Genes, p53 ; Genetic Predisposition to Disease ; Germ-Line Mutation ; Humans ; Li-Fraumeni Syndrome/genetics* ; Tumor Suppressor Protein p53/genetics*

Objective: To explore the clinical implications and prognostic value of TP53 gene mutation and deletion in patients with myelodysplastic syndromes (MDS) . Methods: 112-gene targeted sequencing and interphase fluorescence in situ hybridization (FISH) were used to detect TP53 mutation and deletion in 584 patients with newly diagnosed primary MDS who were admitted from October 2009 to December 2017. The association of TP53 mutation and deletion with several clinical features and their prognostic significance were analyzed. Results: Alterations in TP53 were found in 42 (7.2%) cases. Of these, 31 (5.3%) cases showed TP53 mutation only, 8 (1.4%) cases in TP53 deletion only, 3 (0.5%) cases harboring both mutation and deletion. A total of 37 mutations were detected in 34 patients, most of them (94.6%) were located in the DNA binding domain (exon5-8) , the remaining 2 were located in exon 10 and splice site respectively. Patients with TP53 alterations harbored significantly more mutations than whom without alterations (z=-2.418, P=0.016) . The median age of patients with TP53 alterations was higher than their counterparts[60 (21-78) years old vs 52 (14-83) years old, z=-2.188, P=0.029]. TP53 alterations correlated with complex karyotype and International prognostic scoring system intermediate-2/high significantly (P<0.001) . Median overall survival of patients with TP53 alterations was shorter than the others[13 (95%CI 7.57-18.43) months vs not reached, χ(2)=12.342, P<0.001], while the significance was lost during complex karyotype adjusted analysis in multivariable model. Conclusion: TP53 mutation was more common than deletion in MDS patients. The majority of mutations were located in the DNA binding domain. TP53 alterations were strongly associated with complex karyotype and always coexisted with other gene mutations. TP53 alteration was no longer an independent prognostic factor when complex karyotype were occurred in MDS.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Genes, p53 ; Humans ; In Situ Hybridization, Fluorescence ; Middle Aged ; Mutation ; Myelodysplastic Syndromes/genetics* ; Prognosis ; Tumor Suppressor Protein p53 ; Young Adult

Objective: To analyze the survival and first-line immune-chemotherapy (CIT) of chronic lymphocytic leukemia (CLL) with abnormal TP53 gene in the era of traditional CIT. Methods: The clinical data of 118 CLL patients diagnosed from January 2003 to August 2017 were collected. Survival was analyzed according to indicators including sex, age, Binet risk stratification, B symptoms, β(2)-microglobulin (β(2)-MG) , immunoglobulin heavy chain variable region gene (IGHV) mutation status, chromosome karyotype and TP53 gene deletion/mutation. The efficacy of first-line CIT of 101 CLL patients was further analyzed. Results: Among 118 patients, median progression-free survival (PFS) was 12 (95%CI 10.148-13.852) months and median overall survival (OS) was 53 (95%CI 41.822-64.178) months, only 30.5% patients survived over 5 years. Low β(2)-MG<3.5 mg/L indicated longer PFS (P=0.027) , female and Binet A patients had longer OS (P=0.011 and 0.013, respectively) . Of 118 patients, 17 (14.4%) didn't receive any therapy until follow-up time or the dead time. Among the 101 patients who received ≥1 CIT, median time to first treatment (TTFT) was 1 (0-62) months, patients in Binet A had longer TTFT (P<0.001) compared to the patients in Binet B/C. According to statistical needs, we divided those first-line CIT into four groups: there were 30 cases (29.7%) in mild chemotherapy group (mainly treated with nitrogen mustard phenylbutyrate or rituximab alone) , 32 cases (31.7%) in the fludarabine-containing group, 23 cases (22.8%) in high-dose methyprednisolone (HDMP) containing group and 16 cases (15.8%) in the other chemotherapy group. The first regimen contained HDMP can bring longer PFS (P<0.001) , however the OS between four groups had no statistical differences. Conclusion: CLL patients with abnormal TP53 gene had poor response to immunotherapy, rapid clinical progressing, first-line immunotherapy containing HDMP can prolong PFS and will create an opportunity for patients to participate in clinical trials of novel drugs.
Antineoplastic Combined Chemotherapy Protocols ; Female ; Genes, p53 ; Humans ; Immunotherapy ; Leukemia, Lymphocytic, Chronic, B-Cell/genetics* ; Survival Analysis ; Tumor Suppressor Protein p53/genetics*

Adult ; Cytogenetics ; Genes, p53 ; Humans ; Leukemia, Myeloid, Acute/genetics* ; Mutation ; Prognosis ; Tumor Suppressor Protein p53/genetics*

Aged ; Choriocarcinoma ; diagnostic imaging ; genetics ; therapy ; Genes, p53 ; Humans ; Lung Neoplasms ; diagnostic imaging ; genetics ; therapy ; Male ; Mutation ; Tomography, X-Ray Computed

Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome, with the characteristics of early onset of cancer and high cancer incidence. TP53 is widely accepted as a pathogenic gene of LFS. A 2 years and 6 months old boy is reported in this article, who was diagnosed with embryonal rhabdomyosarcoma (RMS) in the left submandibular region. His brother died of RMS, and his grandmother was diagnosed with breast cancer. TP53 gene mutation detection was performed in this patient and some family members, indicating a missense mutation in exon 8 of the patient: c.844C>T (p.Arg282Trp, heterozygous). TP53 mutation was also found in his mother and sister. The boy met the diagnostic criteria for LFS. Among pediatric patients, the most common LFS diseases include osteosarcoma, adrenocortical cancer, central nervous system tumor, and soft tissue tumor. Additionally, leukemia and lymphoma are also involved. LFS patients have a high risk to suffer secondary or even multiple cancers. Therefore, it is necessary to perform genetic detection for pediatric cancer patients, especially those with hereditary predisposition cancers. TP53 mutation often indicates poor prognosis, so it is important to take active treatment and systematic monitoring for LFS family.
Child, Preschool ; Genes, p53 ; Humans ; Li-Fraumeni Syndrome ; genetics ; Male ; Mutation ; Rhabdomyosarcoma ; genetics

Objective: To investigate the correlation of the single nucleotide polymorphism (SNP) rs1042522 of the tumor protein p53 (TP53) gene with the risk of male infertility. METHODS: This casecontrol study included 380 male patients with idiopathic infertility and 398 normal fertile men as controls from the Nanjing area. We genotyped the SNP rs1042522 of the TP53 gene by Sequence Mass Array and analyzed the correlation of the SNP with male infertility using the logistic regression model. RESULTS: Compared with the normal controls, the patients with idiopathic infertility showed significantly decreased sperm concentration (［77.34±49.24］ vs ［13.13±24.96］ ×106/ml), percentage of progressively motile sperm (［42.55±9.57］ vs ［10.38±5.57］%), serum testosterone level (［14.07±5.36］ vs ［11.89±4.50］ nmol/L), and folliclestimulating hormone level (［16.80±18.20］ vs ［4.55±7.17］ U/L) (P < 0.05) but no statistically significant differences in other parameters. No correlation was observed between the SNP frequencies and male infertility and similar results were found in the subgroups of the cases. CONCLUSIONS SNP rs1042522 of the TP53 gene is not significantly correlated with the risk of male infertility.
Case-Control Studies ; Follicle Stimulating Hormone ; blood ; Gene Frequency ; Genes, p53 ; genetics ; Genetic Predisposition to Disease ; Genotype ; Humans ; Infertility, Male ; blood ; genetics ; Logistic Models ; Male ; Polymorphism, Single Nucleotide ; Sperm Count ; Sperm Motility ; Testosterone ; analogs & derivatives ; blood

OBJECTIVETo investigate the effectiveness and safety of reduced intensity conditioning allogeneic hematopoietic stem cell transplantation (RIC allo-HSCT) in ultra high risk chronic lymphocytic leukemia (CLL) patients with the deletion of p53 to deepen the understanding of allo-HSCT in the treatment of CLL.

METHODSIn this retrospective study, a total of 4 ultra high risk CLL patients with the deletion of p53 in our center between July 2012 and Jan 2014 were enrolled. The RIC regimen was administered and the hematopoietic reconstitution, transplantation related mortality (TRM), overall survival (OS), progress free survival (PFS) were evaluated.

RESULTSWe registered 4 patients with the median age of 56 years (49-61 years), including 3 males and 1 female. The median mononuclear cells (MNC) and CD34(+) cells were 6.54 (2.85-14.7) × 10(8)/kg (recipient body weight) and 5.81 (2.85-7.79) × 10(6)/kg (recipient body weight), respectively. The median time of the neutrophil recovery was 11 days (range of 9-12 days), and the median time of the platelet recovery 5.5 days (range of 0-11 days). Three patients (75%) attained a full donor chimerism at day 28 after transplantation and one (25%) got a mixed chimerism of donor and recipient. During the follow-up at a median time of 26.5 months (range of 21-39 months), 2 (50%) patients developed acute graft versus host disease (aGVHD) grade I and 2 (50%) patients got CMV infection. One patient got herpes zoster virus and EB virus infections. No transplantation related mortality was found in the 4 patients. One patient who was in partial response status progressed 5 months after transplantation, and the other 3 patients remained in durable remission after allo-HSCT.

CONCLUSIONThese results suggested that RIC allo-HSCT showed durable remission, good tolerance and acceptable toxicity, which could be a better option for the treatment of ultra high risk CLL patients with the deletion of p53 and was worth to be investigated and applied widely in future.

Disease-Free Survival ; Female ; Gene Deletion ; Genes, p53 ; Graft vs Host Disease ; Hematopoietic Stem Cell Transplantation ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell ; genetics ; therapy ; Male ; Middle Aged ; Retrospective Studies ; Transplantation Conditioning ; Treatment Outcome ; Tumor Suppressor Protein p53 ; genetics

OBJECTIVE To study the morphology, immunology, cyto- and molecular genetics of a patient with lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM), deletion of P53 gene and rearrangement of clonal T cell receptors-delta (TCR-delta) gene. METHODS The cell morphology and immunocytochemistry were analyzed by bone marrow testing and biopsy. Cellular immunology was analyzed by flow cytometry. Genetic analysis was carried out by chromosome karyotyping, fluorescent in situ hybridization (FISH) and polymerase chain reaction (PCR). Immunoglobulin M (IgM) in serum and urine was assayed by immunofixation electrophoresis. And the effect of chlorambucil therapy was evaluated. RESULTS Bone marrow biopsy suggested that the patient was of B lymphocyte type and had abnormal increase of lymphocytoid plasma cells, which were CD38 and CD138 positive. The patient had a normal male karyotype. FISH and PCR analysis of peripheral blood samples suggested deletion of P53 gene and rearrangement of TCR-delta gene. Immunofixation electrophoresis has detected IgM-kappa in both serum and urine. The patient showed partial response to chlorambucil. CONCLUSION In addition to typical clinical features, bone marrow examination, flow cytometry, histochemistry and immunophenotyping, testing for P53 gene deletion and lymphocyte gene rearrangement can facilitate the diagnosis and treatment of LPL/WM.
Aged ; Gene Rearrangement, delta-Chain T-Cell Antigen Receptor ; Genes, p53 ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Polymerase Chain Reaction ; Waldenstrom Macroglobulinemia ; drug therapy ; genetics

OBJECTIVETo re-analyze the data published in order to explore plausible biological pathways that can be used to explain the anti-aging effect of curcumin.

METHODSMicroarray data generated from other study aiming to investigate effect of curcumin on extending lifespan of Drosophila melanogaster were further used for pathway prediction analysis. The differentially expressed genes were identified by using GeneSpring GX with a criterion of 3.0-fold change. Two Cytoscape plugins including BisoGenet and molecular complex detection (MCODE) were used to establish the protein-protein interaction (PPI) network based upon differential genes in order to detect highly connected regions. The function annotation clustering tool of Database for Annotation, Visualization and Integrated Discovery (DAVID) was used for pathway analysis.

RESULTSA total of 87 genes expressed differentially in D. melanogaster melanogaster treated with curcumin were identified, among which 50 were up-regulated significantly and 37 were remarkably down-regulated in D. melanogaster melanogaster treated with curcumin. Based upon these differential genes, PPI network was constructed with 1,082 nodes and 2,412 edges. Five highly connected regions in PPI networks were detected by MCODE algorithm, suggesting anti-aging effect of curcumin may be underlined through five different pathways including Notch signaling pathway, basal transcription factors, cell cycle regulation, ribosome, Wnt signaling pathway, and p53 pathway.

CONCLUSIONGenes and their associated pathways in D. melanogaster melanogaster treated with anti-aging agent curcumin were identified using PPI network and MCODE algorithm, suggesting that curcumin may be developed as an alternative therapeutic medicine for treating aging-associated diseases.

Aging ; drug effects ; genetics ; Animals ; Cell Cycle ; drug effects ; genetics ; Curcumin ; pharmacology ; Drosophila Proteins ; genetics ; metabolism ; Drosophila melanogaster ; drug effects ; genetics ; Gene Expression Regulation ; drug effects ; Gene Regulatory Networks ; drug effects ; Genes, Insect ; Protein Biosynthesis ; drug effects ; genetics ; Protein Interaction Maps ; drug effects ; genetics ; Receptors, Notch ; genetics ; metabolism ; Ribosomes ; drug effects ; metabolism ; Signal Transduction ; drug effects ; genetics ; Tumor Suppressor Protein p53 ; metabolism ; Wnt Signaling Pathway ; drug effects ; genetics