P53 Gene Mutations Research Articles

Фотосенсибилизатор диметиловый эфир хлорина е6 для фотодинамической терапии саркомы М-1 крыс

Photodynamic therapy (PDT) is a local form of treatment for the complete eradication of solid malignant neoplasms (PDT). In this work, we studied the efficiency of PDT with the photosensi-tizer (PS) chlorin e6 dimethyl ether (DME Che6) in the treatment of positive for the mutant p53 gene sarcoma M-1. To assess the optimal time for tumor irradiation with laser the kinetics of PS accumulation in tumor and surrounding healthy tissues was studied. The tumor response to PDT was assessed with the use of the following criteria: tumor growth inhibition index (%); tumor complete regression (%); absolute growth rate (K) index, it is used in rats with tumor growth after the treatment; increase in the life expectancy in group of treated animals and the control group of tumor-bearing rats; the treatment response criterion – means the absence of signs of tumor re-currence within 90 days after therapy. On the 21st day after the treatment the PDT efficiency for tumor cells devitalization was assessed by examining the areas exposed to laser radiation and data of histological analysis. Results of the study allow us to state that DME Che6 has a high anti-tumor activity in the treatment of M-1 sarcoma. The maximum inhibitory effect of the PS on ma-lignant neoplasms after PDT is achieved if time between the sensitizer introduction and the laser irradiation beginning is optimal. As a result of pathomorphological assessment of material after PDT, no survived tumor cells with expression of the mutant p53 protein were detected.

P53 and EGFR gene mutations in malignant tumors of the lung

Relevance: Increased incidence of lung cancer globally and in Kazakhstan, lack of screening in hereditary cases, high mortality, and low survival of patients necessitate the study of the molecular genetic causes of the disease. At present, gene mutation studies for lung cancer diagnostics are expanding. However, many gene mutations revealed remain undercovered in the
 scientific literature, and there is not enough data on their prognostic and diagnostic value.
 The purpose of the study was to discover the specifics of the р53 gene mutations and reveal the EGFR exon 19 deletions and exon 21 L858R mutations in malignant tumors of the lung of various histogenesis.
 Methods: The mutations were studied in tumors (200 samples) and adjacent tissue (200 samples) of patients with lung cancer (squamous cell carcinoma (SCC) and adenocarcinoma (ADC) of the lung) by polymerase chain reaction (PCR), electrophoresis, and EcoR1- and Pst1-restriction of samples after p53 gene fragments and cDNA amplification and mRNA revertase treatment. Another 263 lung cancer samples were evaluated by real-time PCR for EGFR exon 19 deletions and EGFR exon 21
 L858R mutations.
 Results: The p53 gene was not expressed in 50% of SCC and adenocarcinoma of the lung samples. Restriction revealed p53 mRNA mutations in 100% of SCC and 75% of ADC samples. p53 exon-intron 5-6 was mutated in 50% of ADC and 70% of SCC samples, exon-intron 7-9 – in 60% of SCC cases. EGFR exons 19 and 21 mutations found in 65 of 263 lung tumor samples were associated with increased sensitivity to EGFR tyrosine kinase inhibitors.
 Conclusion: The p53 gene mutations revealed in most samples of SCC and ADC of the lung could be used to diagnose lung cancer and predict its severity. The identified EGFR mutations allow predicting the effectiveness of targeted therapy.

ELUCIDATING THE ROLE OF THE SATB1 GENE IN BREAST CANCER CARCINOGENESIS IN THE PRESENCE OR ABSENCE OF TOCOTRIENOL-RICH FRACTION: EVIDENCE FROM A SYNGENEIC MOUSE MODEL OF BREAST CANCER

Tocotrienols are reported to possess anticancer activities. Recently we showed that the anticancer effects of tocotrienolrich fraction (TRF) may be through inhibition of the special AT-rich sequence-binding protein 1 (SATB1) gene in a syngeneic mouse model of breast cancer (BC). The present study aims to further explore the role of the SATB1 gene in murine BC cells. The expression of the SATB1 gene in the 4T1 murine BC cells was partially knocked down (SATB1-4T1) using the short hairpin RNA (shRNA) technology and these cells were injected into the mammary pads of mice. Control groups were injected with wild-type 4T1 (WT 4T1) cells. When the tumour was palpable, half of the mice in both groups were fed daily with 1 mg TRF and received intraperitoneal injections of dendritic cells pulsed with tumour lysate (DC+TL) once a week for three weeks. The tumour incidence in mice injected with the SATB1-4T1 cells was reduced (p<0.05) and this effect was independent of TRF supplementation. However, in mice injected with WT-4T1, there was inhibition of tumour growth (p<0.05) only in the group fed with TRF. In addition, the expression of S1004A and mutant P53 genes were suppressed in tumours from animals that were injected with the SATB1-4T1 cells, irrespective of TRF supplementation; which was also observed in tumours from mice injected with WT 4T1 cells and fed with TRF. These findings suggest that TRF may work through the SATB1 pathway.

P53 and EGFR gene mutations
 in malignant tumors of the lung

Relevance: Increased incidence of lung cancer globally
 and in Kazakhstan, lack of screening in hereditary cases, high
 mortality, and low survival of patients necessitate the study of
 the molecular genetic causes of the disease. At present, gene
 mutation studies for lung cancer diagnostics are expanding.
 However, many gene mutations revealed remain undercovered
 in the scientific literature, and there is not enough data on their
 prognostic and diagnostic value.
 The purpose of the study was to discover the specifics of
 the р53 gene mutations and reveal the EGFR exon 19 deletions
 and exon 21 L858R mutations in malignant tumors of the lung
 of various histogenesis.
 Methods: The mutations were studied in tumors (200 samples) and adjacent tissue (200 samples) of patients with lung
 cancer (squamous cell carcinoma (SCC) and adenocarcinoma
 (ADC) of the lung) by polymerase chain reaction (PCR), electrophoresis, and EcoR1- and Pst1-restriction of samples after p53
 gene fragments and cDNA amplification and mRNA revertase
 treatment. Another 263 lung cancer samples were evaluated
 by real-time PCR for EGFR exon 19 deletions and EGFR exon 21
 L858R mutations.
 Results: The p53 gene was not expressed in 50% of SCC and
 adenocarcinoma of the lung samples. Restriction revealed p53
 mRNA mutations in 100% of SCC and 75% of ADC samples. p53
 exon-intron 5-6 was mutated in 50% of ADC and 70% of SCC
 samples, exon-intron 7-9 – in 60% of SCC cases. EGFR exons 19
 and 21 mutations found in 65 of 263 lung tumor samples were
 associated with increased sensitivity to EGFR tyrosine kinase
 inhibitors.
 Conclusion: The p53 gene mutations revealed in most
 samples of SCC and ADC of the lung could be used to diagnose
 lung cancer and predict its severity. The identified EGFR mutations allow predicting the effectiveness of targeted therapy

Efficient Generation of P53 Biallelic Mutations in Diannan Miniature Pigs Using RNA-Guided Base Editing.

The base editing 3 (BE3) system, a single-base gene editing technology developed using CRISPR/Cas9n, has a broad range of applications for human disease model construction and gene therapy, as it is highly efficient, accurate, and non-destructive. P53 mutations are present in more than 50% of human malignancies. Due to the similarities between humans and pigs at the molecular level, pig models carrying P53 mutations can be used to research the mechanism of tumorigenesis and improve tumor diagnosis and treatment. According to pathogenic mutations of the human P53 gene at W146* and Q100*, sgRNAs were designed to target exon 4 and exon 5 of the porcine P53 gene. The target editing efficiencies of the two sgRNAs were 61.9% and 50.0%, respectively. The editing efficiency of the BE3 system was highest (about 60%) when C (or G) was at the 5th base. Puromycin screening revealed that 75.0% (21/28) and 68.7% (22/32) of cell colonies contained a P53 mutation at sgRNA-Exon5 and sgRNA-Exon4, respectively. The reconstructed embryos from sgRNA-Exon5-5# were transferred into six recipient gilts, all of which aborted. The reconstructed embryos from sgRNA-Exon4-7# were transferred into 6 recipient gilts, 3 of which became pregnant, resulting in 14 live and 3 dead piglets. Sequencing analyses of the target site confirmed 1 P53 monoallelic mutation and 16 biallelic mutations. The qPCR analysis showed that the P53 mRNA expression level was significantly decreased in different tissues of the P53 mutant piglets (p < 0.05). Additionally, confocal microscopy and western blot analysis revealed an absence of P53 expression in the P53 mutant fibroblasts, livers, and lung tissues. In conclusion, a porcine cancer model with a P53 point mutation can be obtained via the BE3 system and somatic cell nuclear transfer (SCNT).

One-shot dual gene editing for drug-resistant pancreatic cancer therapy

It is challenging to diagnose patients with pancreatic ductal adenocarcinoma (PDAC) early on, and their treatment is often complex. Gemcitabine (GEM) is the first-line treatment for PDAC, but its efficacy is limited in most patients due to the GEM resistance from KRAS and P53 gene mutations. We describe the correction of a double gene mutation and therapeutic effect for the GEM resistant PDAC. Bio-available nanoliposomes (NL) possessing Cas9-ribonucleoproteins and adenine-base editors were developed to conduct KRAS and P53 mutation gene editing directly. NLs were conjugated with EGFR antibodies to tumor-specific delivery, and the anti-cancer effect was verified in vitro and in vivo Model. Our GEM-combinatorial therapeutic strategies using double gene editing systems with one-shot may be a potent therapy for PDAC, overcoming chemoresistance.

Umbilical Cord Blood Microtransplantation in Newly Diagnosed, Elderly Patients with Acute Myeloid Leukemia

Objective: We observed the efficacy and safety of umbilical cord blood microtransplantation (UCBMT) in the treatment of newly diagnosed with acute myeloid leukemia (AML) in the elderly.Methods: Prospective one-arm phase I clinical study. The patients should meet the following criteria: 60-80-year-old; newly diagnosed AML; receive the treatment of chemotherapy combined with UCBMT.Result: In total, 11 patients newly diagnosed with AML received chemotherapy in combination with UCBMT, from November, 2019 to January, 2021, including 7 males and 4 females. The average age was 71 (60-80). For the patients, 7 cases with normal chromosome karyotype, and 2 cases with +8 chromosome, 1 case with 7q- chromosome, and 1 case with karyotype of monomer. In the 7 patients with normal chromosome karyotype, 3 cases were FMS-liketyrosine kinease 3 (FLT3) positive (2 of them in combination with nucleophosmin 1 (NPM1) mutation); in addition, in 4 patients of the 7, one showed double mutation of CEBPA, one showed NPM1 mutation, one showed IDH1 mutation, and one showed IDH2 mutation. In 4 patients with chromosomal abnormalities, one patient showed no special gene, one patient showed ASXL1 mutation, one patient was IDH1 mutation, and one patient was TP53 mutation. All of the patients were treated with IA (IDA 8-10 mg/ m 2/day x 3 days, cytarabine 100 mg/ m 2/day x 7 days) for inducing chemotherapy. For the patients with 60-70-year-old, they were treated with IDA (8 mg/ m 2/day); and for the patients with 70-80-year-old, they were treated with darubicin (10 mg/ m 2/day). In the consolidation phase, the patients were treated with cytarabine (1 g/ m 2, q12h) for 3 consecutive days. There were 3 courses of consolidation chemotherapy. Next, patients received single unrelated cord blood transplantation (UCBT) from China's public umbilical cord blood bank, HLA matching was performed for all patients before treatment. A total of 4 units of UCB with HLA 0-3/6（HLA-A,-B,-DR）matching and the ABO blood type matched with the patient were transfused after induction and consolidation chemotherapy for 24-48 hours, then with follow-up. At the same time, the immunological characteristics of these patients were fully analyzed. We demonstrated that, 8 of 11 patients received one course of induction chemotherapy, and achieved a complete response. The complete response rate was 72.7%. What's more, the median time for neutrophils ≥ 0.5 x 10 9/L and platelete ≥ 20 x 10 9/L was 12 days. There were no treatment-related deaths during induction therapy. The median follow-up was 14 (7-31) months. 1 patient showed monomer karyotype with P53 gene mutation, and got complete remission after one course of induction chemotherapy with IA. However, the patient died for AML recurred. For the other 10 patients, they were alive, and the OS of 1 year was 89.8%. Moreover, we found the expression of PD-1 on CD8 +T cells decreased, while the expression of CD38 increased after therapy. Besides, the proportion of NKp30 +NK cells, as well as the IFN-γ +TFN-α +NK cells increased significantly.Conclusion: UCBMT therapy for newly diagnosed elderly AML patients could accelerate the recovery of hematopoietic function and improve the safety of chemotherapy. This method is effective and worthy of further promotion. DisclosuresNo relevant conflicts of interest to declare.

Valproic Acid Enhanced Temozolomide-Induced Anticancer Activity in Human Glioma Through the p53-PUMA Apoptosis Pathway.

Glioblastoma (GBM), the most lethal type of brain tumor in adults, has considerable cellular heterogeneity. The standard adjuvant chemotherapeutic agent for GBM, temozolomide (TMZ), has a modest response rate due to the development of drug resistance. Multiple studies have shown that valproic acid (VPA) can enhance GBM tumor control and prolong survival when given in conjunction with TMZ. However, the beneficial effect is variable. In this study, we analyzed the impact of VPA on GBM patient survival and its possible correlation with TMZ treatment and p53 gene mutation. In addition, the molecular mechanisms of TMZ in combination with VPA were examined using both p53 wild-type and p53 mutant human GBM cell lines. Our analysis of clinical data indicates that the survival benefit of a combined TMZ and VPA treatment in GBM patients is dependent on their p53 gene status. In cellular experiments, our results show that VPA enhanced the antineoplastic effect of TMZ by enhancing p53 activation and promoting the expression of its downstream pro-apoptotic protein, PUMA. Our study indicates that GBM patients with wild-type p53 may benefit from a combined TMZ+VPA treatment.

Pre-Cancer Diagnosis via TP53 Gene Mutations Applied Ensemble Algorithms

According to current study, individuals with cancer who have a gene mutation have a bad prognosis. Young women with breast cancer had a poorer prognosis than older women, although it is unknown if the p53 gene mutation contributed to this. Due in part to the devastation of cancer, the appropriate technology may help cancer sufferers in regaining their lives. Researchers seek for mutations in cancer-causing gene sequences in order to identify the precancerous stage. While genetic testing may be used to forecast some kinds of cancer, there is presently no effective technique for identifying all cancers caused by TP53 gene mutations. It is one of the most often discovered genetic anomalies in human cancer is a malfunction in the action of the protein P53. As a consequence, the Universal Mutation Database is used to identify gene mutations (UMDCell-line2010).&#x0D; The issue is that, although many basic databases (for example, Excel format databases) exist that include datasets of TP53 gene mutations associated with disease (cancer), this huge database is incapable of detecting cancer. Thus, the purpose the objective of this study is to create an approach for data mining that utilizes a neural network to ascertain the pre-cancerous state. To begin, bioinformatics techniques such as BLAST, CLUSTALW, and NCBI were used to determine whether or not there were any malignant mutations; second, the proposed method was carried out in two stages: to begin, bioinformatics techniques such as BLAST, CLUSTALW, and NCBI were used to determine whether or not there were any malignant mutations; and third, the proposed method was carried out in two stages: to begin, bioinformatics techniques such as To begin, bioinformatics tools such as BLAST and CLUSTAL&#x0D; Vote Algorithms were utilized to classify pre-cancer by malignant mutations in the disease's early stages. The writers teach and evaluate their subjects using a variety of situations, including cross validation and percentages. This page contains a review of the algorithms discussed before.

Sensitive Detection of Single-Nucleotide Polymorphisms by Solid Nanopores Integrated With DNA Probed Nanoparticles.

Single-nucleotide polymorphisms (SNPs) are the abundant forms of genetic variations, which are closely associated with serious genetic and inherited diseases, even cancers. Here, a novel SNP detection assay has been developed for single-nucleotide discrimination by nanopore sensing platform with DNA probed Au nanoparticles as transport carriers. The SNP of p53 gene mutation in gastric cancer has been successfully detected in the femtomolar concentration by nanopore sensing. The robust biosensing strategy offers a way for solid nanopore sensors integrated with varied nanoparticles to achieve single-nucleotide distinction with high sensitivity and spatial resolution, which promises tremendous potential applications of nanopore sensing for early diagnosis and disease prevention in the near future.

Loss of p21ras, p53, and Mdm2 Protein Expression Is Indicative of Worse Prognosis in Myelodysplastic Syndromes.

Myelodysplastic syndromes (MDS) comprise a group of clonal disorders of the hematopoietic stem cell characterized by ineffective hematopoiesis and refractory cytopenias that can progress to acute leukemia. In order to identify molecular events implicated in the pathogenesis of MDS, we analyzed the bone marrow expression and mutational status of ras, p53 and mdm2 genes in a cohort of 25 patients with MDS. The expression of p21ras, p53, and Mdm2 proteins was studied in marrow cytopins stained by APAAP (alkaline phosphatase anti-alkaline phosphatase procedure) using monoclonal antibodies Y13-219, PAb 1801 and 2A10 to detect p21ras, p53 and mdm2 proteins, respectively. N-, K-, H-ras and p53 gene mutations were assessed by PCR-SSCP (polymerase chain reaction/single strand conformation polymorphism) and DNA sequencing to exclude the presence of gene mutations. The quantitative wild-type expression of p21ras, p53 and mdm2 proteins in patient samples (combination of number of cells and staining intensity) was compared to the values of expression of these proteins in 7 normal bone marrow samples. We found overexpression of p21ras and p53 proteins in 12/22 (55%) and 7/23 (30%) of the patients. Five of 7 patients who overexpressed wt-p53 also co-overexpressed wt-p21ras protein. We observed absence of expression of p21ras, p53 and mdm2 in 4/22, 4/23 and 9/19 cases, respectively. Overall survival of patients with absence of p21ras and p53 expression was considerably worse than that of patients with normal expression of these proteins (p=0.0006 to p21ras and p=0.004 to p53 by Log-Rank test; p=0.02 to p21ras and p=0.01 to p53 by Cox proportional hazards model after age, neutrophil and platelet count, and hemoglobin adjustment). We also observed that the patients who exhibited hypoexpression (p=0.055) and absence of mdm2 expression (p=0.07) demonstrated a tendency to have worse prognosis (Log-Rank). There was no correlation between variables p21ras, p53 and mdm2 versus hemoglobin, platelet and neutrophil counts and no association between FAB SMD subcategories and absence of p53 and mdm2 expression by Fisher test (two-tailed), but there was a strong over-representation between absence of p21ras expression and MDS with excess of blasts (p=0.0006). There was a significant correlation between p53 and mdm2 gene expression (p=0.03, Pearson). Only one patient harbored one transversion mutation in codon 12 of K-ras gene and did not correlate with p53 overexpression, but with worse prognosis. No p53 mutation was found. Overall, these findings suggest that the via of signal transduction p21ras/p53 and the auto-regulatory genes p53/mdm2 may be active and play a pivotal role in the pathogenesis of MDS. Hence, loss of bone marrow expression of p21ras, p53 and/or mdm2 proteins is an indicator of worse prognosis in MDS and may serve as early markers of leukemic transformation.

MDMX Is Widely Expressed in Adult Pre-Cursor B Cell B Acute Lymphoblastic Leukemia and Is a Potential Therapeutic Target.

MDMX is a human homolog of murine double minute 2 (HDM2), which like HDM2, is a negative regulator of p53. In pediatric precursor B-cell (pre-B) acute lymphoblastic leukemia (ALL), p53 expression is associated with poor prognosis. In this study, we assessed MDMX, HDM2, p53 and p21 levels in bone marrow samples from 55 adult patients with pre-B ALL diagnosis. A 110-core tissue microrray was subject to immunohistochemical analysis; in which 10% or more tumor cells stained were considered positive. Results were compared with Philadelphia chromosome (Ph) status (37 Ph-, 18 Ph+) and clinical data. MDMX was found to be expressed in 39 of 49 cases (80%), whereas HDM2 was expressed in 14 of 54 cases (26%). All 14 cases positive for HDM2 were also positive for MDMX (P < 0.05). Median survival duration was 138 weeks in the Ph- group and 48 weeks in the Ph+ group (P < 0.001). p53 was expressed more often in the Ph+ group than in Ph- group (10 of 17 versus 10 of 36, P < 0.05), as was p21 (11 of 17 versus 6 of 34, P < 0.003). In the Ph+ group, patients with tumor cells positive for p53, HDM2, and MDMX had a worse prognosis than other patients (35 weeks versus 61 weeks, P < 0.002). Western blot analysis of protein extracts of blasts isolated from patients with pre-B ALL confirmed the expression of MDMX or its variants. Furthermore, only 1 of 5 cases demonstrated missense mutation of p53 genes. Thus MDMX was expressed in most of these cases of pre-B ALL, suggesting that MDMX may be a potential therapeutic target. The higher incidence of MDMX expression seemed to be independent of p53. P21 expression by the blasts of a subset of ALL cases indicated that the p53 pathway was functional.

High Frequency of P53 Mutations Detected by a Microarray Resequencing Assay, the AmpliChip P53 Test, in AML with a Complex Aberrant Karyotype.

Acute myeloid leukemia (AML) is heterogeneous in morphology, cytogenetics, and prognosis. On the basis of cytogenetics it can be subdivided into three groups with favorable, intermediate, or unfavorable prognosis. Accounting for 10%–20% of all AML cases, AML with complex aberrant karyotypes is more frequent at higher ages and is the subgroup with the worst prognosis. AML with complex aberrant karyotype is generally defined by the presence of three or more clonal chromosome abnormalities. Genetically, it has a characteristic pattern of chromosomal gains and losses, resulting also in a unique gene expression pattern including upregulation of genes involved in DNA repair. One of the important characteristics of AML with complex aberrant karyotype is the high incidence of deletions and/or mutations in the tumor suppressor p53 gene (60%–80%) which occur very unfrequently in other AML subgroups. Here we present data on 119 AML cases with complex aberrant karyotypes that were analyzed with the new AmpliChip p53 Test, a microarray-based resequencing test that is designed to detect single nucleotide changes in the entire coding region of the p53 gene. The AmpliChip p53 Test queries for the presence of sequence alterations through comparative analysis of the microarray hybridization pattern of a series of probes from sample DNA to wild type (wt) reference DNA. Starting from genomic DNA, the 10-hour assay includes PCR amplification, fragmentation and labeling, hybridization to the microarray, washing and staining, and mutation data analysis. By use of this technique we have detected p53 mutations located in exons 4–10 in 89/119 (74.8%) samples. These mutations included missense mutations, frameshift mutations, splice site mutations, silent mutations, and nonsense mutations. All 119 samples had also been analyzed in parallel for p53 mutations by a combination of several alternative methods including the predecessor Affymetrix p53 GeneChip microarray, denaturing high performance liquid chromatography (DHPLC), as well as conventional sequencing. The specificity and sensitivity of the AmpliChip p53 Test were compared to the results obtained with these alternative assays. Discordant results were observed in 27 samples when comparing the AmpliChip p53 Test to the alternative assays. Among these 27 samples the AmpliChip p53 Test detected mutations in Exon 10 in 2 samples which had not been tested by DHPLC and further exclusively detected the R72P polymorphism in 9 samples. The remaining group of discordant samples contained:5 samples with a I03 dup 16bp +40 (acctggagggctgggg);3 samples containing a > 2 bp deletion;2 samples with insertion mutations; andone with a mutation in intron 3.Due to technical reasons, all of these aberrations noted above are out of the specifications of the AmpliChip p53 Test. In 5 samples the AmpliChip p53 Test detected additional mutations that were not identified by conventional methods. In conclusion, the AmpliChip p53 Test is a robust and rapid diagnostic tool that allows to identify a poor prognostic subset of AML. Unraveling the biology of this disease may provide new pathophysiologic insights applicable to therapeutic intervention, especially for the targeted therapy of AML with complex aberrant karyotype.

Oncological Follow-up with 2-[18F]-FDG PET/CT in Li-Fraumeni Syndrome

Li-Fraumeni syndrome is a rare disorder caused by abnormalities of the tumor-suppressor protein P53 gene. We present the case of a 26-years-old female diagnosed with bilateral ductal carcinoma. The genetic panel for breast cancer gene 1 (BRCA1) and BRCA2 mutations was negative and positive heterozygous germline tumor protein P53 gene mutations, considering Li-Fraumeni syndrome. A 2-[18F]-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) was used for postsurgical staging to show the right lung hypermetabolic nodule. A lobectomy was accomplished, and histopathology reported pulmonary adenocarcinoma. A year later, oncological follow-up was conducted with 2-[18F]-FDG PET/CT without evidence of abnormalities.

Mutational analysis of p53 gene in cervical cancer and useful polymorphic variants in exons 3 and 4

BackgroundFactors contributing to the pathogenesis and progression of cervical cancer include poor attitude to screening and health intervention, late presentation, among others. Mutations in p53 gene have been attributed to several cancer cases. The present study was designed to find relationships between the mutation patterns in p53 gene and cervical carcinoma staging. Such knowledge could contribute to early diagnosis of cervical cancer.ResultsFrom the sequence analysis of p53 gene fragment isolated by polymerase chain reactions (PCR), nineteen (19) polymorphic variants were identified. Missense mutations occurred in 47% of the samples, 32% were silent mutations, 16% were frameshift mutations and 5% nonsense mutations. Socio-biological characteristics of the study participants revealed that 60% have husbands with multiple sexual partners and that only 23.3% of the participants have ever had the Papanicolaou (Pap) smear test prior to diagnosis, whilst 20% were unaware of the screening test.ConclusionsIncreased severity of cervical carcinoma staging as revealed from the histopathological analysis was found to be associated with accumulation of higher levels of mutations in the p53 gene. Molecular analysis of p53 gene mutations may prove useful as a screening biomarker for cervical cancer.

The G199X and V157fs mutations in the TP53 gene promote malignancy in serous ovarian cancer: an analysis using whole-exome sequencing.

BackgroundThe carcinogenic mechanisms underlying serous ovarian cancer are not fully understood.MethodsWhole-exome sequencing and targeted sequencing were performed in ovarian cancer samples to identify novel molecular markers involved in the process of cell malignancy in ovarian cancer. In vitro experiments, the oncogenic roles such as cell proliferation, migration and invasion of TP53 G199X and V157fs mutations were investigated deeply.ResultsThe present study identified the G199X and V157fs point mutations in the tumor protein P53 gene (TP53). The rate of TP53 mutation was 59.2% in a cohort of 76 ovarian cancer patients, compared with 9.0% in a cohort of 156 healthy women. Kaplan-Meier analysis showed that patients with a TP53 mutation had a lower 5-year overall survival (OS) rate compared with patients harboring wild type TP53. In vitro experiments in an ovarian cancer cell line demonstrated that the G199X and V157fs mutants inhibited P53 protein expression, enhanced proliferation, promoted migration and increased invasion.ConclusionsThis study identified two novel markers, TP53 G199X and V157fs mutations in TP53. Functional assays indicated that these mutations enhanced the malignant phenotype in ovarian cancer cells. These novel markers will assist in the diagnosis of ovarian tumors and represent potential targets for the treatment of TP53 mutant ovarian cancers.

IL-6 promotes MYC-induced B cell lymphomagenesis independent of STAT3.

The inflammatory cytokine IL-6 is known to play a causal role in the promotion of cancer, although the underlying mechanisms remain to be completely understood. Interplay between endogenous and environmental cues determines the fate of cancer development. The Eμ-myc transgenic mouse expresses elevated levels of c-Myc in the B cell lineage and develops B cell lymphomas with associated mutations in p53 or other genes linked to apoptosis. We generated Eμ-myc mice that either lacked the IL-6 gene, or lacked the STAT3 gene specifically in B cells to determine the role of the IL-6/JAK/STAT3 pathway in tumor development. Using the Eμ-myc lymphoma mouse model, we demonstrate that IL-6 is a critical tumor promoter during early stages of B cell lymphomagenesis. IL-6 is shown to inhibit the expression of tumor suppressors, notably BIM and PTEN, and this may contribute to advancing MYC-driven B cell tumorigenesis. Several miRNAs known to target BIM and PTEN are upregulated by IL-6 and likely lead to the stable suppression of pro-apoptotic pathways early during the tumorigenic process. STAT3, a classical downstream effector of IL-6, appears dispensable for Eμ-myc driven lymphomagenesis. We conclude that the growth-promoting and anti-apoptotic mechanisms activated by IL-6 are critically involved in Eμ-myc driven tumor initiation and progression, but the B cell intrinsic expression of STAT3 is not required.

Photodynamic Therapy of Sarcoma M-1 in Rats with Photosensitizer Photoran E6.

We studied the effectiveness of photodynamic therapy with the photosensitizer Photoran E6 on the model of rat sarcoma M-1 positive for mutant p53 gene. Experiments showed that Photoran E6 exhibits high antitumor activity in photodynamic therapy of solid tumor of the connective tissue. Photodynamic therapy carried out during the optimal period after injections of Photoran E6 with the determined parameters of laser exposure allows achieving the maximum inhibitory effect on sarcoma M-1: 100% cured animals. Immunohistochemical study revealed no live tumor cells with expression of the mutant p53 protein in areas of photodynamic exposure.

Human papillomavirus, gene mutation and estrogen and progesterone receptors in breast cancer: a cross-sectional study

Introductionrecent studies show a good relationship between breast cancer (BC) and human papillomaviruses (HPV) wich is responsible for about 18% of BC cases. This study aimed to assess the relationship between different genotypes of HPV and the expression of P53 and retinoblastoma (RB) genes and estrogen and progesterone receptors in BC among Sudanese women.Methodsone hundred and fifty tissue blocks were obtained from females diagnosed with BC. Positive samples were used to determine genotypes with an applied biosystem (ABI 3730XL) genetic analyzer for sequencing and immunohistochemistry.Results13/150 samples showed HPV DNA. High-risk HPV-16 was detected in 5 cases, high-risk-HPV-58 was found in four cases, and HPV-18 was detected in three cases. Low-risk-HPV-11 was detected in a single invasive lobular carcinoma (ILC) case. P53 and RB gene mutations were detected in 35 and 30 BC cases, respectively. P53 gene mutation was frequently identified in grade (III) BC while RB gene mutation was positive in grade (II). Grade (II) BC had a higher incidence of HPV-16 and 58. On the other hand, HPV-18 had a higher incidence in grade (III). Estrogen and progesterone receptors were expressed in 94 and 79 HPV cases among the study group, respectively.Conclusionthis study elucidates the associations between HPV genotypes and BC. A statistically significant association was observed among p53 and RB gene mutations and different BC histological types. On the other hand, there was a statistically insignificant association between HPV genotyping and different BC gradings, BC histological types, P53 and RB genes mutations, and estrogen and progesterone receptor expression. Also, there was a statistically insignificant association among estrogen and progesterone receptors expression and BC grading. RB gene mutation was significantly associated with different BC grades. On the other hand, there was a statistically insignificant association between progesterone receptor expression and BC.

Does GSM-like 1800 MHz radiofrequency cause KRAS and p53 mutations in colon? : Histopatologically and microbiologically changes in colon

Aim: The aim of this study was to determine effects of 1800 MHz magnetic field on amout of colonic Bactroides and Fusobacterium and colon pathology in rats and determination of KRAS and p53 gene mutation in colon.Materials and Methods: In the present study, three groups were prepared as control, sham and RFR. The RFR group rats were exposed to 1800 MHz GSM-like RFR for 12 weeks as 45 minutes per day. An electromagnetic energy generator was used to generate 1800 MHz RF radiation in the RFR group. At the end of experiments, colons were dissected from rats for histopathological examination and determination of KRAS and p53 mutations. Fecal speciments were collected for bacterial detection. DNA was isolated from fecal bacterias and colon.Results: No differences were observed between sham and control groups, histopathologically. Corrupted gland structure, mucosal edema and inflammatory cell infiltration were observed at mucosal epithelum in the RFR group. An increase in the amount of collagen and fibrosis were detected in the electromagnetic field group. Number of goblet cells showed a statistically significant decrease in electromagnetic field group compared to both the control and sham groups (P<0.05). The increase in the amount of Fusobacterium it was significantly higher in the RFR group compared to the control group. In the quantity of Bacteroides, no differences were observed between the groups. KRAS and Tp53 mutation analysis of all samples were found to be wild type, at the colon tissues. No significant difference observed between the control group and the electromagnetic field treated group.Conclusion: These results support, for 12 weeks 45 min/day exposure to GSM-like RFR caused histopathological damage in rat colon. Also, the amount of Fusobacterium is increased. But RFR exposure did not caused to KRAS and P53 mutations in colon tissue.