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PubMed2003

[When is it useful to look for TP53 germline gene mutations in families of oncology patients?].

BACKGROUND: The Li-Fraumeni syndrome is a relatively rare familial cancer syndrome associated with germline mutations in the tumour-suppressor gene TP53. Members of affected families can suffer from a wide variety of tumours. Identification of a germline TP53 mutation is particularly important in families of patients affected by one of several characteristic types of tumours. METHODS AND RESULTS: The data used for the distribution analysis of mean age at the cancer diagnosis in TP53 mutation carriers and in the Czech population were extracted from a database of 176 families (469 cancers in 346 patients) with germline TP53 mutations and from Czech statistical data of cancer incidence in years 1994 to 1998 (UZIS). The comparison of the age distribution of the relative tumour incidence in these two groups clearly separated childhood adrenocortical sarcoma, rhabdomyosarcoma, osteosarcoma and brain tumour patients. In their families genetic counselling should be recommended. CONCLUSIONS: Patients with low age at diagnosis of these tumours, particularly patients with additional personal or family history of malignancy, should be considered as potential TP53 mutation carriers. It should be relevant not only for the treatment and follow-up of the patients but also for preventive measures aimed at other members of their families.

Adolescent↗

PubMed2003

[Point mutation of TP53 suppressor gene in pre-neoplastic and neoplastic lesions of the stomach].

BACKGROUND: In the current model for the development of gastric cancer, regions of multifocal atrophic gastritis give rise to intestinal metaplasia, dysplasia and finally, adenocarcinoma. AIM: To study the frequency and characteristics of TP53 gene mutations in preneoplastic and neoplastic lesions of the stomach. MATERIAL AND METHODS: DNA sequencing of the TP53 gene was performed in 46 patients with gastric carcinoma. Normal mucosa, intestinal metaplasia and invasive adenocarcinoma tissues were obtained by scraping 6-micron histological sections from formalin-fixed and paraffin-embedded tissue. RESULTS: DNA sequencing of exons 5-9 of the TP53 gene demonstrated a mutation in 31% of patients. These findings were seen both in tumoral tissue (13 cases) and in intestinal metaplasia (2 cases). Most mutations were found in exons 5 and 8, and the majority of them were transitions (10 out of 19 mutations). DISCUSSION: Patients with gastric cancer showed a frequency of TP53 mutations similar to that previously communicated in populations with low gastric cancer risk. Moreover, there was a predominance of transitions, genetic alterations that are identified with carcinogenesis associated with N-nitrosamine compounds. Finally, mutations of TP53 gene were detected in areas of intestinal metaplasia.

Adenocarcinoma↗

PubMedDate not supplied

Different risk relations with smoking for non-small-cell lung cancer: comparison of TP53 and TP73 genotypes.

BACKGROUND: The association between TP53/TP73 gene polymorphisms and tobacco smoking was evaluated with regard to risk of non-small cell lung cancer (NSCLC). METHODS: A case-control study with 192 histologically confirmed NSCLC cases and 241 non-cancer controls was conducted. Subjects were genotyped for TP53 Arg72Pro and TP73 G4C14 to A4T14 polymorphisms by PCR-based methods. Risk and interactions were assessed as odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The analyses according to TP53 genotypes for the risk of tobacco smoking illustrated that risk with heavy smoking was much higher for subjects with the TP53 ProPro genotype (OR: 16.4, 95% CI 1.77-151.7) as compared with those with TP53 ArgArg/ArgPro (3.36, 1.69-6.68). Similar analyses for TP73 genotypes did not show any differences for NSCLC risk. CONCLUSION: A risk relation of heavy smoking for the NSCLC is suggested with the TP53 but not the TP73 polymorphism.

Adult↗

PubMed2003

TP53 gene mutations predict the response to neoadjuvant treatment with 5-fluorouracil and mitomycin in locally advanced breast cancer.

PURPOSE: Recent studies have found an association between certain TP53 mutations and resistance to anthracycline-based primary medical therapy in breast cancer. The purpose of this study was to investigate whether TP53 mutational status also might influence the response to a non-anthracycline-containing regimen in primary breast cancer. EXPERIMENTAL DESIGN: Thirty-five patients with locally advanced breast cancer were investigated for TP53 mutations before receiving combination chemotherapy with 5-fluorouracil (1000 mg/m(2) on days 1 and 2) and mitomycin (6 mg/m(2) on day 2), administered every 3 weeks for 2-10 cycles in the neoadjuvant setting. RESULTS: Mutations in the TP53 gene, in particular those affecting loop domains L2 or L3 of the p53 protein, were associated with lack of response to chemotherapy (i.e., increase in the diameter product of tumor lesion by >/=25%; P = 0.177 for all mutations and P = 0.006 for those affecting L2/L3 domains, respectively). No statistically significant correlation between TP53 LOH and response to therapy was seen. CONCLUSION: This study revealed a significant association between lack of response to 5-fluorouracil and mitomycin and mutations affecting the L2/L3 domains of the p53 protein. Together with our previous finding that such mutations predict resistance to weekly doxorubicin, our data suggest that mutations affecting this particular domain of the p53 protein may cause resistance to several different cytotoxic compounds applied in breast cancer treatment.

Adult↗

PubMed2005

OGG1 Cys326 variant, allelic imbalance of chromosome band 3p25.3 and TP53 mutations in ovarian cancer.

A Ser326Cys amino acid variant encoded by OGG1 that removes the highly mutagenic 8-oxo-7,8-dihydroguanine adducts resulting from the oxidative damage produced by reactive oxygen species, has been suggested to reduce activity of the enzyme and result in an increase in G:C --> T:A transversions. Carriers homozygous for the Cys326 variant have been associated with increased risk in some cancers. In this study, we tested the association of this polymorphism with epithelial ovarian cancer (EOC) (n=91 cases) in comparison with women unaffected by the disease (n=57). Although the genotype encoding the homozygous Cys326 variant was found more often in cases (11%) than controls (9%), this was not statistically significant (p=0.297). As OGG1 at chromosome band 3p25.3 overlaps a region exhibiting allelic imbalance (AI) in EOC, we also examined the frequency of AI of the OGG1 locus and its association with somatic mutations in the TP53 tumor suppressor gene, which is frequently mutated in EOC. The frequency of AI and TP53 mutations in EOC was 32 and 37%, respectively. Although the proportion of EOC cases harboring the genotype homozygous for Cys326 was greater in TP53 mutation-positive cases (5 of 34, 15%) than mutation-negative cases (5 of 57, 9%), the distribution of genotypes was not significantly different (p=0.289). Four of the six heterozygous Ser326/Cys326 samples exhibiting AI, displayed loss of the Ser326 variant. About 16% of samples exhibited both AI of the OGG1 locus and a TP53 mutation. Proportionately more EOC samples harbored a mutation in the group of samples exhibiting AI (15 of 29, 52%) in comparison to the group of samples with no AI (19 of 62, 31%) (p=0.036). Although the OGG1 Cys326 variant appears to play a minor role in conferring increased risk of ovarian cancer, the observed AI of the OGG1 locus in association with TP53 somatic mutations warrants further investigation in this disease.

Allelic Imbalance↗

PubMed2006

The TP53 codon 72 polymorphism and predisposition to adrenocortical cancer in Polish patients.

The TP53 polymorphism occurs at codon 72 of exon 4 with two alleles encoding either arginine or proline. The association between this common polymorphism and risk of different cancers has been extensive studied, however various reports are controversial. We have analyzed the 72Pro polymorphic variant in patients with adrenocortical tumors to evaluate whether 72G--> C substitution at codon 72 of TP53 gene may be associated with increased risk for malignancy in adrenal cortex in comparison to the control group. DNA extracted from peripheral leucocytes of 46 Polish patients with adrenocortical tumors (17 malignant and 29 benign) and 50 controls was examined by PCR-HD method followed by direct sequencing. TP53 polymorphism in codon 72 was found in 47% of ACC cases, in 28% of patients with adenomas and in 24% of controls. The genotype Arg/Arg, Arg/Pro and Pro/Pro distribution was respectively 53%/35%/12% for cancers, 72%/28%/0% for benign tumors and 76%/24%/0% for controls. High frequency of 72Pro allele in patients with carcinoma (29%) in comparison to the benign tumors (14%) and controls (12%) was statistically analyzed. We found that 72Pro variant of TP53 gene was associated with a significantly increased risk of ACC (OR = 3.05; 95% CI = 1.17-7.91, p=0.03). Our results suggest that the TP53 codon 72 polymorphism could be associated with susceptibility for adrenocortical cancer in the examined Polish patients.

Adrenal Cortex Neoplasms↗

PubMed1995

TP53 mutations emerge at early phase of myelodysplastic syndrome and are associated with complex chromosomal abnormalities.

We examined TP53 mutation in 57 patients with myelodysplastic syndrome (MDS) at either the MDS phase or at the terminal leukemic phase using polymerase chain reaction-mediated single-strand conformation polymorphism (PCR-SSCP) analysis. TP53 mutations within exons 5 through 8 were found in seven patients. All these mutations were detected at the presentation of MDS whether these patients showed leukemic transformation or not. TP53 mutations were frequently found in patients with loss of the short arm of chromosome 17 (17p-) (three of seven patients with 17p-, 43%) and complex karyotypic abnormalities (five of 14, 38%). Among the seven patients with the TP53 mutation, four patients progressed to acute leukemia within 7 months from the diagnosis of MDS, and the remaining three died within 7 months without leukemic transformation. These findings suggest that mutations of the TP53 can be implicated in leukemic transformation and a poor prognosis in MDS.

Acute Disease↗

PubMed1995

Germline mutations in the TP53 gene.

Since the majority of germline mutations in the TP53 gene seem to occur in LFS or LFL families, and these are rare, research is best conducted in a collaborative setting (Li and Fraumeni, in press). In a report from a meeting at Bethesda in 1993, the following areas were outlined for collaborative study: the correlation (if any) of phenotypes with specific mutation; age specific penetrance; cumulative cancer incidence; gender differences in tumour development in carriers; the effects of DNA damaging agents on individuals with a TP53 mutation; the frequency of TP53 germline mutations in cohorts of patients with rare childhood tumours (eg adrenocortical carcinoma); and the psychosocial aspects of predictive TP53 testing. In addition, if, as seems likely from recent data, X irradiation in these individuals induces DNA damage that is tolerated, urgent collaborative studies are needed to investigate new methods of screening, such as magnetic resonance imaging. Treatment modalities should be carefully chosen, and for this reason alone, predictive testing may be desirable in all LFS and LFL families. Individuals carrying TP53 mutations could be offered chemoprevention within trials in an effort to reduce their mortality from cancer.

Amino Acid Sequence↗

PubMed1996

TP53 tumour suppressor gene: clues to molecular carcinogenesis and cancer therapy.

The tumour suppressor gene product TP53 is clearly a component in several biochemical pathways, including transcription, DNA repair, genomic stability, cell cycle control and apoptosis, that are central to human carcinogenesis. TP53 is functionally inactivated by mutational, viral and cellular mechanisms in the majority of human cancers. Analysis of the spectrum of TP53 mutations provides clues to the aetiology and molecular pathogenesis of cancer. Recent insight into the TP53 mediated biochemical pathways of cell cycle arrest and apoptosis has provided further understanding of the mechanisms related to TP53 mediated tumour suppression. This in turn may provide the potential molecular targets for the development of rational multimodality cancer therapy, including chemotherapy, immunotherapy and gene therapy strategies. The convergence of previously parallel lines of basic, clinical and epidemiological investigation may provide an opportunity for the rapid transfer of research findings from the laboratory to the clinic.

Animals↗

PubMed1997

Germ-line mutations of TP53 in Li-Fraumeni families: an extended study of 39 families.

We have previously reported on the analysis of TP53 coding mutations in 12 classic Li-Fraumeni syndrome (LFS) families plus 9 families that were Li-Fraumeni-like (LFL) families (J. M. Birch et al., Cancer Res., 54: 1298-1304, 1994). Mutations were found in 6 of 12 LFS families and in 1 of 9 LFL families. We have now extended these studies to include an additional nine LFS and nine LFL families, and TP53 mutations have been detected in eight of nine LFS families and in three of nine LFL families. Six of the new mutations described here are the same as those previously identified in other Li-Fraumeni families and are missense mutations at codons 245, 248, and 273 (in two families); a nonsense mutation at codon 209; and a mutation at the splice donor site in exon 4. The other five mutations are novel germ-line mutations and include missense mutations at codons 136 and 344, a 2-bp deletion within codon 191, a splice acceptor mutation in intron 3, and a 167-bp deletion of part of exon 1 and intron 1. In addition, we have detected a codon 175 mutation in a family previously reported as TP53 negative. To summarize all of the data from the families we have studied in this and our previous report (J. M. Birch et al., Cancer Res., 54: 1298-1304, 1994), mutations have been detected in 15 of 21 LFS families (71%) and in 4 of 18 LFL families (22%). These figures are somewhat higher than those previously reported by us and others for the frequency of TP53 mutations in LFS and LFL families. This could reflect our analysis of all 11 exons of TP53, including noncoding regions, as well as the use of direct sequencing rather than other less-sensitive mutation detection methods.

Female↗

PubMed1997

[Molecular analysis of tumor suppressor genes p16INK4 and TP53 of osteosarcomas in Spanish children].

OBJECTIVE: Alterations affecting tumor suppressor genes, specifically p16INK4 and TP53, have been shown to be involved in the development of human cancer due to their important role in the control of normal cell cycle progression. As the genetic events leading to the development of pediatric osteosarcoma remain partially unclear, we have tested the possibility that a significant number of pediatric osteosarcoma patients harbor mutations in these genes. PATIENTS AND METHODS: We have analyzed 64 samples (fresh tissues, paraffin embedded biopsies and peripheral blood lymphocytes) corresponding to 38 pediatric osteosarcoma patients. TP53 mutations were analyzed by DGGE (Denaturing Gradient Gel Electrophoresis) analysis of exons 5 through 8. We searched for deletions in the p16INK4 gene by PCR (Polymerase Chain Reaction) analysis and point mutations were screened by means of SSCP (Single Strand Conformation Polymorphisms). RESULTS: Our analysis showed that 18.4% of the samples harbored mutations in the coding region of TP53 and that 7% had a homozygous deletion of the p16INK4 gene. Our results suggest that p16INK4 deletions may constitute a bad prognostic factor and that TP53 alterations may be correlated, although not statistically, with reduced survival time. CONCLUSIONS: Mutations of the TP53 and deletion of p16INK4 tumor suppressor genes seem to be involved in the development of pediatric osteosarcoma. Moreover, alterations of these genes may constitute a prognostic factor related with poor prognosis or decreased survival time.

Bone Neoplasms↗

PubMed1998

The presence of wild-type TP53 is necessary for the radioprotective effect of the Bowman-Birk proteinase inhibitor in normal fibroblasts.

In the present study we have demonstrated that the Bowman-Birk proteinase inhibitor (BBI) protected normal fibroblasts from a radiation-induced reduction in cell survival, whereas in transformed fibroblasts no radioprotective effect was observed. It was shown that BBI reduced the radiation-induced protein stabilization and DNA-binding activity of TP53 (formerly known as p53) in normal fibroblasts. In transformed fibroblasts, BBI failed to induce these effects. The analysis of the TP53 gene in transformed fibroblasts revealed a mutation in exon 5. As a consequence of this mutation, the expression of the TP53 downstream gene CDKN1A (p21/WAF1/Cip1) is blocked. Based on experiments using TP53 antisense oligonucleotides, the radioprotective effect of BBI could be correlated with the function of wild-type TP53. Thus BBI can be considered as a selective radioprotective agent for normal human fibroblasts.

Base Sequence↗

PubMed1998

Presence and location of TP53 mutation determines pattern of CDKN2A/ARF pathway inactivation in bladder cancer.

Transformation and immortalization require the inactivation of key cell cycle regulatory genes. We examined 19 bladder cancer cell lines derived from 17 patients for alterations in TP53, RB1, CDKN2A, and ARF. Twelve cell lines had a mutation in exons 5-11 of TP53 and, with only one exception, a concomitant loss of RB1 protein expression. Another group of seven cell lines had a wild-type TP53 gene or a mutation in exons 1-4 of TP53 and concomitant alterations in both CDKN2A and ARF in every case. This demonstrates the requirement, in all but one line, for inactivation of both the CDKN2A/RB1 and ARF/TP53 pathways in bladder cancer cell lines and provides the first evidence for potential differences in the penetrance of mutations in the transactivation and DNA-binding domains of TP53.

DNA Methylation↗

PubMed2026

Targeting TP53 in triple-negative breast cancer: Molecular pathogenesis, therapeutic implications, and emerging pharmacological strategies.

Triple-negative breast cancer (TNBC) remains a highly aggressive and therapeutically challenging subtype, defined by the absence of oestrogen, progesterone, and HER2 expression. Tumour Protein 53 (TP53) mutations represent the most frequent genetic alteration, occurring in over 80% of cases and driving tumour initiation, progression, and therapeutic resistance. Mutant p53 proteins not only lose canonical tumour-suppressive functions but also often acquire gain-of-function (GOF) oncogenic properties that promote metastasis, genomic instability, and resistance to mechanisms like ferroptosis. This review examines the biological role of TP53 in TNBC pathogenesis and evaluates emerging pharmacological strategies aimed at targeting these vulnerabilities. Key approaches include the pharmacological reactivation of mutant p53 using small molecules such as APR-246, COTI-2, and the mutation-specific reactivator rezatapopt (PC14586), which has shown significant clinical tumour reduction in Y220C-mutant patients. Other strategies involve targeted protein degradation, the exploitation of synthetic lethal interactions (e.g., Chk1 or Aurora kinase B inhibition), and the use of natural products like cryptolepine or piperine derivatives. Recent clinical evidence further highlights the potential of combining epigenetic agents like decitabine with chemotherapy in TP53-mutant populations. Integrating TP53 mutation status into biomarker-driven treatment paradigms is a pivotal step toward achieving precision oncology and improving clinical outcomes for patients with TNBC.

Precision oncology↗

PubMed2026

The impact of EGFR subtype combined with TP53 co-mutation status on survival outcomes with front-line osimertinib in non-small cell lung cancer (NSCLC).

BACKGROUND: Osimertinib is a standard therapy for EGFR-mutant NSCLC. However, markers to better identify those at risk for poor outcomes are needed. This is the largest study to date evaluating the impact of EGFR subtype combined with TP53 co-mutation status on survival endpoints with front-line osimertinib. METHODS: Patients from a U.S. clinical-genomic database with advanced EGFR-mutant NSCLC receiving front-line osimertinib were studied. Real-world progression-free survival (rwPFS) and overall survival (OS) were determined using Kaplan-Meier methods, and multivariable Cox regression compared outcomes after accounting for relevant clinical covariates. RESULTS: Of 606 patients, 277 (46%) had EGFR L858R, 384 (63%) had TP53 co-mutations, and 186 (30.7%) had both. Bearing L858R vs. exon 19 deletions (rwPFS: hazard ratio [HR] 1.4, P = 0.001; OS: HR 1.3, P = 0.01) or a TP53 co-mutation vs. wildtype (rwPFS: HR 1.5, P < 0.001; OS: HR 1.6, P < 0.001) predicted inferior outcomes. Especially short median rwPFS (10.1 vs. 21.4 months, HR 2.2, P < 0.001) and OS (21.3 vs. 53.4 months, HR 2.3, P < 0.001) were observed in patients with both markers (L858R/TP53-mutant) as compared to neither (exon 19 deletion/TP53-wildtype). CONCLUSIONS: Having EGFR L858R or a TP53 co-mutation were independent predictors of inferior rwPFS and OS with front-line osimertinib. Patients with both unfavorable alterations had the shortest survival. Risk stratifying using a combination of these markers can assist in identifying patients for novel trials or approved intensified therapies.

Humans↗

PubMed1999

c-MYC, RB-1, TP53, and centromere 8 and 17 copy number in B-cell non-Hodgkin's lymphomas assessed by dual-color fluorescence in situ hybridization.

Dual-color interphase FISH was performed to B-cell Non-Hodgkin's lymphomas to detect numerical genetic alterations in c-MYC, RB-1, TP53 and centromere 8 and 17. The probe combinations c-MYC/centromere 8, RB-1/centromere 8 and TP53/centromere 17 were applied, and the hybridization signals scored in a correlated fashion. Copy number aberrations was found in 24 of 45 lymphomas examined (53%). Nine tumors (20%) had increased c-MYC gene copy number (three to 8 copies). Seven of these nine had increase in c-MYC copies relative to centromere 8 copy number. Allelic loss of RB-1 was found in 9 tumors (20%), one tumor lacked both alleles. Nine cases (20%) showed hemizygous TP53 deletion. TP53 deletion was significantly associated with high-grade histology (P = 0.02). Numerical alterations in c-MYC and RB-1 were not associated with prognosis. Patients with hemizygous TP53 deletion had shorter survival (relative risk = 6.1, P<0.001) than the ones with two or more alleles.

Centromere↗

PubMed1997

Three germline mutations in the TP53 gene.

Three germline mutations in the TP53 tumor-suppressor gene are reported, two of which are not reported previously. A missense mutation at codon 265 of TP53 was found in three patients of a family that complied with the definition of the Li-Fraumeni syndrome. A nonsense mutation in codon 306 was found in a woman who had had a rhabdomyosarcoma at age 4 and a subsequent breast cancer at age 22. She was part of a Li-Fraumeni-like family, but the parental origin of the mutation could not be traced. Finally, while screening for somatic alterations in TP53 in a series of 141 sporadic breast tumors, we detected a constitutional missense mutation in codon 235 in a woman diagnosed with breast cancer at age 26 and a recurrence 4 years later. The recurrence, but not the primary tumor, showed an additional missense mutation at codon 245 as well as loss of the wild-type allele. This suggests that the 245 mutation was particularly important for tumor progression and that there might exist heterogeneity in terms of cancer predisposition potential among the various germline TP53 mutations.

Breast Neoplasms↗

PubMed1999

TP53 mutation and haplotype analysis of two large African American families.

Two large apparently unrelated African American families with a high incidence of breast cancer and other tumors characteristic of Li-Fraumeni breast sarcoma cancer family syndrome were studied. Mutation screening revealed that in both families the affected members carried a germline mutation of the TP53 gene at codon 133 (ATG--> ACG, M133T). In order to determine whether an ancestral haplotype was shared by these two families, polymorphic markers within and flanking the TP53 gene were studied. Haplotype analysis using five markers revealed an identical haplotype shared by the two families. Loss of heterozygosity at the TP53 locus in the probands' tumor tissues from each family was observed; in each case, the retained allele carried the common haplotype. The frequency of this haplotype in the general African American population is <0.003. This unique haplotype, combined with the rare TP53 mutation, suggests that these African American families share a common ancestry. This finding suggests that other African Americans may be carriers of this mutation and thus may be at risk of early-onset breast cancer or other cancers characteristic of the Li-Fraumeni breast sarcoma cancer family syndrome. The finding of recurring mutations in African Americans may facilitate carrier screening and identification in this population.

Alleles↗