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PubMed2026

Integrated morphologic, immunophenotypic, and molecular profiling of advanced upper tract urothelial carcinoma across tumor compartments supports biopsy-based testing.

Upper tract urothelial carcinoma (UTUC) is an aggressive malignancy with limited molecular characterization in advanced disease. FGFR3 alterations are well established in low-grade urothelial carcinoma, but their prevalence, stability, and biological significance in locally advanced and metastatic UTUC remain only partially defined. We performed an integrated morphologic, immunohistochemical, and molecular analysis of 24 locally advanced and/or metastatic UTUC from 20 patients. FGFR3 status was assessed by RT-PCR across multiple tumor compartments, including biopsies, primary tumors, lymph-node metastases, and distant metastatic sites. Immunohistochemistry included CK20, CK5, GATA3, p53, and mismatch repair proteins. Targeted next-generation sequencing (NGS) was used to characterize co-occurring genomic alterations and to assess concordance with p53 immunophenotype. FGFR3 alterations were identified in 50% of patients and in 54.2% of analyzed tumors. FGFR3 status showed high intra-patient stability, with concordance between primary tumors and distant metastases in 90% of cases, whereas concordance with lymph node metastases was lower (50%), suggesting site-specific clonal divergence. Despite advanced stage, 92.3% of FGFR3-altered tumors displayed papillary urothelial carcinoma morphology, and most showed a luminal immunophenotype (61.5% by CK20/CK5 and 69.2% by GATA3/CK5). Targeted NGS revealed additional pathogenic alterations in 75% of patients, most frequently involving RTK/RAS/MAPK signaling (70%), cell-cycle regulation (25%), and PI3K/AKT pathway components (10%). TP53 mutations co-occurred with FGFR3 alterations in 60% of FGFR3-mutated patients and showed 90.4% concordance with p53 immunohistochemistry. Finally, a few cases exhibited complex, multi-site FGFR3 mutational patterns, consistent with intratumoral clonal evolutions. In conclusion, FGFR3 alterations are frequent and remarkably stable in advanced UTUC, even in high-grade and metastatic disease. These findings support the reliability of FGFR3 testing on limited diagnostic material and reinforce its relevance for therapeutic stratification. UTUC emerges as a molecularly dynamic disease in which early oncogenic drivers such as FGFR3 continue to shape tumor biology and therapeutic vulnerability at advanced stages.

Humans↗
PubMed2004

Oncolytic virotherapy as a novel strategy for pancreatic cancer.

We have developed a novel gene therapy that targets genetic alterations in pancreatic cancer using oncolytic replication-selective adenoviruses in tumor cells. E1B-55kDa-deleted adenovirus (AxE1AdB) can selectively replicate in TP53-deficient human cancer cells but not cells with functional TP53. Consecutive injection with AxE1AdB markedly inhibited the growth of human pancreatic tumors in severe combined immunodeficiency disease mice. Furthermore, AxE1AdB displayed the ability to enhance gene expression as a virus vector. It is reported that uracil phosphoribosyl transferase (UPRT) overcomes 5-FU resistance. The therapeutic advantage of a replication-selective adenovirus that expresses UPRT (AxE1AdB-UPRT) was thus evaluated in an intraperitoneum-disseminated tumor model. Combined treatment with 5-FU and AxE1AdB-UPRT dramatically reduced the disseminated tumor burden without causing toxicity in normal tissues. We also clarified the process of AxE1AdB-inhibited tumor angiogenesis through the preserved E1A region: an adenoviral E1A protein binds to pRB, forcing the quiescent cell into the S phase. We constructed a double-mutant, replication-selective adenovirus (AxdAdB-3) containing a mutation in the RB-binding motif of the E1A region and a deletion of large E1B-55kDa. AxdAdB-3 swiftly induced cancer cell death in vitro and showed a potent antitumor effect in vivo. These results strongly suggest that AxdAdB-3 possesses a wider therapeutic potential than previously believed, given that most pancreatic cancers have abnormalities in both the TP53 and RB pathways.

Adenoviridae↗
PubMed2026

Efficacy and Genomic Analysis of HER2-Mutant Metastatic Triple-Negative Breast Cancer Treated with Neratinib Alone or with Trastuzumab in the SUMMIT Basket Trial.

PURPOSE: Human epidermal growth factor receptor 2 (HER2) mutations occur in 1% to 3% of triple-negative breast cancers (TNBC), representing a novel target for biomarker-directed treatment. In the SUMMIT basket trial (NCT01953926), patients with HER2-mutant, metastatic TNBC received neratinib (240 mg/day) or neratinib + trastuzumab (N + T; neratinib 240 mg/day, intravenous trastuzumab 8 mg/kg initially and then 6 mg/kg every 3 weeks). We report final results from the neratinib and N + T TNBC cohorts. PATIENTS AND METHODS: Primary endpoint: investigator-assessed objective response rate at first postbaseline tumor assessment (ORRfirst); secondary endpoints included confirmed ORR by investigator, clinical benefit rate (CBR), and progression-free survival (PFS); exploratory endpoint included circulating tumor DNA (ctDNA) collected at baseline, during treatment, and at the end of treatment. RESULTS: Twenty-seven patients were enrolled between July 2014 and September 2021. Confirmed ORRs were 40% [95% confidence interval (CI), 12.2-73.8] for neratinib (n = 10) and 35.3% (95% CI, 14.2-61.7) for N + T (n = 17). CBRs were 40% (95% CI, 12.2-73.8) and 47.1% (95% CI, 23-72.2), respectively; median PFS times were 2.89 (95% CI, 0.95-5.52) and 6.24 months (95% CI, 2.10-8.18), respectively. HER2 mutation variant allele frequencies in ctDNA from patients with response or stable disease decreased upon treatment and increased upon progression. Serial ctDNA sequencing revealed emergence or increase in on-pathway (ERBB3) and off-pathway (KRAS and TP53) mutations. The most common treatment-emergent adverse events were diarrhea, nausea, and constipation. CONCLUSIONS: N + T in patients with HER2-mutant metastatic TNBC seemed to prolong responses versus neratinib alone, representing a novel approach for patients with biomarker-defined metastatic TNBC. Based on these and previously published data, neratinib-based combinations are endorsed by the National Comprehensive Cancer Network guidelines for patients with hormone receptor-positive or -negative metastatic breast cancer with activating HER2 mutations. See related commentary by Lloyd et al., p. 3715.

Adult↗
PubMed2026

Prognostic value of circulating tumor DNA and copy-number alterations in patients receiving tandem [225Ac]Ac-/[177Lu]Lu-PSMA-617 therapy for metastatic castration-resistant prostate cancer: a prospective observational study.

BACKGROUND: Prostate-specific membrane antigen-targeted radioligand therapy (PSMA-RLT) demonstrates clinical efficacy in metastatic castration-resistant prostate cancer (mCRPC), yet robust biomarkers for dynamic treatment monitoring and resistance remain lacking. We investigated circulating tumor DNA (ctDNA)-derived tumor fraction (TFx) and genome-wide copy-number alterations (CNAs) as non-invasive biomarkers of treatment response and resistance biology. METHODS: Seventy-eight patients with advanced mCRPC receiving tandem [225Ac]Ac-/[177Lu]Lu-PSMA-617 were prospectively enrolled. Plasma samples collected longitudinally (n = 172) underwent ultra-low-pass whole-genome sequencing. TFx was estimated using ichorCNA, and recurrent CNAs were identified using GISTIC2.0. Associations with progression and overall survival (OS) were assessed using Cox proportional hazards models, including time-dependent analyses. RESULTS: Baseline TFx differed across metastatic disease stages (p = 0.027) and dynamic TFx changes paralleled PSA kinetics during early treatment. Modelled as a time-dependent variable, TFx was associated with a significantly increased risk of progression (HR 4.9, 95% CI 1.2-20.1, p = 0.026). Unsupervised clustering identified distinct high- and low-CNA burden groups strongly correlated with TFx (p = 8.09 × 10⁻8). High CNA burden was associated with shorter median OS (8.3 vs 13.8 months). Multivariable analysis identified baseline logPSA and logALP as independent predictors of OS. Recurrent CNAs affected key tumor suppressors (PTEN, RB1, BRCA2, ATM) and were enriched in pathways related to TP53 signalling, homologous recombination repair, and oncogenic signaling. Longitudinal analyses demonstrated persistence and expansion of specific amplifications at progression. CONCLUSIONS: ctDNA-derived TFx represents a dynamic biomarker of treatment response and progression risk, while CNA profiling provides insight into resistance mechanisms in mCRPC treated with PSMA-RLT. These findings support the integration of ctDNA-based biomarkers into clinical stratification and real-time monitoring strategies.

Humans↗
PubMed2004

Delivery systems and molecular targets of mechanism-based therapies for GBM.

Glioblastoma multiforme (GBM) is the most common malignant brain tumor of adults and is in great need of novel diagnostic and therapeutic approaches. Diagnosis is beginning to consider a tumor's genetic status and in the future may incorporate gene expression or proteomic profiles. Genetic alterations in gliomas that are being used in classification include TP53 and retinoblastoma pathway disruption, PTEN mutations, epidermal growth factor receptor amplification and 1p/19q losses. Molecular mechanisms are being exploited to treat glioblastoma multiforme. Tyrosine kinase inhibitors directed at epidermal growth factor receptor (ZD1839, OSI-774) are being explored. Farnesyltransferase inhibitors (R115777) block activation of the ras pathway and may be effective. Antagonists of the endothelin receptor (e.g., atrasentan) expressed on blood vessels may block the high degree of angiogenesis in gliomas. Tumors lacking methylthioadenosine phosphorylase are sensitive to inhibitors of de novo adenosine synthesis (SDX-102) since they lack a salvage pathway. Future goals are to tailor therapies to a tumor's molecular, proteomic or genomic status ,and manage glioblastoma multiformes as in chronic diseases in a multidisciplinary clinical setting.

Antineoplastic Agents↗
PubMed2005

A radiation-induced acute apoptosis involving TP53 and BAX precedes the delayed apoptosis and neoplastic transformation of CGL1 human hybrid cells.

Exposing CGL1 (HeLa x fibroblast) hybrid cells to 7 Gy of X rays results in the onset of a delayed apoptosis in the progeny of the cells 10 to 12 cell divisions postirradiation that correlates with the emergence of neoplastically transformed foci. The delayed apoptosis begins around day 8 postirradiation and lasts for 11 days. We now demonstrate that the delayed apoptosis is also characterized by the appearance of approximately 50-kb apoptotic DNA fragments and caspase 3 activation postirradiation. In addition, we confirm that stabilization of TP53 and transactivation of pro-apoptosis BAX also occurs during the delayed apoptosis and show that anti-apoptosis BCL-X(L) is down-regulated. To test whether the delayed apoptosis was due to a nonfunctional acute TP53 damage response in CGL1 cells, studies of acute apoptosis were completed. After irradiation, CGL1 cells underwent an acute wave of apoptosis that involves TP53 stabilization, transactivation of BAX gene expression, and a rapid caspase activation that ends by 96 h postirradiation. In addition, the acute onset of apoptosis correlates with transactivation of a standard wild-type TP53-responsive reporter (pG13-CAT) in CGL1 cells after radiation exposure. We propose that the onset of the delayed apoptosis is not the result of a nonfunctional acute TP53 damage response pathway but rather is a consequence of X-ray-induced genomic instability arising in the distant progeny of the irradiated cells.

Apoptosis↗
PubMed1999

Isolation and characterization of a novel TP53-inducible gene, TP53TG3.

We applied the differential mRNA display method to isolate genes regulated by wild-type TP53 in cells of a colon-cancer line (SW480) in which we had established an inducible TP53 expression system under the control of the lactose operon. Here we report isolation and characterization of a novel TP53-inducible gene, termed TP53TG3 (TP53 target gene 3). Its DNA sequence was identical to sequences present in two BAC clones that had been mapped to chromosome band 16p13. The gene expressed several transcripts by alternative splicing; the two major transcripts, TP53TG3a and TP53TG3b, encoded 124- and 132-amino-acid peptides that were expressed predominantly in testis. Immunohistochemical analysis using cancer cells (HeLa or H1299) that had been transfected with plasmid DNA designed to express the MYC-fused TP53TG3 proteins indicated that these products were present mainly in the cytoplasm 20 hr after transfection. However, 40 hr after transfection, the recombinant proteins had accumulated in the nuclei of some cells. Because no known nuclear localization domain was present in the amino acid sequence, we suspect that this protein plays an important role in the TP53-mediated signaling pathway, when it forms complexes with other protein(s) and is transferred by them into the nucleus. Genes Chromosomes Cancer 26:329-335, 1999.

Amino Acid Sequence↗
PubMed2003

p15INK4b, p14ARF, and p16INK4a inactivation in sporadic and neurofibromatosis type 1-related malignant peripheral nerve sheath tumors.

PURPOSE: Malignant peripheral nerve sheath tumor (MPNST) can arise sporadically or in association with neurofibromatosis type 1. Deletions at the 9p21 locus have been reported in these tumors. To additionally characterize the status of this chromosomal region, in this study we performed a comprehensive, mostly PCR-based molecular analysis of the three tumor suppressor genes p15(INK4b), p14(ARF) and p16(INK4a) located at the 9p21 locus in 26 cryopreserved MPNSTs. EXPERIMENTAL DESIGN: Fourteen neurofibromatosis type 1-related and 12 sporadic cases were investigated for homozygous deletion coupled with fluorescent in situ hybridization, promoter methylation, and mutational analysis, as well as m-RNA expression. RESULTS: The results showed that an inactivation of one or more genes occurred in 77% of MPNSTs and was mainly achieved through homozygous deletion (46%), which, in turn, encompassed all of the three tandemly linked genes in 83% of the deleted cases. Promoter methylation was at a less extent involved in gene silencing (18%), and no mutations were found. Loss of function at DNA level strongly correlated with loss of mRNA expression accounting for 80% of the cases. Because of the close relationship between p14(ARF) and TP53 and between p15(INK4b)/p16(INK4a) and Rb, these results support a model of a coinactivation of TP53 and Rb pathways in 75% of MPNSTs, with functional consequences on cell growth control and apoptosis. CONCLUSIONS: The inactivation of the 9p21 locus is a frequent and peculiar hallmark of MPNST genetic profile leading also to an impaired apoptosis that could be taken into account in treatment planning of these tumors.

Adult↗
PubMed2005

Mutation analysis of DKK1 and in vivo evidence of predominant p53-independent DKK1 function in gliomas.

DKK1 protein belongs to a family of inhibitors of the Wnt/beta1-catenin signaling pathway. Sporadic mutations affecting almost each major player of the Wnt/beta1-catenin pathway have been described in a variety of human carcinomas. DKK1 translation can be induced by p53, thereby linking TP53 and Wnt/beta1-catenin signaling pathways. These findings raise questions in regard to human gliomas, which similar to carcinomas carry a high rate of mutations in TP53. To analyze DKK1 for its role in initiation or progression, we screened a series of 73 brain tumors for structural alterations in the entire coding sequence by single-strand conformation polymorphism and direct sequencing. While several sequence variants were detected, there were no obvious mutations affecting DKK1. Further, we analyzed the prevalence of mRNA from TP53, DKK1 and CTNNB1 and of p53 and beta1-catenin protein in a series of human gliomas with and without mutations in TP53. Transcription and expression of CTNNB1/beta1-catenin and DKK1 proved to be independent of TP53/p53. These data support in vivo function of DKK1, independent of p53, in human gliomas with no major impact on their pathogenesis.

Blotting, Southern↗
PubMed2004

Genetics of breast cancer.

Breast cancer has all the hallmarks of a multistep genetic disease. Somatic and germ-line mutations have been described in several tumor suppressor genes, and oncogenes are found to be amplified. Genes in the ATM-CHK2-TP53 cell-cycle checkpoint pathway are mutated in relation to breast cancer, particularly TP53 at the somatic level. Germ-line mutations in BRCA1 and BRCA2, in which DNA repair function is interrupted, account for the majority of familial breast cancers. The mechanism behind the frequent instability of the genomes of breast cancer cells has been poorly understood, but recent functional findings on oncogenes and tumor suppressor genes have provided substantial information on the matter. Some recent developments in drug therapy are based on molecular and genomic findings about breast cancer pathogenesis.

Animals↗
PubMed2001

Induction of gene expression as a monitor of exposure to ionizing radiation.

The complex molecular responses to genotoxic stress are mediated by a variety of regulatory pathways. The transcription factor TP53 plays a central role in the cellular response to DNA-damaging agents such as ionizing radiation, but other pathways also play important roles. In addition, differences in radiation quality, such as the exposure to high-LET radiation that occurs during space travel, may influence the pattern of responses. The premise is developed that stress gene responses can be employed as molecular markers for radiation exposure using a combination of informatics and functional genomics approaches. Published studies from our laboratory have already demonstrated such transcriptional responses with doses of gamma rays as low as 2 cGy, and in peripheral blood lymphocytes (PBLs) irradiated ex vivo with doses as low as 20 cGy. We have also found several genes elevated in vivo 24 h after whole-body irradiation of mice with 20 cGy. Such studies should provide insight into the molecular responses to physiologically relevant doses, which cannot necessarily be extrapolated from high-dose studies. In addition, ongoing experiments are identifying large numbers of potential biomarkers using microarray hybridization and various irradiation protocols including expression at different times after exposure to low- and high-LET radiation. Computation-intensive informatics analysis methods are also being developed for management of the complex gene expression profiles resulting from these experiments. With further development of these approaches, it may be feasible to monitor changes in gene expression after low-dose radiation exposure and other physiological stresses that may be encountered during manned space flight, such as the planned mission to Mars.

Gene Expression↗
PubMed2005

Mutation of TP53 gene is involved in carcinogenesis of hepatic undifferentiated (embryonal) sarcoma of the adult, in contrast with Wnt or telomerase pathways: an immunohistochemical study of three cases with genomic relation in two cases.

BACKGROUND/AIMS: Hepatic undifferentiated (embryonal) sarcoma (HUS) is an exceptional hepatic malignant tumor in adults. Genetic studies were never reported in adult cases. METHODS: In this study concerning three cases of HUS occurring in adult, we studied the three classical ways of carcinogenesis i.e. the TP53 (p53), Wnt (CTNNB1/beta-catenin and AXIN1) and telomerase (hTERT) pathways. We studied the expression of p53, beta-catenin and telomerase catalytic subunit hTERT by immunohistochemistry in the three cases; we determined TP53 gene mutation in two cases and the genome-wide allelotype, AXIN1, and CTNNB1/beta-catenin gene mutation in one case. RESULTS: Immunohistochemistry showed an overexpression of p53 in more than 80% of tumoral cells; furthermore, mutations of TP53 were observed in two cases, involving the sequence-specific DNA binding domain. In contrast, no mutation was found in CTNNB1/beta-catenin and AXIN1 genes. Tumoral cells did not show hTERT staining nor nuclear expression of beta-catenin. In addition, allelotype analysis in one case showed loss of heterozygosity of chromosome 7p, 11p, 17p, 22q, and allelic imbalance of 1p, 8p, 20q. CONCLUSIONS: In this report of HUS in three adult patients, we emphasize the role of TP53 pathway in carcinogenesis of this rare tumor. This point could be of interest for therapeutic strategies.

Adolescent↗
PubMed2025

Systematic understanding of mechanism of Shenfu decoction improve the prognosis of ischemic stroke using a network pharmacology and animal experiment approach.

OBJECTIVE: To explore the active compounds and the mechanism of Shenfu decoction (, SFD) against ischemic stroke (IS) through network pharmacology and animal experiments. METHODS: SFD components were retrieved from the Traditional Chinese Medicine (TCM) database. The Online Mendelian Inheritance in Man (OMIM), Comparative Toxicogenomics Database (CTD) and Therapeutic Target Database (TTD) database were used to retrieve the IS-related disease targets. The herb-compound-target network was built by Cytoscape 3.7.1 software. The core targets were obtained using protein-protein interaction (PPI) network. The core targets of SFD were further analyzed through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). We then performed molecular docking between the hub proteins and key active compounds. Finally, we conducted animal experiments to verify the regulation of SFD on apoptosis following IS. RESULTS: There were 221 corresponding targets and 25 components related to Chinese medicine throughout the compound-target network. The core targets of SFD in the treatment of IS was tumor protein P53 (Tp53), mitogen-activated protein kinase 3 (MAPK3), MAPK1, heat shock proteins 90AA1 and alpha serine/threonine-protein kinase1. There were 221 GO items in GO function enrichment analysis and 106 signaling pathways in KEGG, mainly including negative regulation of the apoptosis process, vascular endothelial growth factor signaling pathways, NOD-like receptor signaling pathway, etc. Among them, Tp53, MAPK3, and MAPK1 were docked with small molecule compounds. Through animal research, we confirmed the effect of SFD on apoptosis following stroke. CONCLUSION: This study demonstrates that SFD can treat IS through multiple targets and pathways, and provides new perspectives for exploring the core targets and mechanisms of SFD against IS.

Drugs, Chinese Herbal↗
PubMed2002

Relationship between p53 dysfunction, CD38 expression, and IgV(H) mutation in chronic lymphocytic leukemia.

Established adverse prognostic factors in chronic lymphocytic leukemia (CLL) include CD38 expression, relative lack of IgV(H) mutation, and defects of the TP53 gene. However, disruption of the p53 pathway can occur through mechanisms other than TP53 mutation, and we have recently developed a simple screening test that detects p53 dysfunction due to mutation of the genes encoding either p53 or ATM, a kinase that regulates p53. The present study was conducted to examine the predictive value of this test and to establish the relationship between p53 dysfunction, CD38 expression, and IgV(H) mutation. CLL cells from 71 patients were examined for IgV(H) mutation, CD38 expression, and p53 dysfunction (detected as an impaired p53/p21 response to ionizing radiation). Survival data obtained from 69 patients were analyzed according to each of these parameters. Relative lack of IgV(H) mutation (less than 5%; n = 45), CD38 positivity (antigen expressed on more than 20% of malignant cells; n = 19), and p53 dysfunction (n = 19) were independently confirmed as adverse prognostic factors. Intriguingly, all p53-dysfunctional patients and all but one of the CD38(+) patients had less [corrected] than 5% IgV(H) mutation. Moreover, patients with p53 dysfunction and/or CD38 positivity (n = 31) accounted for the short survival of the less mutated group. These findings indicate that the poor outcome associated with having less than 5% IgV(H) mutation may be due to the overrepresentation of high-risk patients with p53 dysfunction and/or CD38 positivity within this group, and that CD38(-) patients with functionally intact p53 may have a prolonged survival regardless of the extent of IgV(H) mutation.

ADP-ribosyl Cyclase↗
PubMed2001

Induction of telomerase activity by irradiation in human lymphoblasts.

Neuhof, D., Ruess, A., Wenz, F. and Weber, K. J. Induction of Telomerase Activity by Irradiation in Human Lymphoblasts. Radiat. Res. 155, 693-697 (2001). Telomerase activity is a radiation-inducible function, which suggests a role of this enzyme in DNA damage processing. Since the tumor suppressor TP53 plays a central role in the regulation of the cellular response to DNA damage, our study explored the ability of ionizing radiation to change telomerase activity and telomere length in two closely related human lymphoblast cell lines with different TP53 status. TK6 cells (wild-type TP53) and WTK1 cells (mutated TP53) were exposed to different doses of X rays, and telomerase activity was measured by PCR ELISA at different times after irradiation. A dose-dependent increase in telomerase activity was observed. One hour after irradiation with 4 Gy, TK6 and WTK1 cells showed an approximately 2.5-fold increase; for lower doses (0.1 to 1 Gy), telomerase induction was seen only in TK6 cells. Telomerase induction was observed by 0.5 h after irradiation, with a further increase up to 24 h. Irradiated TK6 and WTK1 cells had longer telomeres (+1.3 kb) than unirradiated cells 14 days after exposure. Our data demonstrate a dose-dependent induction of telomerase activity and lengthening of telomeres by ionizing radiation in human lymphoblasts. Induction of telomerase activity by radiation does not generally appear to be controlled by the TP53-dependent DNA damage response pathway. However, for low doses, induction of telomerase requires wild-type TP53.

Cell Line↗
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↗
PubMedDate not supplied

Mutations in exons 6 and 7 of TP53 gene correlate positively with serum tumor necrosis factor alpha independent of microsatellite instability in BAT26 gene in Egyptian patients with endometrial carcinoma.

UNLABELLED: Abnormalities in the TP53 gene are the most frequent genetic alterations in human cancers. The role and mechanism of TP53 mutations have been well studied in many types of human cancer. Similarly, the presence of microsatellite instability (MSI) in the DNA mismatch repair system (hMSH2) may provide evidence of faulty DNA mismatch repair. One of the most important locations of MSI is the BAT26 gene. In addition, deranged serum cytokines, especially elevated levels of the tumor necrosis factor (TNF) alpha, have been found in many gynecological conditions. AIMS: The current study aimed at evaluating mutations in exons 6 and 7 of TP53 and the presence of microsatellite instability in BAT26 of the hMSH2 system in Egyptian patients with endometrial carcinoma. The study also evaluated whether there was a correlation between any of these genetic mutations/instability and the tissue expression of estrogen and progesterone receptors and the serum TNF-alpha level. PATIENTS AND METHODS: The current study included 2 groups: a control group comprising 20 healthy women aged 52.21 +/- 5.80 years attending the clinic for routine checkups and 40 patients with endometrial cancer aged 55.30 +/- 6.21 years. Mutations in TP53 and BAT26 were evaluated using polymerase chain reaction-single-strand conformational polymorphism (PCR-SSCP) and automated sequencing while serum TNF-alpha was measured using an ELISA technique. Estrogen and progesterone receptor expression in biopsy tissue was evaluated using immunohistochemical staining. RESULTS: Seven of the 40 patients (17.5%) were positive for TP53 gene alterations in exon 6, while 9 patients (22.5%) were positive for TP53 alterations in exon 7. Cases positive for TP53 mutations had higher tumor stages. Ten patients (25%) showed MSI in BAT26. Nearly all patients with mutations in BAT26 had a strong family history for endometrial cancer (chi2=13.33, p<0.05). There was no positive correlation between the presence of MSI in the BAT26 gene and mutations in the TP53 gene or high serum TNF-alpha levels. Cases positive for TP53 mutations had a significantly higher level of TNF-alpha than cases negative for TP53 mutations (p<0.05). Cases showing mutations in exon 6 or 7 of TP53 showed a significantly higher intensity of immunohistochemical staining for estrogen and progesterone receptor expression in biopsy tissue than cases negative for mutations. (chi2=8.11, p<0.05). CONCLUSION: Our results suggest that the development of endometrial carcinoma is probably mediated through a multi-step carcinogenesis pathway and mutation of TP53 does not necessarily result from the presence of microsatellite instability in BAT26. The high serum TNF-alpha levels detected in our patients may represent an immunological antitumor response that was particularly evident in cases positive for TP53 mutations.

Base Sequence↗
PubMed2001

TP53 gene mutations, nuclear p53 accumulation, expression of Waf/p21, Bcl-2, and CD95 (APO-1/Fas) proteins are not prognostic factors in de novo glioblastoma multiforme.

Glioblastoma multiforme (WHO grade IV; GBM) is the most common primary brain tumor with a median survival of less than one year despite multimodal treatment regimens. However, a small subgroup of GBM patients has a better clinical outcome, with a small number of patients surviving several years. Apoptosis, a genetically determined program of cell suicide, may be induced as a consequence of critical DNA damage. However, due to defects in the signaling pathways, cancer cells may escape apoptosis, despite carrying irreversible DNA damage. In the present study, we have analyzed tumors of two age-matched, equally treated groups of GBM patients with different postoperative time to tumor progression (TTP), defined as 'short-term' for TTP of less than 6 months (n = 54), and 'long-term' for TTP of more than 12 months (n = 39) for alterations in apoptosis regulatory pathways: Mutations of the TP53 tumor suppressor gene and/or nuclear accumulation of its gene product p53, expression of Waf/p21, CD95 (Apo1/Fas), and Bcl-2. TP53 mutations were found in 12 out of 54 (22%) GBMs of short-term survivors and 8 out of 35 (23%) tumors of long-term survivors; the respective numbers for nuclear p53 protein accumulation were 12/53 (23%) and 10/37 (27%). Waf1/p21 expression was found in 13/53 (25%) tumors of short-term survivors and 9/35 (26%) GBMs of long-term survivors. The respective numbers for Bcl-2 expression were 25/42 (60%) and 22/36 (61%) and for CD95 (Apo1/Fas) expression 20/49 (41%) and 14/36 (39%) GBMs. The percentage of alterations in genes/proteins involved in the apoptotic pathway investigated here was virtually identical in the two groups of clinically different GBM patients. Thus, our data imply that none of these alterations investigated per se has a strong impact on the overall survival of GBM patients.

Adult↗