unknown subcellular structures. Exogenous expression of TP53 induced expression of DSCP1, but more interestingly, DSCP1 was induced by strong genotoxic stresses not only in TP53-maintaining cells but also in TP53-dysfunctioning cells, although the induction was much more efficient in the former than in the latter. In cultured cancer cells, the basal expression level appeared to depend on the functional status of TP53. Moreover, exogenous overexpression of DSCP1 retarded cancer cell growth in vitro. These results indicate that DSCP1 is a stress-inducible gene in both a TP53 dependent and independent manner and that its protein product can inhibit cancer cell growth.

Amino Acid Sequence↗

PubMedDate not supplied

TP53 abnormalities are frequent and early events in the sequential pathogenesis of gallbladder carcinoma.

BACKGROUND: Gallbladder carcinoma (GBC) is a frequent neoplasm in Hispanic and native American populations. GBC is preceded by gallstones, chronic cholecystitis and dysplastic changes of the gallbladder epithelium. The knowledge of the molecular events involved in its pathogenesis is scarce. AIMS: We investigated the role of TP53 inactivation in the sequential pathogenesis of GBC. METHODS: Invasive tumor-, dysplastic- and histologically normal GB epithelial-cells were obtained from archival formalin-fixed tissues from GBC and GB from gallstone patients without GBC. Normal GB epithelia from 5 non-gallstone specimens were also studied. DNA extracted was examined for loss of heterozygosity (LOH) using 2 microsatellite markers and for TP53 mutations at exons 5 to 8. RESULTS: GBCs demonstrated a high frequency of LOH (81%) and mutation (67%), and both abnormalities indicating gene inactivation were detected in 52%. Similar frequency of TP53 abnormalities and gene inactivation (38%) were detected in their accompanying normal and dysplastic epithelia. Noteworthy, one third of normal and dysplastic epithelia obtained from GBs of gallstone patients without GBC demonstrated either TP53 allele loss or mutation, but gene inactivation was less frequent (11%). Most mutations affected exons 5 and 7, and they were more frequently missense point mutations. The same TP53 mutation was detected in only a subset (27%) of comparisons between non-malignant epithelia adjacent to GBCs, indicating that TP53 mutation occurs independently at several epithelial foci. CONCLUSIONS: These findings indicate that TP53 abnormalities are early and frequent events in the pathogenesis of GBC, starting from chronic cholecystitis.

Aged↗

PubMed2006

TP53 codon 72 polymorphism in radiation-associated human papillary thyroid cancer.

The study investigated an association between the germline polymorphism at TP53 codon 72 and the development of papillary thyroid cancer (PTC) following exposure to radiation from the Chernobyl accident. TP53 genotype was examined in 48 pediatric/adolescent (age at diagnosis <18 years) and 68 adult post-Chernobyl patient with PTC, 53 adult patients with sporadic PTC and 313 healthy individuals from Russian-Ukrainian population. In addition, we evaluated loss of heterozygosity for TP53 and the allele expression ratio. The genotype of the patients was correlated with clinicopathological data. Arg TP53 homozygotes were found to be significantly underrepresented among adults with post-Chernobyl PTC, but not in children and adolescents when compared with sporadic PTC cases and the general population. In the tumors, cell transformation did not lead to allelic loss or biased TP53 allele expression in heterozygous individuals. None of TP53 genotypes specifically associated with tumor stage and morphology, however there were particular correlations with lymph node status in certain age groups of radiation-associated cases not seen in sporadic PTCs. The findings suggest TP53 allele combinations other than Arg/Arg may contribute to the risk of development of PTC in individuals exposed to radiation during their late childhood, adolescence or in young adulthood.

Adolescent↗

PubMed1997

The relationship between TP53 mutations and overexpression of p53 and prognosis in malignant gliomas of childhood.

The prognosis for children with high-grade gliomas remains somewhat unpredictable. Although prolonged disease control is sometimes achieved after surgery, radiotherapy, and chemotherapy, most patients exhibit rapid disease progression. Because p53-dependent apoptosis mechanisms are involved in the cytotoxic effects of irradiation and chemotherapy, we questioned whether p53 status might be associated with outcome in childhood malignant gliomas. Therefore, we examined p53 status, both immunohistochemically and by direct sequencing of exons 5-8, in a series of 29 archival pediatric malignant non-brainstem gliomas treated consecutively at our institution between 1975 and 1992. Eighteen tumors had dense p53 staining in the majority of cells, although only 11 had mutations of the p53 gene (TP53). On univariate analysis, there was a significant association between p53 overexpression and a shorter progression-free survival (PFS) and overall survival (OS; P = 0.019 and 0.013, respectively; rank sum test). In addition, there was a significant association between TP53 mutations and a poorer PFS (P = 0.04), and a strong trend toward a shorter OS among patients with TP53 mutations (P = 0.06). Median PFS and OS for patients with TP53-mutated tumors were 6 months and 16 months, respectively, and for those with p53 overexpression 5.5 months and 14 months, respectively, versus 16 months and 25 months, respectively, for those without TP53 mutations and 25 months and >4 years, respectively, for those without p53 overexpression. The percentage of patients in this series with TP53 mutations (37.9%) was substantially higher than in previous studies of childhood gliomas and comparable to the frequency of mutations noted in adult gliomas. However, both TP53 mutation and p53 overexpression were significantly less frequent in tumors from children younger than 4 than from older children (P = 0.02 and 0.01, respectively). These results indicate that p53 mutation and expression status may be associated with prognosis in childhood malignant gliomas, and thus may provide a basis for stratifying patients biologically in future malignant glioma studies.

Adolescent↗

PubMed2006

Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer.

CONTEXT: Genetic testing for inherited mutations in BRCA1 and BRCA2 has become integral to the care of women with a severe family history of breast or ovarian cancer, but an unknown number of patients receive negative (ie, wild-type) results when they actually carry a pathogenic BRCA1 or BRCA2 mutation. Furthermore, other breast cancer genes generally are not evaluated. OBJECTIVE: To determine the frequency and types of undetected cancer-predisposing mutations in BRCA1, BRCA2, CHEK2, TP53, and PTEN among patients with breast cancer from high-risk families with negative (wild-type) genetic test results for BRCA1 and BRCA2. DESIGN, SETTING, AND PARTICIPANTS: Between 2002-2005, probands from 300 US families with 4 or more cases of breast or ovarian cancer but with negative (wild-type) commercial genetic test results for BRCA1 and BRCA2 were screened by multiple DNA-based and RNA-based methods to detect genomic rearrangements in BRCA1 and BRCA2 and germline mutations of all classes in CHEK2, TP53, and PTEN. MAIN OUTCOME MEASURES: Previously undetected germline mutations in BRCA1, BRCA2, CHEK2, TP53, and PTEN that predispose to breast cancer; frequencies of these mutations among families with negative genetic test results. RESULTS: Of the 300 probands, 52 (17%) carried previously undetected mutations, including 35 (12%) with genomic rearrangements of BRCA1 or BRCA2, 14 (5%) with CHEK2 mutations, and 3 (1%) with TP53 mutations. At BRCA1 and BRCA2, 22 different genomic rearrangements were found, of sizes less than 1 kb to greater than 170 kb; of these, 14 were not previously described and all were individually rare. At CHEK2, a novel 5.6-kb genomic deletion was discovered in 2 families of Czechoslovakian ancestry. This deletion was found in 8 of 631 (1.3%) patients with breast cancer and in none of 367 healthy controls in the Czech and Slovak Republics. For all rearrangements, exact genomic breakpoints were determined and diagnostic primers validated. The 3 families with TP53 mutations included cases of childhood sarcoma or brain tumors in addition to multiple cases of breast cancer. CONCLUSIONS: The mutational spectra of BRCA1 and BRCA2 include many high-penetrance, individually rare genomic rearrangements. Among patients with breast cancer and severe family histories of cancer who test negative (wild type) for BRCA1 and BRCA2, approximately 12% can be expected to carry a large genomic deletion or duplication in one of these genes, and approximately 5% can be expected to carry a mutation in CHEK2 or TP53. Effective methods for identifying these mutations should be made available to women at high risk.

Adult↗

PubMed1997

TP53 protein accumulation and gene mutation in relation to overexpression of MDM2 protein in ovarian borderline tumours and stage I carcinomas.

Three hundred and seventy-four early-stage ovarian tumours, including 27 borderline tumours and 347 stage I carcinomas, were investigated immunohistochemically for overexpression of the TP53 and MDM2 proteins. TP53 (p53) and MDM2 alterations were detected in 15 and 4 per cent of borderline tumours, and in 50 and 13 per cent of stage I carcinomas, respectively. Mutations in the TP53 gene (exons 5-8) were demonstrated in 29 of the 50 stage I carcinomas studied, using denaturing gel electrophoresis followed by direct sequencing. TP53 overexpression was seen less often in tumours of mucinous and endometrioid type than in tumours of other histological types and more often in moderately and poorly differentiated than in well differentiated tumours. MDM2 protein overexpression was seen more often in clear cell carcinoma than in tumours of other histological types. These results indicate that TP53 abnormalities play a crucial role, and MDM2 abnormalities a minor role, in the development of early-stage ovarian carcinoma. There was no significant association between TP53 or MDM2 alterations and survival in multivariate analysis.

Adolescent↗

PubMed1998

High prevalence of codon 213Arg-->Stop mutations of the TP53 gene in human ovarian cancer in the southwestern part of The Netherlands.

As in many human malignancies, TP53 mutations are the most common genetic alterations in malignant human ovarian tumours. An approach often used in the determination of TP53 status is immunohistochemical staining of the protein. Non-missense mutations, especially those of the null type, causing premature termination codons and resulting in truncated proteins, may often not be detectable by immunohistochemistry. Therefore, current estimates of TP53 alterations in ovarian cancer may be inaccurate. By using polymerase chain reaction-single strand conformation polymorphism analysis and sequencing techniques, we have found a high prevalence of TP53 non-missense mutations in exons 5-8 in ovarian tumour specimens from patients from the southwestern part of The Netherlands. Twenty-nine of 64 tumours showed mutations, of which 10 were non-missense mutations. The majority (9 of 10) of these non-missense mutations, including 7 nonsense mutations and 2 frameshift deletions, were null type mutations and could not be detected by immunohistochemical staining. Five of the 7 nonsense mutations were mutations at codon 213 (Arg-->Stop). The nature of the high prevalence of this nonsense mutation in our series of ovarian carcinomas remains unknown. In addition to the 9 null type mutations, a splice junction mutation was encountered. In conclusion, we have observed a high prevalence (13%) of ovarian tumours with null type mutations in exons 5-8 that did not result in immunostaining. Our data suggest that, especially in ovarian cancer, immunological assessment of TP53 is not an adequate tool to study TP53 alteration. A frequent nonsense mutation at codon 213 in 5 (8%) of 64 tumour specimens represents an important finding.

Adult↗

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↗

PubMed2002

High sensitivity of detection of TP53 somatic mutations by fluorescence-assisted mismatch analysis.

We analyzed exons 5-9 of the TP53 gene in 41 breast cancers using direct sequencing, PCR-SSCP (single-strand conformation polymorphism), and fluorescence-assisted mismatch analysis (FAMA), to test the level of specificity and sensitivity of each method. A major issue for the correct detection of TP53 somatic mutations in primary tumors is often represented by the large amount of normal DNA, which can cause excessive dilution of the mutant allele, with consequent possible false-negative results. High sensitivity upon dilution of the mutant allele has been demonstrated for FAMA, a method based on the chemical cleavage of a mismatch within heteroduplex DNA molecules. Exons 5-9 of the TP53 gene were analyzed by FAMA using only two long bifluorescent fragments. Differences in sensitivity, accuracy, and specificity were observed among the above-mentioned procedures. Thirteen of the 41 samples (31.7%) revealed TP53 genetic alterations by automated sequencing, 19 samples (46.3%) were positive for SSCP, whereas 14 samples (34%) showed variants detectable by FAMA. Seven samples were positive in SSCP, but negative in both FAMA and sequencing assays; however, 2 SSCP-negative samples revealed evident signals by FAMA, indicating the presence of TP53 mutations. One of the latter samples showed the alteration by sequence analysis, whereas the other failed to reveal the mutation signal even by sequencing, as a consequence of the very small amount of the mutant allele resulting from the excess of contaminating normal DNA. Our results show that FAMA may represent a suitable and accurate assay for the routine diagnosis of TP53 somatic mutations in DNAs from solid tumor biopsies.

Base Pair Mismatch↗

PubMed1991

Mutation in the TP53 gene in colorectal carcinoma detected by polymerase chain reaction.

The human TP53 gene is a possible tumor suppressor since TP53 gene mutations are observed in greater than 70% of sporadic colorectal carcinoma DNAs. In genomic DNAs from seven colon cancer cell samples, a 405 base pair DNA fragment containing exon 5, intron 5, and exon 6 of the TP53 gene was amplified by polymerase chain reaction and analyzed for mutations. One sample [human colon cancer (HCC) 278] was found to have a TP53 mutation altering the amino acid glutamine 167 in exon 5. A deletion of 2 bases changed glutamine 167 (CAG) to alanine (GCA) and the resulting frame-shift produced an in-frame stop codon at amino acid 179. While the normal TP53 gene gives rise to a 53 kD protein, the estimated size of this mutant TP53 protein if expressed would be approximately 20 kD.

Adenocarcinoma↗

PubMed1993

No germline TP53 mutations detected in familial and bilateral testicular cancer.

Mutations in the TP53 gene are considered to be among the most common genetic alterations in human cancers. Both somatic and germline mutations have been found. Using polymerase chain reaction (PCR), constant denaturant gel electrophoresis (CDGE), and denaturing gradient gel electrophoresis (DGGE), we have examined 32 patients with bilateral and familial germ cell tumors (GCT) and two patients with sporadic GCT for germline mutations within the conserved regions of the gene. In addition, 15 tumors were screened for somatic mutations and analyzed for loss of heterozygosity (LOH) at the TP53 locus. Twelve tumors were analyzed for expression of TP53 via immunohistochemistry. Neither germline nor somatic TP53 mutations were detected. LOH was observed in one of five informative cases. No tumors showed increased expression of TP53 protein. These results indicate that alterations in the TP53 gene are not important for the predisposition to and development of GCT.

Carcinoma in Situ↗

PubMed1994

Evidence that wild-type TP53, and not genes on either chromosome 1 or 11, controls the tumorigenic phenotype of the human fibrosarcoma HT1080.

The specific transfer of normal chromosomes via microcell fusion has been instrumental in identifying putative tumor suppressor gene loci in a variety of human cancers. Using this same technique it has been proposed that the tumorigenicity of the human fibrosarcoma cell line HT1080 is controlled by functionally distinct tumor suppressor genes on human chromosomes I and II. To address these results and perhaps further localize the suppressive effect to particular regions on these two chromosomes, we transferred into HT1080 seven different fibroblast-derived human chromosomes containing either intact or discrete portions of chromosome I or II. Interestingly, we found no evidence of genes on these chromosomes that could alter the growth of HT1080 either in vitro or in vivo. Based on these results we were left with the possibility that a gene, or genes, residing on an entirely different chromosome(s) was involved in the tumorigenesis of HT1080. Since TP53 mutation has been documented in a variety of human tumor types, and we found both copies of TP53 to be mutated in HT1080, we were prompted to examine its role by both cDNA transfection and chromosome transfer. Although by cDNA transfection we found that expression of exogenous wild-type TP53 was incompatible with continued proliferation of HT1080 cells in vitro, chromosome 17 transfer studies revealed that a more physiologic expression of exogenous wild-type TP53 could be tolerated in vitro while being completely incompatible with growth in vivo. These studies demonstrate a differential effect of TP53 growth inhibition and clearly show that TP53 tumor suppressing function can be independent from its potent growth suppressing effect in vitro.

Animals↗

PubMed1994

TP53 alterations and clinical outcome in low grade astrocytomas.

Thirty-eight WHO grade II astrocytomas and 10 malignant recurrent gliomas in these patients were examined for the presence of TP53 alterations. Seventeen/38 low grade astrocytomas and 6/10 malignant recurrent tumors harbored mutations of the gene detected by SSCP analysis and direct sequencing of PCR products. TP53 mutations in five out of six high grade mutant tumors were already present in the corresponding low grade astrocytomas. In two cases, TP53 mutations present in the low grade astrocytoma could not be demonstrated in the recurrent glioma. Immunohistochemistry with two different antibodies to the human TP53 protein revealed nuclear immunoreaction of tumor cells in 11/38 low grade and in 8/10 recurrent tumors. There was no correlation between the presence of TP53 alteration and clinical course. We conclude that, although TP53 mutations are detectable in a substantial fraction of WHO grade II astrocytomas, they do not appear to play a role in the malignant progression of these tumors and they are not of prognostic significance.

Amino Acid Sequence↗

PubMed2003

TP53, p14ARF, p16INK4a and H-ras gene molecular analysis in intestinal-type adenocarcinoma of the nasal cavity and paranasal sinuses.

Intestinal-type adenocarcinoma (ITAC) of the nasal cavity and paranasal sinuses is an uncommon tumor associated with occupational exposure to dusts of different origin. Few investigations addressed molecular alterations in ITAC mainly focused on TP53, K-ras and H-ras gene mutations. The occurrence of TP53, p14(ARF) and p16(INK4a) deregulation and H-ras mutations was investigated in 21 consecutive and untreated ITACs cases, 17 with known professional exposure. No H-ras mutations were found. In patients with known exposure, cumulative evidence of TP53 or p14(ARF) alterations accounted for 88% and the evidence of p16(INK4a) alterations for 65%, respectively. TP53 mutations were present in 44% of the ITACs, consisted of G:C-->A:T transitions in 86%, and involved the CpG dinucleotides in 50% of the cases. LOH at the locus 17p13 and an uncommon high rate of p53 stabilization were detected in 58% and 59% of the cases, respectively. p14(ARF)and p16(INK4a) promoter methylation accounted for 80% and 67% respectively, and LOH at the locus 9p21 occurred in 45% of the cases. Interestingly, all dust-exposed tumors with p16(INK4a) alterations shared TP53 or p14(ARF) deregulation. The present results show a close association of this occupational tumor with TP53, p14(ARF) and p16(INK4a) gene deregulation. Given the important role that these genes play in cell growth control and apoptosis, the knowledge of ITAC genetic profile may be helpful in selecting more tailored treatments.

Adenocarcinoma↗

PubMed2001

TP53 gene mutations in Hodgkin lymphoma are infrequent and not associated with absence of Epstein-Barr virus.

Reed-Sternberg (RS) cells, the neoplastic cells of Hodgkin lymphoma (HL) have clonal immunoglobulin gene rearrangements. The presence of somatic mutations suggests a germinal center origin, whereas the presence of crippling mutations suggests rescue of RS precursors from apoptosis by a transforming event. Epstein-Barr virus (EBV), which can be detected in 30-50% of HL cases, probably plays a role in this transforming event. The frequent presence of p53 protein expression in RS cells also suggests a role of the TP53 gene in this escape from apoptosis. Although mutations of the TP53 gene occur infrequently in RS cells, it has been suggested that in EBV-negative cases this gene mutation may be fundamental for the inhibition of apoptosis. In this study, we tested the hypothesis that there is an inverse correlation between the presence of TP53 gene mutations and the presence of EBV. In 21 of 67 cases EBV encoded small RNA (EBER)1-2 mRNAs were detected. Immunostaining for p53 protein revealed positivity in all 67 cases with variable percentages of positive cells and staining intensity. Screening for mutations in exons 5, 6, 7 and 8 of the TP53 gene in single RS cells obtained by laser microdissection from 26 HL specimens and 4 HL-derived cell lines revealed mutations in 2 of 15 EBV-positive cases and in 1 of 11 EBV-negative cases. Our results confirm the presence of infrequent (11.5%) TP53 gene mutations in HL and suggest that mutations of the TP53 gene are not correlated to the absence of EBV.

Gene Rearrangement↗

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↗