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1.
Article in Chinese | WPRIM | ID: wpr-921975

ABSTRACT

OBJECTIVE@#To explore the clinical characteristics and prognostic values of TP53 gene variant in patients with acute leukemia(AL).@*METHODS@#The clinical data of 44 newly diagnosed AL patients with TP53 variant detected by next generation sequencing (NGS) were analyzed retrospectively. Targeted sequencing technique containing 108 leukemia-related genes was used for variant analysis, and conventional R-banding technique was used for karyotype analysis. The clinical features, cytogenetics, gene variant, curative effect and survival of AL patients with TP53 gene variant were analyzed.@*RESULTS@#The median age of AML patients with TP53 gene variant (46 years) was higher than that of ALL patients (17.5 years), and the median number of bone marrow blasts (40.5%) was lower than the latter (89.2%), the differences were statistically significant (P< 0.01). A total of 28 cases of abnormal karyotype were detected, of which 25 cases were complex karyotype, 16 cases were monomeric karyotype, 14 cases had -17/17p-. The detection rates of TP53 in complex karyotype, monomeric karyotype and -17/17p- were 59.5%, 38.1% and 33.3%, respectively. Subgroup analysis showed that the detection rate of TP53 gene abnormalities in AML and ALL complex karyotypes was 73.1% and 40% respectively, the difference was statistically significant. A total of 41 TP53 gene variant types were found, and the median variant frequency was 43.58%. 75.6% variant was located in the DNA binding domain. The concomitant variant genes were mainly TET2 and IKZF1. Among 18 AML and 17 ALL patients who could be evaluated the curative effect, the CR rate of one course of treatment was 22.2% and 94.12% respectively, and the difference was statistically significant. The median RFS of 4 cases of AML with CR and 16 cases of ALL with CR were 174 and 246 days respectively, the difference was statistically insignificant. The median OS of AML and ALL was 20 and 375 days respectively, the difference was statistically significant.@*CONCLUSION@#The TP53 gene variant is associated with the complex karyotype of AML, but has no significant effect on ALL. The variant site of TP53 gene was mainly distributed in the DNA binding domain. The remission rate of AML with TP53 gene variant was lower than that of ALL. The prognosis of AL patients with TP53 gene variant is poor, so allogeneic hematopoietic stem cell transplantation should be performed as soon as possible to prolong the survival of the patients.


Subject(s)
Acute Disease , Humans , Leukemia, Myeloid, Acute/genetics , Middle Aged , Mutation , Retrospective Studies , Tumor Suppressor Protein p53/genetics
2.
Article in Chinese | WPRIM | ID: wpr-880803

ABSTRACT

OBJECTIVE@#To investigate the effect of palbociclib on cell cycle progression and proliferation of human renal tubular epithelial cells.@*METHODS@#Human renal tubular epithelial cell line HK-2 was treated with 1, 5, 10, and 20 μmol/L of palbociclib, and the changes in cell proliferation and viability were examined by cell counting and CCK8 assay. EDU staining was used to assess the proliferation of HK-2 cells following palbiciclib treatment at different concentrations for 5 days. The effect of palbociclib on cell cycle distribution of HK-2 cells was evaluated using flow cytometry. SA-β-Gal staining and C12FDG senescence staining were used to detect senescence phenotypes of HK-2 cells after palbociclib treatment at different concentrations for 5 days. The relative mRNA expression levels of P16, P21, and P53 and the genes associated with senescence-related secretion phenotypes were detected by RT-PCR, and the protein expressions of P16, P21 and P53 were detected by Western blotting.@*RESULTS@#Palbociclib inhibited HK-2 cell proliferation and induced cell cycle arrest in G1 phase. Compared with the control cells, HK-2 cells treated with high-dose (10 μmol/L) palbociclib exhibited significantly suppressed cell proliferation activity, and the inhibitory effect was the most obvious on day 5 (@*CONCLUSIONS@#Palbociclib induces HK-2 cell senescence by causing cell growth arrest and delaying cell cycle progression.


Subject(s)
Cell Cycle , Cell Cycle Checkpoints , Cellular Senescence , Epithelial Cells , Humans , Piperazines/pharmacology , Pyridines/pharmacology , Tumor Suppressor Protein p53/genetics
3.
Biol. Res ; 53: 13, 2020. tab, graf
Article in English | LILACS | ID: biblio-1100919

ABSTRACT

BACKGROUND: Gallbladder cancer (GBC) is the most common tumor of the biliary tract. The incidence of GBC shows a large geographic variability, being particularly frequent in Native American populations. In Chile, GBC represents the second cause of cancer-related death among women. We describe here the establishment of three novel cell lines derived from the ascitic fluid of a Chilean GBC patient, who presented 46% European, 36% Mapuche, 12% Aymara and 6% African ancestry. RESULTS: After immunocytochemical staining of the primary cell culture, we isolated and comprehensively characterized three independent clones (PUC-GBC1, PUC-GBC2 and PUC-GBC3) by short tandem repeat DNA profiling and RNA sequencing as well as karyotype, doubling time, chemosensitivity, in vitro migration capability and in vivo tumorigenicity assay. Primary culture cells showed high expression of CK7, CK19, CA 19-9, MUC1 and MUC16, and negative expression of mesothelial markers. The three isolated clones displayed an epithelial phenotype and an abnormal structure and number of chromosomes. RNA sequencing confirmed the increased expression of cytokeratin and mucin genes, and also of TP53 and ERBB2 with some differences among the three cells lines, and revealed a novel exonic mutation in NF1. The PUC-GBC3 clone was the most aggressive according to histopathological features and the tumorigenic capacity in NSG mice. CONCLUSIONS: The first cell lines established from a Chilean GBC patient represent a new model for studying GBC in patients of Native American descent.


Subject(s)
Humans , Animals , Male , Middle Aged , Antigens, Tumor-Associated, Carbohydrate/genetics , Indians, South American/genetics , Gallbladder Neoplasms/genetics , Ascitic Fluid/metabolism , Tumor Cells, Cultured , Carcinogenicity Tests , Chile , DNA Fingerprinting , Tumor Suppressor Protein p53/genetics , Cisplatin/pharmacology , Mice, Inbred NOD , Clone Cells/drug effects , Clone Cells/metabolism , Sequence Analysis, RNA , Receptor, ErbB-2/genetics , Genes, erbB-2/genetics , Gene Expression Profiling , Cell Line, Tumor/drug effects , Cell Line, Tumor/metabolism , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Epithelial Cells/metabolism , Keratin-19/genetics , Keratin-7/genetics , Carcinogenesis/genetics , Gallbladder Neoplasms/metabolism , Antineoplastic Agents/pharmacology
4.
J. pediatr. (Rio J.) ; 94(4): 432-439, July-Aug. 2018. tab, graf
Article in English | LILACS | ID: biblio-954624

ABSTRACT

Abstract Objective: To evaluate the clinical features associated with adrenocortical hormone overexpression and familial cancer profiling as potential markers for early detection of adrenocortical tumors in children from South and Southeast Brazil. Methods: The clinical manifestations and anthropometric measurements of 103 children diagnosed with adrenocortical tumors were analyzed. Results: Between 1982 and 2011, 69 girls and 34 boys diagnosed with adrenocortical tumors were followed-up for a median time of 9.0 years (0-34 years). Signs of androgen overproduction alone (n = 75) or associated with cortisol (n = 18) were present in 90.3%. TP53 p.R337H mutation was found in 90.5% of patients. Stages I, II, III, and IV were observed in 45.6%, 27.2%, 19.4%, and 7.8% of patients, respectively. At diagnosis, there were no significant differences in height (p = 0.92) and weight (p = 0.22) among children with adrenocortical tumors, but children with virilization alone had significantly higher height-for-age Z-scores (0.92 ± 1.4) than children with hypercortisolism alone or combined (−0.32 ± 1,8; p = 0.03). The five-year overall survival was 76.7% (SD ± 4.2). Patients with advanced-stage disease had a significantly worse prognosis than those with limited disease (p < 0.001). During follow-up, ten of 55 p.R337H carrier parents developed cancer, whereas none of the 55 non-carriers did. Conclusions: Signs of adrenocortical hormone overproduction appear early, even in cases with early-stage. These signs can be identified at the physical examination and anthropometric measurements. In southern Brazil, pediatric adrenocortical tumor is a sentinel cancer for detecting families with germline p.R337H mutation in TP53 gene.


Resumo Objetivo: Avaliar as manifestações clínicas da hiperexpressão de hormônios do córtex da adrenal e câncer familiar como marcadores para a detecção precoce de tumores adrenocorticais em crianças do Sul e Sudeste do Brasil. Pacientes e métodos: Foram analisadas as manifestações clínicas e antropométricas de 103 crianças diagnosticadas com tumores adrenocorticais. Resultados: Entre 1982 e 2011, 69 meninas e 34 meninos diagnosticados com tumores adrenocorticais foram acompanhados por um tempo mediano de nove anos (0-34). Ao diagnóstico, sinais de virilização isolada (n = 75) ou associada ao cortisol (n = 18) estavam presentes em 90,3% dos pacientes; a mutação do gene TP53 p.R337H foi identificada em 90,5% dos pacientes. Os pacientes foram classificados em estádio I (45,6%), II (27,2%), III (19,4%) e IV (7,8%). Ao diagnóstico, não houve diferença significativa para as medidas de altura (p = 0,92) e de peso (p = 0,22) entre as crianças com tumores adrenocorticais, mas crianças com virilização tiveram escore-Z mais elevado para a idade (0,92 ± 1,4) do que aquelas com hipercortisolismo isolado ou combinado (−0,32 ± 1,8; p = 0,03). A sobrevida global de cinco anos foi de 76,7% (DP ± 4,2). Pacientes com estádios avançados tiveram pior prognóstico (p < 0,001). Durante o seguimento, 10 dos 55 genitores portadores da p.R337H desenvolveram câncer, enquanto que nenhum caso ocorreu entre os 55 não portadores. Conclusões: Os sinais de hiperprodução de hormônios adrenocorticais aparecem precocemente no desenvolvimento do tumor e podem ser identificados pelo exame físico e pelas medidas antropométricas na consulta pediátrica de rotina. O tumor adrenocortical pediátrico é sentinela para a detecção de câncer em famílias que segregam a mutação germinativa p.R337H do gene TP53.


Subject(s)
Humans , Male , Female , Infant , Child, Preschool , Child , Genes, p53/genetics , Tumor Suppressor Protein p53/genetics , Adrenal Cortex Neoplasms/diagnosis , Adrenal Cortex Neoplasms/genetics , Germ-Line Mutation/genetics , Genetic Predisposition to Disease/genetics , Pedigree , Longitudinal Studies , Neoplasm Staging
5.
Rev. bras. ginecol. obstet ; 40(2): 79-85, Feb. 2018. tab, graf
Article in English | LILACS | ID: biblio-958959

ABSTRACT

Abstract Objective The current study evaluated the expression of WW domain-containing oxidoreductase (WWOX), its association with clinicopathological features and with p53, Ki-67 (cell proliferation) and CD31 (angiogenesis) expression in patients with invasive cervical squamous cell carcinoma (ICSCC). To the best of our knowledge, no other study has evaluated this association. Methods Women with IB stage-ICSCC (n = 20) and women with uterine leiomyoma (n = 20) were prospectively evaluated. Patients with ICSCC were submitted to type BC1 radical hysterectomy and pelvic lymphadenectomy. Patients in the control group underwent vaginal hysterectomy. Tissue samples were stained with hematoxylin and eosin for histological evaluation and protein expression was detected by immunohistochemistry studies. Results The WWOX expression was significantly lower in the tumor compared with the expression in thebenign cervix (p = 0.019). TheWWOXexpressionwas inversely associated with the CD31 expression in the tumor samples (p = 0.018). There was no association betweentheWWOXexpression with the p53 expression (p = 0.464)or the Ki-67expression (p = 0.360) in the samples of invasive carcinoma of the cervix. There was no association between the WWOX expression and tumor size (p = 0.156), grade of differentiation (p = 0.914), presence of lymphatic vascular invasion (p = 0.155), parametrium involvement (p = 0.421) or pelvic lymph node metastasis (p = 0.310) in ICSCC tissue samples. Conclusion The results suggested that WWOX may be involved in ICSCC carcinogenesis, and this marker was associated with tumor angiogenesis.


Resumo Objetivo O presente estudo avaliou a expressão do WWOX, sua associação com características clinicopatológicas e com a expressão do p53, ki-67 (proliferação celular) e CD31 (angiogênese) em pacientes com carcinoma invasivo de células escamosas do colo uterino, ou simplesmente câncer do colo uterino (CCE). Métodos Foram avaliadas prospectivamente pacientes com CCE no estágio IB (n = 20) e mulheres com mioma uterino, no grupo controle (n = 20). As pacientes com CCE foram submetidas à histerectomia radical e à linfadenectomia pélvica do tipo B-C1. As mulheres no grupo-controle foram submetidas à histerectomia vaginal. As amostras de tecido foramcoradas comhematoxilina e eosina para avaliação histológica e a expressão das proteínas foi detectada por imuno-histoquímico. Resultados A expressão do WWOX foi significativamente menor no tumor quando comparada com sua expressão no colo do útero benigno (p = 0,019). A expressão tumoral de CD31 foi inversamente associada à expressão de WWOX (p = 0,018). Sua expressão não foi associada à expressão tumoral de p53 e Ki-67 em pacientes com CCE (p = 0,464 e p = 0,360, respectivamente). Não houve associação entre a expressão de WWOX e o tamanho do tumor (p = 0,156), grau de diferenciação (p = 0,914), presença de invasão vascular linfática (p = 0,155), comprometimento do paramétrio (p = 0,421) ou metástase dos linfonodos pélvicos (p = 0,310) em pacientes com CCE. Conclusão Os resultados sugeriram que o WWOX pode estar envolvido na carcinogênese do CICECU e esse marcador foi associado à angiogênese tumoral.


Subject(s)
Humans , Female , Adult , Aged , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/pathology , Gene Expression Regulation, Neoplastic , Uterine Cervical Neoplasms/genetics , Uterine Cervical Neoplasms/pathology , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Proteins/genetics , Cell Proliferation , WW Domain-Containing Oxidoreductase/genetics , Neovascularization, Pathologic , Immunohistochemistry , Carcinoma, Squamous Cell/chemistry , Uterine Cervical Neoplasms/chemistry , Prospective Studies , Tumor Suppressor Protein p53/analysis , Tumor Suppressor Proteins/analysis , WW Domain-Containing Oxidoreductase/analysis , Middle Aged
6.
Braz. j. infect. dis ; 21(3): 248-254, May-June 2017. tab
Article in English | LILACS | ID: biblio-839224

ABSTRACT

ABSTRACT Objective: To evaluate the association between p53 polymorphisms and human papillomavirus (HPV) E6/E7 mRNA expression. Methods: We analyzed 175 cervical samples from women aged 16-69 years old who were tested for HPV E6/E7 mRNA expression (NucliSENS® EasyQ® HPV). The samples were divided into three groups: positive (n = 75) those with positive HPV E6/E7 mRNA expression and positive high-risk HPV Hybrid Capture (HR-HC) test; negative (n = 52) those with negative HPV E6/E7 mRNA expression and positive HR-HC; and control (n = 48) those with negative HPV E6/E7 mRNA expression and negative HR-HC. The p53 polymorphisms at codons 11, 72, and 248 were evaluated through polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: The frequency of the arginine/arginine homozygous genotype at codon 72 was significantly higher in the positive (49.3%) than in the negative (32.7%) and control groups (20.8%, p = 0.002*). The frequency of the arginine allele was also significantly higher in the positive (67.3%) than in the negative (53.8%) and control groups (38.5%, p < 0.001*). The arginine/arginine homozygous genotype was significantly associated with positive HPV E6/E7 mRNA expression (positive group) compared with negative and control groups (odds ratio: 2.633; 95% CI, 1.399-4.954, p = 0.003). The frequency of arginine/arginine homozygous genotype at codon 72 remained significantly more frequent in the positive group of women aged ≥30 years than in the other two groups. Conclusion: The presence of the p53 arginine/arginine homozygous genotype at codon 72 was significantly associated with the positive HPV E6/E7 mRNA expression.


Subject(s)
Humans , Female , Adolescent , Adult , Middle Aged , Aged , Young Adult , Papillomaviridae/genetics , RNA, Messenger/metabolism , Oncogene Proteins, Viral/genetics , Cervical Intraepithelial Neoplasia/virology , Papillomavirus Infections/virology , Papillomavirus E7 Proteins/genetics , Arginine/genetics , Polymorphism, Restriction Fragment Length , Codon , RNA, Viral , Uterine Cervical Neoplasms/virology , Polymerase Chain Reaction , Tumor Suppressor Protein p53/genetics , Genotype
7.
Int. braz. j. urol ; 43(1): 36-46, Jan.-Feb. 2017. tab, graf
Article in English | LILACS | ID: biblio-840810

ABSTRACT

ABSTRACT Objectives The aim of this study was to assess the possible role of HPV in the development of prostate cancer (PCa) and investigate the distribution of the p53 codon 72 polymorphism in PCa in a Turkish population. Materials and methods A total of 96 tissues, which had been obtained using a radical surgery method, formalin-fixed and parafin-embedded, were used in this study. The study group consisted of 60 PCa tissues (open radical prostatectomy) and the control group contained 36 benign prostatic hyperplasia tissues (BPH) (transvesical open prostatectomy). The presence of HPV and the p53 codon 72 polymorphism was investigated in both groups using real-time PCR and pyrosequencing. Results The results of the real-time PCR showed no HPV DNA in any of the 36 BPH tissue samples. HPV-DNA was positive in only 1 of the 60 PCa samples (1.7%). The HPV type of this sample was identified as HPV-57. The distribution of the three genotypes, Arg/Arg, Arg/Pro and Pro/Pro was found to be 45.6, 45.6, and 8.8% in the PCa group and 57.1%, 34.3% and 8.6% in the control group, respectively. Compared with the control group, patients with PCa had a higher frequency of the Arg/Pro genotype and Proline allele (odds ratio (OR)=1.67, 95% confidence interval (CI)=0.68-4.09, p=0.044; OR=1.13, 95% CI=0.76-1.68, p=0.021, respectively). Conclusions The results of the study do not support the hyphothesis that prostate cancer is associated with HPV infection but indicated that Proline allele can be a risk factor in the development of PCa in the Turkish population.


Subject(s)
Humans , Male , Aged , Aged, 80 and over , Papillomaviridae/isolation & purification , Polymorphism, Genetic , Prostatic Neoplasms/genetics , Prostatic Neoplasms/virology , Tumor Suppressor Protein p53/genetics , Papillomavirus Infections/complications , Prostatectomy , Prostatic Hyperplasia/genetics , Prostatic Hyperplasia/pathology , Prostatic Hyperplasia/virology , Prostatic Neoplasms/surgery , Prostatic Neoplasms/pathology , Turkey , Codon/genetics , DNA, Viral , Proline/genetics , Retrospective Studies , Risk Factors , Paraffin Embedding , Genetic Association Studies , Neoplasm Grading , Genotyping Techniques , Real-Time Polymerase Chain Reaction , Genotype , Middle Aged
8.
Article in English | WPRIM | ID: wpr-69709

ABSTRACT

Glioblastoma (GBM) can be classified into molecular subgroups, on the basis of biomarker expression. Here, we classified our cohort of 163 adult GBMs into molecular subgroups according to the expression of proteins encoded by genes of alpha thalassemia/mental retardation syndrome X-linked (ATRX), isocitrate dehydrogenase (IDH) and TP53. We focused on the survival rate of molecular subgroups, depending on each and various combination of these biomarkers. ATRX, IDH1 and p53 protein expression were evaluated immunohistochemically and Kaplan-Meier analysis were carried out in each group. A total of 15.3% of enrolled GBMs demonstrated loss of ATRX expression (ATRX-), 10.4% expressed an aberrant IDH1 R132H protein (IDH1+), and 48.4% exhibited p53 overexpression (p53+). Survival differences were statistically significant when single protein expression or different combinations of expression of these proteins were analyzed. In conclusion, in the case of single protein expression, the patients with each IDH1+, or ATRX-, or p53- GBMs showed better survival than patients with counterparts protein expressed GBMs. In the case of double protein pairs, the patients with ATRX-/p53-, ATRX-/IDH1+, and IDH1+/p53- GBMs revealed better survival than the patients with GBMs with the remained pairs. In the case of triple protein combinations, the patients with ATRX-/p53-/IDH+ showed statistically significant survival gain than the patients with remained combination of proteins-expression status. Therefore, these three biomarkers, individually and as a combination, can stratify GBMs into prognostically relevant subgroups and have strong prognostic values in adult GBMs.


Subject(s)
Adult , Aged , Biomarkers, Tumor/metabolism , Brain Neoplasms/diagnosis , DNA Helicases/metabolism , Disease-Free Survival , Glioblastoma/diagnosis , Humans , Immunohistochemistry , Isocitrate Dehydrogenase/metabolism , Kaplan-Meier Estimate , Middle Aged , Nuclear Proteins/metabolism , Retrospective Studies , Tumor Suppressor Protein p53/genetics , Young Adult
9.
Article in English | WPRIM | ID: wpr-59848

ABSTRACT

BACKGROUND: Little is known of the mutation and tumor spectrum of Korean patients with Li-Fraumeni syndrome (LFS). Owing to the rarity of LFS, few cases have been reported in Korea thus far. This study aimed to retrospectively review the mutations and clinical characteristics of Korean patients with LFS. METHODS: TP53 mutation was screened in 89 unrelated individuals at the Samsung Medical Center in Korea, from 2004 to 2015. Six additional mutation carriers were obtained from the literature. RESULTS: We identified nine different mutations in 14 Korean patients (male to female ratio=0.3:1). Two such frameshift mutations (p.Pro98Leufs*25, p.Pro27Leufs*17) were novel. The recurrent mutations were located at codons 31 (n=2; p.Val31Ile), 175 (n=3; p.Arg175His), and 273 (n=4; p.Arg273His and p.Arg273Cys). The median age at the first tumor onset was 25 yr. Ten patients (71%) developed multiple primary tumors. A diverse spectrum of tumors was observed, including breast (n=6), osteosarcoma (n=4), brain (n=4), leukemia (n=2), stomach (n=2), thyroid (n=2), lung (n=2), skin (n=2), bladder (n=1), nasal cavity cancer (n=1), and adrenocortical carcinoma (n=1). CONCLUSIONS: There was considerable heterogeneity in the TP53 mutations and tumor spectrum in Korean patients with LFS. Our results suggest shared and different LFS characteristics between Caucasian and Korean patients. This is the first report on the mutation spectrum and clinical characteristics from the largest series of Korean LFS patients.


Subject(s)
Adolescent , Adult , Asian Continental Ancestry Group/genetics , Base Sequence , Child , Child, Preschool , Codon , Female , Frameshift Mutation , Germ-Line Mutation , Humans , Infant , Li-Fraumeni Syndrome/genetics , Male , Middle Aged , Neoplasms, Multiple Primary , Polymorphism, Genetic , Republic of Korea , Retrospective Studies , Tumor Suppressor Protein p53/genetics , Young Adult
11.
Article in English | WPRIM | ID: wpr-157207

ABSTRACT

The development of hepatocellular carcinoma (HCC) is a complex process, and HCC arises from the accumulation of multiple genetic alterations leading to changes in the genomic landscape. Current advances in genomic technologies have revolutionized the search for genetic alterations in cancer genomes. Recent studies in which all coding exons in HCC were sequenced have shed new light on the genomic landscape of this malignant disease. Catalogues of these somatic mutations and systematic analysis of catalogued mutations will lead us to uncover candidate HCC driver genes, although further functional validation is needed to determine whether these genes play a causal role in the development of HCC. This review provides an overview of previously known oncogenes and new oncogene candidates in HCC that were uncovered from recent exome or whole-genome sequencing studies. This knowledge provides direction for future personalized treatment approaches for patients with HCC.


Subject(s)
Carcinoma, Hepatocellular/pathology , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Liver Neoplasms/pathology , Mutation , Oxidative Stress , Precision Medicine , Telomerase/metabolism , Transcription Factors/genetics , Tumor Suppressor Protein p53/genetics
12.
Article in English | WPRIM | ID: wpr-72395

ABSTRACT

Vorinostat (VOR) has been reported to enhance the cytotoxic effects of doxorubicin (DOX) with fewer side effects because of the lower DOX dosage in breast cancer cells. In this study, we investigated the novel mechanism underlying the synergistic cytotoxic effects of VOR and DOX co-treatment in cervical cancer cells HeLa, CaSki and SiHa cells. Co-treatment with VOR and DOX at marginal doses led to the induction of apoptosis through caspase-3 activation, poly (ADP-ribose) polymerase cleavage and DNA micronuclei. Notably, the synergistic growth inhibition induced by the co-treatment was attributed to the upregulation of the pro-apoptotic protein Bad, as the silencing of Bad expression using small interfering RNA (siRNA) abolished the phenomenon. As siRNA against p53 did not result in an increase in acetylated p53 and the consequent upregulation of Bad, the observed Bad upregulation was mediated by acetylated p53. Moreover, a chromatin immunoprecipitation analysis showed that the co-treatment of HeLa cells with VOR and DOX increased the recruitment of acetylated p53 to the bad promoter, with consequent bad transactivation. Conversely, C33A cervical cancer cells containing mutant p53 co-treated with VOR and DOX did not exhibit Bad upregulation, acetylated p53 induction or consequent synergistic growth inhibition. Together, the synergistic growth inhibition of cervical cancer cell lines induced by co-treatment with VOR and DOX can be attributed to the upregulation of Bad, which is induced by acetylated p53. These results show for the first time that the acetylation of p53, rather than histones, is a mechanism for the synergistic growth inhibition induced by VOR and DOX co-treatments.


Subject(s)
Acetylation , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Survival/drug effects , Chromatin/metabolism , Doxorubicin/pharmacology , Drug Synergism , Female , HeLa Cells , Humans , Hydroxamic Acids/pharmacology , Transcriptional Activation , Tumor Suppressor Protein p53/genetics , Uterine Cervical Neoplasms/metabolism , bcl-Associated Death Protein/genetics
13.
Article in English | WPRIM | ID: wpr-161407

ABSTRACT

Diamond-Blackfan anemia (DBA) is a congenital bone marrow failure syndrome characterized by hypoproliferative anemia, associated physical malformations and a predisposition to cancer. DBA has been associated with mutations and deletions in the large and small ribosomal protein genes, and genetic aberrations have been detected in approximately50-60% of patients. In this study, nine Korean DBA patients were screened for mutations in eight known DBA genes (RPS19, RPS24, RPS17, RPS10, RPS26, RPL35A, RPL5 and RPL11) using the direct sequencing method. Mutations in RPS19, RPS26 and RPS17 were detected in four, two and one patient, respectively. Among the mutations detected in RPS19, two mutations were novel (c.26T>A, c.357-2A>G). For the mutation-negative cases, array-CGH analysis was performed to identify copy-number variations, and no deletions involving the known DBA gene regions were identified. The relative mRNA expression of RPS19 estimated using real-time quantitative PCR analysis revealed two- to fourfold reductions in RPS19 mRNA expression in three patients with RPS19 mutations, and p53 protein expression analysis by immunohistochemistry showed variable but significant nuclear staining in the DBA patients. In conclusion, heterozygous mutations in the known DBA genes RPS19, RPS26 and RPS17 were detected in seven out of nine Korean DBA patients. Among these patients, RPS19 was the most frequently mutated gene. In addition, decreased RPS19 mRNA expression and p53 overexpression were observed in the Korean DBA patients, which supports the hypothesis that haploinsufficiency and p53 hyperactivation represent a central pathway underlying the pathogenesis of DBA.


Subject(s)
Anemia, Diamond-Blackfan/genetics , Female , Gene Frequency , Humans , Infant, Newborn , Male , Mutation , RNA, Messenger/genetics , Republic of Korea , Ribosomal Proteins/genetics , Tumor Suppressor Protein p53/genetics
14.
Article in English | WPRIM | ID: wpr-163734

ABSTRACT

BACKGROUND: Specific cytogenetic aberrations detected by conventional karyotyping or FISH play a major role in the diagnosis, prognosis, and treatment of patients with acute leukemia. The FISH technique enhances the capacity of conventional karyotyping to detect subtle chromosomal aberrations. Multiprobe FISH assay (Cytocell, UK) can hybridize multiple probes to a single slide, thereby increasing the detection rate of cytogenetic aberrations. This study aimed to evaluate multiprobe FISH in detecting cytogenetic abnormalities in acute leukemia. METHODS: Thirty newly diagnosed acute leukemia patients who attended the hematology clinic at Dong-A University Hospital from October 2008 to October 2012 were enrolled in the study. The multiprobe FISH results were compared with those of G-banding. RESULTS: Multiprobe FISH detected the chromosomal aberrations identified by G-banding, as well as additional aberrations in 6 of 30 (20.0%) cases, which included ETV6/RUNX1 translocation, p16 deletion, TP53 deletion, and IGH break-apart. CONCLUSIONS: The multiprobe FISH assay was a more sensitive and reliable technique compared with G-banding. It was also more cost-effective and yielded faster results.


Subject(s)
Acute Disease , Adolescent , Adult , Aged , Child , Child, Preschool , Chromosome Banding , Core Binding Factor Alpha 2 Subunit/genetics , Gene Deletion , Humans , In Situ Hybridization, Fluorescence , Karyotyping , Leukemia/diagnosis , Leukemia, Myeloid, Acute/diagnosis , Male , Middle Aged , Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Proto-Oncogene Proteins c-ets/genetics , Repressor Proteins/genetics , Translocation, Genetic , Tumor Suppressor Protein p53/genetics , Young Adult
15.
IJRM-Iranian Journal of Reproductive Medicine. 2013; 11 (6): 473-478
in English | IMEMR | ID: emr-138381

ABSTRACT

Endometriosis is a female health disorder that occurs when cells from the lining of the uterus grow in other areas of the body. The cause of endometriosis is unknown. The purpose of this study was to investigate TP53 gene codon 72 polymorphism in women with endometriosis and compared it with healthy samples in Isfahan. We undertook a case-control study to examine the possible association of the TP53 gene codon 72 polymorphism with the risk of endometriosis in Isfahan. Ninety whole blood specimens from normal people as controls and ninety endometriosis specimens were analyzed. p53 codon 72 genotypes were identified using allele-specific polymerase chain reaction. Frequency of genotype Arg/Arg [Arginine/Arginine] in the samples of endometriosis was 28.9% and in healthy samples 42.2%. Frequency of genotype Pro/Pro [Proline/Proline] in the samples of endometriosis was 15.6% and in healthy ones. Frequency of heterozygote's Arg/Pro was 55.6% in endometriosis samples and 54.45% in healthy ones 3.3%. By comparing statistical genotype Pro/Pro with two other genotypes in both groups there was a statistical meaningful difference between control group and endometriosis group. [p=0.009, CI=95%, OR=5.34 [1047-19.29]]. Recent research shows that genotype Pro/Pro codon72 exon4 TP53 gene may be one predisposing genetic factor for endometriosis in Isfahan


Subject(s)
Humans , Female , Tumor Suppressor Protein p53/genetics , Genes, p53 , Polymorphism, Genetic , Genotype , Codon , Case-Control Studies , Polymerase Chain Reaction , Biomarkers, Tumor/genetics
16.
Article in Korean | WPRIM | ID: wpr-140147

ABSTRACT

BACKGROUND/AIMS: Serrated adenomas of the colon show mixed characteristics of both hyperplastic and adenomatous polyps. Serrated adenomas are known to progress via the serrated pathway than the adenoma-carcinoma pathway. The aim of this study was to evaluate the characteristics of traditional serrated adenomas compared to hyperplastic polyps and tubular adenomas by using immunohistochemical staining for p53, Bcl-2, and Ki-67. METHODS: Age, sex, location, size and the immunoexpression of p53, Bcl-2, and Ki-67 were retrospectively analyzed in 20 traditional serrated adenomas, 20 hyperplastic polyps, and 20 tubular adenomas from January 2007 to December 2012 at The Catholic University of Korea, Yeouido St. Mary's Hospital. RESULTS: There was no difference in Bcl-2 and p53 expression between traditional serrated adenomas and hyperplastic polyps. Ki-67 Expression of traditional serrated adenomas was higher than that of hyperplastic polyps (p=0.001). Ki-67 and p53 expression was similar between traditional serrated and tubular adenomas. Bcl-2 expression of traditional serrated adenomas was lower than that of tubular adenomas (p=0.001). Regarding the expression of p53, Bcl-2, and Ki-67 in traditional serrated adenomas, there were no statistical differences among age, sex, location, and size. CONCLUSIONS: Our study suggested that Ki-67 may be helpful in distinguishing traditional serrated adenomas from hyperplastic polyps, and p53 expression may be ineffective in distinguishing between traditional serrated and tubular adenomas. From Bcl-2 expression, it is suggested that the tumorigenesis of traditional serrated adenomas is lower than that of tubular adenomas.


Subject(s)
Adenoma/genetics , Aged , Colonic Polyps/physiopathology , Colorectal Neoplasms/genetics , Female , Gene Expression Regulation, Neoplastic , Humans , Immunohistochemistry , Ki-67 Antigen/genetics , Male , Middle Aged , Proto-Oncogene Proteins c-bcl-2/genetics , Retrospective Studies , Tumor Suppressor Protein p53/genetics
17.
Article in Korean | WPRIM | ID: wpr-140146

ABSTRACT

BACKGROUND/AIMS: Serrated adenomas of the colon show mixed characteristics of both hyperplastic and adenomatous polyps. Serrated adenomas are known to progress via the serrated pathway than the adenoma-carcinoma pathway. The aim of this study was to evaluate the characteristics of traditional serrated adenomas compared to hyperplastic polyps and tubular adenomas by using immunohistochemical staining for p53, Bcl-2, and Ki-67. METHODS: Age, sex, location, size and the immunoexpression of p53, Bcl-2, and Ki-67 were retrospectively analyzed in 20 traditional serrated adenomas, 20 hyperplastic polyps, and 20 tubular adenomas from January 2007 to December 2012 at The Catholic University of Korea, Yeouido St. Mary's Hospital. RESULTS: There was no difference in Bcl-2 and p53 expression between traditional serrated adenomas and hyperplastic polyps. Ki-67 Expression of traditional serrated adenomas was higher than that of hyperplastic polyps (p=0.001). Ki-67 and p53 expression was similar between traditional serrated and tubular adenomas. Bcl-2 expression of traditional serrated adenomas was lower than that of tubular adenomas (p=0.001). Regarding the expression of p53, Bcl-2, and Ki-67 in traditional serrated adenomas, there were no statistical differences among age, sex, location, and size. CONCLUSIONS: Our study suggested that Ki-67 may be helpful in distinguishing traditional serrated adenomas from hyperplastic polyps, and p53 expression may be ineffective in distinguishing between traditional serrated and tubular adenomas. From Bcl-2 expression, it is suggested that the tumorigenesis of traditional serrated adenomas is lower than that of tubular adenomas.


Subject(s)
Adenoma/genetics , Aged , Colonic Polyps/physiopathology , Colorectal Neoplasms/genetics , Female , Gene Expression Regulation, Neoplastic , Humans , Immunohistochemistry , Ki-67 Antigen/genetics , Male , Middle Aged , Proto-Oncogene Proteins c-bcl-2/genetics , Retrospective Studies , Tumor Suppressor Protein p53/genetics
18.
Article in English | WPRIM | ID: wpr-144094

ABSTRACT

Li-Fraumeni syndrome (LFS) is a rare, inherited syndrome associated with increased risk of various early-onset tumors. Since the introduction of classic LFS criteria, various criteria have been proposed to include patients with incomplete LFS features, which make up Li-Fraumeni-like syndromes (LFL). Germline missense mutations of TP53 are the primary cause of LFS and LFL. Mutations mostly reside in the DNA-binding domain of the gene and have a dominant-negative effect (DNE) over alternate wild-type alleles. Germline TP53 mutation c.566C>T results in the missense mutation GCC (Ala) to GTC (Val) at codon 189 (A189V) and has been reported in a case of multiple primary colon tumors. Herein we report a second case of the same mutation in a breast cancer patient, who has familial history of late-onset malignancies. Due to the relatively late onset of malignancies, neither case fulfils previously defined criteria for the syndrome. Mutational analysis for breast tissue in this patient showed a loss of heterozygosity. These clinical features may suggest a relatively weak DNE of A189V compared to other TP53 mutations, and in silico predictions and in vitro findings of the function of A189V mutant protein are conflicting. Considering the increased risk of malignancies and the therapeutic implications for patients who have a TP53 mutation, care must be taken when treating those who are suspected of possessing cancer-prone traits due to TP53 mutation, especially when there is a family history of late-onset cancer with low penetrance.


Subject(s)
Adolescent , Adult , Breast Neoplasms/complications , Combined Modality Therapy , Exons , Female , Genotype , Heterozygote , Humans , Li-Fraumeni Syndrome/complications , Middle Aged , Multimodal Imaging , Mutation, Missense , Pedigree , Sequence Analysis, DNA , Tumor Suppressor Protein p53/genetics , Young Adult
19.
Article in English | WPRIM | ID: wpr-144087

ABSTRACT

Li-Fraumeni syndrome (LFS) is a rare, inherited syndrome associated with increased risk of various early-onset tumors. Since the introduction of classic LFS criteria, various criteria have been proposed to include patients with incomplete LFS features, which make up Li-Fraumeni-like syndromes (LFL). Germline missense mutations of TP53 are the primary cause of LFS and LFL. Mutations mostly reside in the DNA-binding domain of the gene and have a dominant-negative effect (DNE) over alternate wild-type alleles. Germline TP53 mutation c.566C>T results in the missense mutation GCC (Ala) to GTC (Val) at codon 189 (A189V) and has been reported in a case of multiple primary colon tumors. Herein we report a second case of the same mutation in a breast cancer patient, who has familial history of late-onset malignancies. Due to the relatively late onset of malignancies, neither case fulfils previously defined criteria for the syndrome. Mutational analysis for breast tissue in this patient showed a loss of heterozygosity. These clinical features may suggest a relatively weak DNE of A189V compared to other TP53 mutations, and in silico predictions and in vitro findings of the function of A189V mutant protein are conflicting. Considering the increased risk of malignancies and the therapeutic implications for patients who have a TP53 mutation, care must be taken when treating those who are suspected of possessing cancer-prone traits due to TP53 mutation, especially when there is a family history of late-onset cancer with low penetrance.


Subject(s)
Adolescent , Adult , Breast Neoplasms/complications , Combined Modality Therapy , Exons , Female , Genotype , Heterozygote , Humans , Li-Fraumeni Syndrome/complications , Middle Aged , Multimodal Imaging , Mutation, Missense , Pedigree , Sequence Analysis, DNA , Tumor Suppressor Protein p53/genetics , Young Adult
20.
Indian J Cancer ; 2012 Jan-Mar; 49(1): 137-143
Article in English | IMSEAR | ID: sea-144564

ABSTRACT

Chronic lymphocytic leukemia (CLL) was largely considered to be a disease of slow progression, standard treatment with Chlorambucil and having almost similar prognosis. With the introduction of molecular methods for understanding the disease pathophysiology in CLL there has been a remarkable change in the approach towards the disease. The variation in B-cell receptor response and immunoglobulin heavy chain variable region (IGHV) mutation, genetic aberration and defect in apoptosis and proliferation has had an impact on therapy initiation and prognosis. Early diagnosis of molecular variant is therefore necessary in CLL.


Subject(s)
Chromosome Aberrations , Humans , Immunoglobulin Heavy Chains/genetics , Immunoglobulin Variable Region/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/therapy , Lymphocytosis/diagnosis , Mutation , Prognosis , Receptors, Antigen, B-Cell/genetics , Tumor Suppressor Protein p53/genetics , ZAP-70 Protein-Tyrosine Kinase/genetics
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