TP53 - tumor protein p53
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Publication
Journal: International journal of surgical pathology
March/27/2019
Abstract
Background. Ovarian carcinosarcomas are rare aggressive biphasic tumors. Evidence suggests that these tumors are monoclonal and that the sarcoma component is derived from a stem cell undergoing divergent differentiation. Currently, there remains a paucity of data regarding its origin, with few reports suggesting an association with serous tubal intraepithelial carcinoma (STIC) by immunohistochemistry and genetics. Objective. We sought to determine the relationship of carcinosarcoma to high-grade serous carcinoma and STIC by investigating for similar mutation signatures through next-generation sequencing. Methodology. A case of carcinosarcoma with associated high-grade serous carcinoma and STIC was macrodissected, and next-generation sequencing was performed on each component separately. Results. The STIC, high-grade serous carcinoma component, and chondrosarcoma component were all diffusely positive for p53 and p16 by immunohistochemistry. Next-generation sequencing demonstrated an identical TP53 gene c.376-1G>A 5' splice site pathogenic mutation in all 3 components. Conclusions. Our findings suggest that carcinosarcomas may also originate from the fallopian tube.
Publication
Journal: Molecular & cellular oncology
November/6/2019
Abstract
Cyclin-dependent kinase -4 and -6 (CDK4/6) inhibitors are currently being assessed in clinical trials for the treatment of many cancers including melanoma. While investigating the mechanisms of CDK4/6 inhibitor resistance in melanoma, we uncovered a mechanism of action of these inhibitors in regulating the expression of both the mouse double minute 4 (MDM4) oncogene and tumor protein p53 (TP53).
Publication
Journal: APMIS : acta pathologica, microbiologica, et immunologica Scandinavica
October/19/2019
Abstract
Biliary tract cancers (BTC) are a rare heterogeneous disease group with a dismal prognosis and limited treatment options. The mutational landscape consists of genetic aberrations both shared by and characteristic for anatomical location. Here we present exome sequencing data on 22 genes from a phase 2 trial using a clinically validated panel used in patients with colorectal cancer.A total of 56 patients were included in a one-armed phase 2 trial investigating the treatment combination of capecitabine, gemcitabine, oxaliplatin and cetuximab. Tissue DNA yield and quality allowed analysis of 30 patients on our panel including 22 genes.ARID1A (33%) and TP53 (33%) were found to be most frequently mutated followed by KRAS mutations found in 20% of the patients. Mutational aberrations in ARID1A were found more prevalent than expected, whereas TP53 and KRAS where in concordance with earlier reported data. Mutation in CTNNB1 was significantly associated with poor prognosis.Our panel is clinically validated and suitable for a high volume of samples to detect mutations in patients with BTC. However, it is reasonable to assume that the clinical utility could be optimized in this patient group by extending the panel to include BTC specific mutations with potential therapeutic consequences such as IDH1/2, FGFR-fusions, ERBB3 and BRCA1/2.
Publication
Journal: Theranostics
October/29/2019
Abstract
Resistance to preoperative chemoradiotherapy (CRT) is a major obstacle to cancer treatment in patients with locally advanced rectal cancer. This study was to explore genome alterations in rectal cancer under CRT stress. Methods: Whole-exome sequencing (WES) was performed on 28 paired tumors collected before and after CRT from the same patients who did not respond to CRT treatment. Somatic point mutations and copy number variations were detected by VarScan2 and Exome CNVs respectively using paired tumor and blood samples. Somatic alterations associated with CRT resistance were inferred considering differences in significantly mutated genes, mutation counts and cancer cell fraction between matched pre- and post-CRT tumors. We employed SignatureAnalyzer to infer mutation signatures and PyClone to decipher clonal evolution and examine intratumoral heterogeneity in tumors before and after CRT. The associations between intratumoral heterogeneity and patients' survival were analyzed using the log-rank test and the Cox regression model. Results: (i) Recurrent mutations in CTDSP2, APC, KRAS, TP53 and NFKBIZ confer selective advantages on cancer cells and made them resistant to CRT treatment. (ii) CRT alters the genomic characteristics of tumors at both the somatic mutation and the copy number variation levels. (iii) CRT-resistant tumors exhibit either a branched or a linear evolution pattern. (iv) Different recurrent mutation signatures in pre-CRT and post-CRT patients implicate mutational processes underlying the evolution of CRT-resistant tumors. (v) High intratumoral heterogeneity in pre- or post-CRT is associated with poor patients' survival. Conclusion: Our study reveals genome landscapes in rectal cancer before and after CRT and tumors evolution under CRT stress. The treatment-associated characteristics are useful for further investigations of CRT resistance in rectal cancer.
Publication
Journal: BMC complementary and alternative medicine
July/5/2019
Abstract
Wumei Pill (WMP), a famous herbal formula, has been widely used to treat digestive system diseases in clinical practice in China for centuries. We have found a correlation between the indications of WMP and the typical symptoms of pancreatic neoplasms. However, the pharmacological mechanisms of WMP still remain unknown.In the present work, we used a network pharmacological method to predict its underlying complex mechanism of treating pancreatic neoplasms. Firstly, we obtained relative compounds of WMP based on TCMSP database, TCM database@Taiwan and TCMID database and collected potential targets of these compounds by target fishing. Then we built the pancreatic neoplasms target database by CTD, TTD, PharmGKB. Based on the matching results between WMP potential targets and pancreatic neoplasms targets, we built a PPI network to analyze the interactions among these targets and screen the hub targets by topology. Furthermore, DAVID bioinformatics resources were utilized for the enrichment analysis on GO_BP and KEGG.A total of 80 active ingredients and 77 targets of WMP were picked out. The results of DAVID enrichment analysis indicated that 58 cellular biological processes (FDR < 0.01) and 17 pathways (FDR < 0.01) of WMP mostly participated in the complex treating effects associated with proliferation, apoptosis, inflammatory response and angiogenesis. Moreover, 17 hub nodes of WMP (PTGS2, BCL2, TP53, IL6, MAPK1, EGFR, EGF, CASP3, JUN, MAPK8, MMP9, VEGFA, TNF, MYC, AKT1, FOS and TGFB1) were recognized as potential targets of treatments, implying the underlying mechanisms of WMP acting on pancreatic neoplasms.WMP could alleviate the symptoms of pancreatic neoplasms through the molecular mechanisms predicted by network pharmacology. This study proposes a strategy to elucidate the mechanisms of Traditional Chinese Medicine (TCM) at the level of network pharmacology.
Publication
Journal: Nature communications
June/25/2019
Abstract
Anaplastic thyroid cancer (ATC) and advanced differentiated thyroid cancers (DTCs) show fatal outcomes, unlike DTCs. Here, we demonstrate mutational landscape of 27 ATCs and 86 advanced DTCs by massively-parallel DNA sequencing, and transcriptome of 13 ATCs and 12 advanced DTCs were profiled by RNA sequencing. TERT, AKT1, PIK3CA, and EIF1AX were frequently co-mutated with driver genes (BRAFV600E and RAS) in advanced DTCs as well as ATC, but tumor suppressors (e.g., TP53 and CDKN2A) were predominantly altered in ATC. CDKN2A loss was significantly associated with poor disease-specific survival in patients with ATC or advanced DTCs, and up-regulation of CD274 (PD-L1) and PDCD1LG2 (PD-L2). Transcriptome analysis revealed a fourth molecular subtype of thyroid cancer (TC), ATC-like, which hardly reflects the molecular signatures in DTC. Furthermore, the activation of JAK-STAT signaling pathway could be a potential druggable target in RAS-positive ATC. Our findings provide insights for precision medicine in patients with advanced TCs.
Publication
Journal: Biochemical and biophysical research communications
July/10/2006
Abstract
Recent reports have shown that MDM2 may attenuate hypertrophy of cardiac myocytes. However, mechanism of MDM2 involving in this process is unclear. In this study, we identified a novel specific MDM2-binding protein TCAP by the yeast two-hybrid screen. It was validated by GST pull-down and co-immunoprecipitation assays. Confocal analysis showed that MDM2 and TCAP co-localized in the nucleus, and elevated MDM2 expression could alter the subcellular localization of TCAP. Notably, MDM2 downregulated the protein level of TCAP through the proteasomal pathway, and this downregulation was inhibited by p14(ARF). In addition, our results suggested that the degradation of TCAP by MDM2 was through the ubiquitin-independent pathway. Given that TCAP is a key component involving in the cardiac hypertrophy, the degradation of TCAP by MDM2 might be connected with the roles of MDM2 in cardiac hypertrophy. Further investigation will focus on the biological significance of MDM2-TCAP interaction in cardiac hypertrophy.
Publication
Journal: Medical molecular morphology
May/29/2019
Abstract
Pathological diagnosis of intraductal apocrine lesions can be challenging, because even benign apocrine lesions often show atypical cytology, and immunohistochemistry is of little assistance. A new diagnostic method for apocrine lesions is desirable. The mutations present in apocrine lesions have not been well studied. We performed a MassARRAY multiplex polymerase chain reaction (PCR) study of benign and malignant apocrine lesions, which included 152 mutations of 18 genes. We found that four of 11 benign lesions showed AKT1 or PIK3CA mutations, one of four noninvasive apocrine carcinomas showed a FBX4 mutation, two of 15 invasive apocrine carcinomas showed a PIK3CA mutation, and one invasive apocrine carcinoma showed both PIK3CA and TP53 mutations. The mutation frequency did not differ significantly between benign and malignant lesions (p = 0.683). We demonstrated that both benign and malignant apocrine lesions may contain mutations of genes in the PI3K-AKT pathway, this pathway could be a good therapeutic target of these diseases.
Publication
Journal: Epigenomics
November/8/2019
Abstract
Aim: To investigate the associations between LINE1 methylation, an indicator for genome-wide hypomethylation, molecular and clinicopathological characteristics of gastric cancer (GC) patients. Patients & methods:LINE1 methylation statuses were examined in paired cancerous, non-neoplastic mucosa from 217 GC and gastric mucosa from separate group of 224 noncancer patients. CpG island methylator phenotype, TP53 and KRAS mutation, MLH1 methylation status and promoter hypermethylation of GC related and H. pylori-related genes were examined. Results: Lower LINE1 methylation was observed in primary GC compared with non-neoplastic gastric mucosa and associated with CpG island methylator phenotype, TP53 mutation, MLH1 methylation and promoter hypermethylation of GC related and H. pylori-related genes. Conclusion: Lower LINE1 methylation correlates specific molecular subtypes and promoter hypermethylation in GC.
Publication
Journal: Cell cycle (Georgetown, Tex.)
November/23/2019
Abstract
DNA damage can be generated in multiple ways from genotoxic and physiologic sources. Genotoxic damage is known to disrupt cellular functions and is lethal if not repaired properly. We compare the transcriptional programs activated in response to genotoxic DNA damage induced by ionizing radiation (IR) in abl pre-B cells from mice deficient in DNA damage response (DDR) genes Atm, Mre11, Mdc1, H2ax, 53bp1, and DNA-PKcs. We identified a core IR-specific transcriptional response that occurs in abl pre-B cells from WT mice and compared the response of the other genotypes to the WT response. We also identified genotype specific responses and compared those to each other. The WT response includes many processes involved in lymphocyte development and immune response, as well as responses associated with the molecular mechanisms of cancer, such as TP53 signaling. As expected, there is a range of similarity in transcriptional profiles in comparison to WT cells, with Atm-/- cells being the most different from the core WT DDR and Mre11 hypomorph (Mre11A/A) cells also very dissimilar to WT and other genotypes. For example, NF-kB-related signaling and CD40 signaling are deficient in both Atm-/- and Mre11A/A cells, but present in all other genotypes. In contrast, IR-induced TP53 signaling is seen in the Mre11A/A cells, while these responses are not seen in the Atm-/- cells. By examining the similarities and differences in the signaling pathways in response to IR when specific genes are absent, our results further illustrate the contribution of each gene to the DDR. The microarray gene expression data discussed in this paper have been deposited in NCBI's Gene Expression Omnibus (GEO) (http://www.ncbi.nlm.nih.gov/geo/) and are accessible under accession number GSE116388.
Publication
Journal: Annals of surgical oncology
November/19/2019
Publication
Journal: Cancer chemotherapy and pharmacology
November/1/2019
Abstract
The current study was designed to evaluate the toxicity of the secondary metabolites of Lactobacillus plantarum against the human breast cancer cell line (MCF-7) and the Drosophila melanogaster.In this study, toxicity analyses of secondary metabolites of Lactobacillus plantarum were analyzed on breast cancer cells, and the Drosophila melanogaster. After application, in the MCF-7 cell line, expression levels of RRAS-2, TP53, BCL-2, APAF-1, CASP-3, FADD, CASP-7, BOK genes; in D. melanogaster; expression levels of RAS64B P53, BUFFY, DARK, DECAY, FADD, DRICE, and DEBCL genes were determined by RT-PCR. In addition, analysis of L. plantarum secondary metabolite was performed by GC-MS method and molecular binding poses of secondary metabolites and human enzymes were investigated in silico.

RESULTS
Drosophila melanogaster being used as a model organism where some of the human genes were preserved. The IC50 value of the secondary metabolite in the MCF-7 cell line was determined to be 0.0011 mg/ml. Lethal concentration 50 (LC50) and 99 (LC99) values of secondary metabolites against fruit fly adults were 0.24 mg/ml and 0.54 mg/ml, respectively. The expression levels of BCL-2 and BUFFY genes which are anti-apoptotic in human and fruit flies have been reduced, and at the same time, increased expression of DECAY, FADD, RAS64B apoptotic genes in D. melanogaster.

The substance detected in the secondary metabolite content and encoded as L13 (3-phenyl-1, 2, 4-benzotriazine) has been observed to have high binding affinity in the studied genes.
Publication
Journal: Genes & development
October/17/2001
Abstract
The glucocorticoid receptor (GR) and the tumor suppressor p53 mediate different stress responses. We have studied the mechanism of their mutual inhibition in normal endothelial cells (HUVEC) in response to hypoxia, a physiological stress, and mitomycin C, which damages DNA. Dexamethasone (Dex) stimulates the degradation of endogenous GR and p53 by the proteasome pathway in HUVEC under hypoxia and mitomycin C treatments, and also in hepatoma cells (HepG2) under normoxia. Dex inhibits the functions of p53 (apoptosis, Bax, and p21(WAF1/CIP1) expression) and GR (PEPCK and G-6-Pase expression). Endogenous p53 and GR form a ligand-dependent trimeric complex with Hdm2 in the cytoplasm. Disruption of the p53-HDM2 interaction prevents Dex-induced ubiquitylation of GR and p53. The ubiquitylation of GR requires p53, the interaction of p53 with Hdm2, and E3 ligase activity of Hdm2. These results provide a mechanistic basis for GR and p53 acting as opposing forces in the decision between cell death and survival.
Publication
Journal: Technology in cancer research & treatment
February/25/2019
Abstract
The aim of the study was to estimate breast cancer risk conferred by individual single-nucleotide polymorphisms of breast cancer susceptibility genes.We analyzed the 48 tagging single-nucleotide polymorphisms of 8 breast cancer susceptibility genes involved in the monoubiquitinated FANCD2-DNA damage repair pathway in 734 Chinese women with breast cancer and 672 age-matched healthy controls.Forty-five tagging single-nucleotide polymorphisms were successfully genotyped by SNPscan, and the call rates for each tagging single-nucleotide polymorphisms were above 98.9%. We found that 13 tagging single-nucleotide polymorphisms of 5 genes ( Parter and localizer of Breast cancer gene2 ( PALB2), Tumour protein 53 ( TP53), Nijmegen breakage syndrome 1, Phosphatase and tensin homolog deleted from chromosome 10 ( PTEN), and Breast cancer gene 1 ( BRCA1-interacting protein 1)) were significantly associated with breast cancer risk. A total of 5 tagging single-nucleotide polymorphisms (rs2299941 of PTEN, rs2735385, rs6999227, rs1805812, and rs1061302 of Nijmegen breakage syndrome 1) were tightly associated with breast cancer risk in sporadic cases, and 5 other tagging single-nucleotide polymorphisms (rs1042522 of TP53, rs2735343 of PTEN, rs7220719, rs16945628, and rs11871753 of BRCA1-interacting protein 1) were tightly associated with breast cancer risk in familial and early-onset cases.Some of the tagging single-nucleotide polymorphisms of 5 genes ( PALB2, TP53, Nijmegen breakage syndrome 1, PTEN, and BRCA1-interacting protein 1) involved in the monoubiquitinated FANCD2-DNA damage repair pathway were significantly associated with breast cancer risk.
Publication
Journal: Pancreas
August/12/2019
Abstract
The aims of this study were to identify genetic characteristics of intraductal papillary mucinous neoplasm (IPMN)-associated pancreatic ductal carcinoma (PDC) and to detect these markers using pancreatic juice.From 76 cases, 102 tissues were obtained: 29 cases were noninvasive IPMN, 18 were PDC derived from IPMN (D-PDC; noninvasive part, n = 16; invasive part, n = 18), and 29 were PDC concomitant with IPMN (C-PDC; IPMN part, n = 10; PDC part, n = 29). Moreover, pancreatic juice samples from 28 cases were obtained (noninvasive IPMN, n = 13; D-PDC, n = 7; C-PDC, n = 8). Fifty-one cancer-related genes were analyzed by next-generation sequencing.TP53 mutation rates in D-PDC, C-PDC, and noninvasive IPMN were 67%, 66%, and 10%, respectively. Moreover, KRAS mutational patterns between 2 simultaneous tumors differed in 1 (6.3%) of the 16 D-PDC cases and in 8 (80%) of the 10 C-PDC cases (P = 0.0006). TP53 or multiple KRAS mutations were detected using pancreatic juice more frequently in C-PDC cases than in noninvasive IPMN cases (75% and 23%, respectively, P = 0.03).Multiple KRAS mutations along with TP53 mutation are genetic markers for C-PDC, which could be detected using pancreatic juice preoperatively.
Publication
Journal: Haematologica
August/30/2019
Abstract
To identify genomic alterations contributing to the pathogenesis of high risk chronic lymphocytic leukemia beyond the well established role of TP53 aberrations, we comprehensively analyzed 75 relapsed/refractory and 71 treatment naive high risk cases from prospective clinical trials by single nucleotide polymorphism arrays and targeted next generation sequencing. Increased genomic complexity was a hallmark of relapsed/refractory and treatment naive high risk chronic lymphocytic leukemia. In relapsed/refractory cases previously exposed to the selective pressure of chemo(immuno)therapy, gain(8)(q24.21) and del(9)(p21.3) were found particularly enriched. Both alterations affected key regulators of cell cycle progression, namely MYC and CDKN2A/B. While homozygous CDKN2A/B loss has been directly associated with Richter transformation, we did not find this association for heterozygous loss of CDKN2A/B. Gains in 8q24.21 were either focal gains in a MYC enhancer region or large gains affecting the MYC locus, but only the latter type was highly enriched in relapsed/refractory chronic lymphocytic leukemia (17%). In addition to a high frequency of NOTCH1 mutations (23%), we found recurrent genetic alterations in SPEN (4% mutated), RBPJ (8% deleted) and SNW1 (8% deleted), all affecting a protein complex that represses transcription of NOTCH1 target genes. We investigated the functional impact of these alterations on HES1, DTX1 and MYC gene transcription and found de repression of these NOTCH1 target genes particularly with SPEN mutations. In summary, we provide new insights into the genomic architecture of high risk chronic lymphocytic leukemia, define novel recurrent DNA copy number alterations and refine knowledge on del(9p), gain(8q) and alterations affecting NOTCH1 signaling. The study was registered at ClinicalTrials.gov with number NCT01392079.
Publication
Journal: Metabolic engineering
September/18/2019
Abstract
Metabolic reprogramming is considered a hallmark of malignant transformation. However, it is not clear whether the network of metabolic reactions expressed by cancers of different origin differ from each other nor from normal human tissues. In this study, we reconstructed functional and connected genome-scale metabolic models for 917 primary tumor samples across 13 types based on the probability of expression for 3765 reference metabolic genes in the sample. This network-centric approach revealed that tumor metabolic networks are largely similar in terms of accounted reactions, despite diversity in the expression of the associated genes. On average, each network contained 4721 reactions, of which 74% were core reactions (present in >95% of all models). Whilst 99.3% of the core reactions were classified as housekeeping also in normal tissues, we identified reactions catalyzed by ARG2, RHAG, SLC6 and SLC16 family gene members, and PTGS1 and PTGS2 as core exclusively in cancer. These findings were subsequently replicated in an independent validation set of 3662 genome-scale metabolic models. The remaining 26% of the reactions were contextual reactions. Their inclusion was dependent in one case (GLS2) on the absence of TP53 mutations and in 94.6% of cases on differences in cancer types. This dependency largely resembled differences in expression patterns in the corresponding normal tissues, with some exceptions like the presence of the NANP-encoded reaction in tumors not from the female reproductive system or of the SLC5A9-encoded reaction in kidney-pancreatic-colorectal tumors. In conclusion, tumors expressed a metabolic network virtually overlapping the matched normal tissues, raising the possibility that metabolic reprogramming simply reflects cancer cell plasticity to adapt to varying conditions thanks to redundancy and complexity of the underlying metabolic networks. At the same time, the here uncovered exceptions represent a resource to identify selective liabilities of tumor metabolism.
Publication
Journal: Scientific reports
July/31/2019
Abstract
In this work we explored metabolic aspects of human primary leukemic lymphocytes that hold a potential impact on the treatment of Bruton tyrosine kinase (BTK)-driven diseases. Our results suggest that there is crosstalk between Bruton tyrosine kinase (BTK) signaling and bioenergetic stress responses. In primary chronic lymphocytic leukemia (CLL) lymphocytes, pharmacological interference with mitochondrial ATP synthesis or glucose metabolism affects BTK activity. Conversely, an inhibitor of BTK used clinically (ibrutinib) induces bioenergetic stress responses that in turn affect ibrutinib resistance. Although the detailed molecular mechanisms are still to be defined, our work shows for the first time that in primary B cells, metabolic stressors enhance BTK signaling and suggest that metabolic rewiring to hyperglycemia affects ibrutinib resistance in TP53 deficient chronic lymphocytic leukemia (CLL) lymphocytes.
Publication
Journal: Leukemia
December/21/2018
Abstract
Acute promyelocytic leukemia (APL) is characterized by t(15;17)(q22;q21), resulting in a PML-RARA fusion that is the master driver of APL. A few cases that cannot be identified with PML-RARA by using conventional methods (karyotype analysis, FISH, and RT-PCR) involve abnormal promyelocytes that are fully in accordance with APL in morphology, cytochemistry, and immunophenotype. To explore the mechanisms involved in pathogenesis and recurrence of morphologically diagnosed APL, we performed comprehensive variant analysis by next-generation sequencing in 111 pediatric patients morphologically diagnosed as APL. Structural variant (SV) analysis in 120 DNA samples from both diagnosis and relapse stage identified 95 samples with RARA rearrangement (including 94 with PML-RARA and one with NPM-RARA) and two samples with KMT2A rearrangement. In the eligible 13 RNA samples without any RARA rearrangement at diagnosis, one case each with CPSF6-RARG, NPM1-CCDC28A, and TBC1D15-RAB21 and two cases with a TBL1XR1-RARB fusion were discovered. These uncovered fusion genes strongly suggested their contributions to leukemogenesis as driver alternations and APL phenotype may arise by abnormalities of other members of the nuclear receptor superfamily involved in retinoid signaling (RARB or RARG) or even by mechanisms distinct from the formation of aberrant retinoid receptors. Single-nucleotide variant (SNV) analysis in 77 children (80 samples) with RARA rearrangement showed recurrent alternations of primary APL in FLT3, WT1, USP9X, NRAS, and ARID1A, with a strong potential for involvement in pathogenesis, and WT1 as the only recurrently mutated gene in relapsed APL. WT1, NPM1, NRAS, FLT3, and NSD1 were identified as recurrently mutated in 17 primary samples without RARA rearrangement and WT1, NPM1, TP53, and RARA as recurrently mutated in 9 relapsed samples. The survival of APL with RARA rearrangement is much better than without RARA rearrangement. Thus, patients morphologically diagnosed as APL that cannot be identified as having a RARA rearrangement are more reasonably classified as a subclass of AML other than APL, and individualized treatment should be considered according to the genetic abnormalities.
Publication
Journal: Clinical cancer research : an official journal of the American Association for Cancer Research
December/29/2018
Abstract
The purpose of this study is to characterize the mutational landscape across the spectrum of urothelial carcinoma (UC) to identify mutational features and potential therapeutic targets.

EXPERIMENTAL DESIGN
Using targeted exome sequencing (n = 237 genes), we analyzed the mutation spectra of 82 low-grade nonmuscle-invasive bladder cancers (LG-NMIBC), 126 high-grade (HG) NMIBC, 199 muscle-invasive bladder cancers (MIBC), 10 LG-upper tract urothelial cancers (LG-UTUC), and 55 HG-UTUC.

RESULTS
FGFR3 and KDM6A mutations were significantly more common in LG-NMIBC (72% and 44%, respectively) versus other bladder subtypes. FGFR3 alterations were also enriched in LG-UTUC versus HG-UTUC tumors (80% vs. 16%). In contrast, TP53 and RB1 mutations were significantly more frequent in all 3 HG urothelial carcinoma subtypes than in LG-NIMBC (45%-58% vs. 4%; 9%-22% vs. 0; respectively). Among LG-NMIBC tumors, KDM6A mutations were more common in women than in men (71% vs. 38%). HG-NMIBC and MIBC had higher tumor mutational burden (TMB) than LG-NMIBC (P = 0.001 and P < 0.01, respectively). DNA-damage repair (DDR) alterations were associated with a higher TMB in HG-NMIBC and MIBC tumors, and these two tumor types were also enriched for an APOBEC mutational signature compared with LG-NMIBC and HG-UTUC. Alterations in FGFR3, PIK3CA, and EP300 correlated with worse overall survival in HG-UTUC and occurred concurrently.

CONCLUSIONS
Our analysis suggests that a fraction of MIBCs likely arise from precursor lesions other than LG-NMIBC. KDM6A mutations are twice as common in women with LG-NIMBC than those in men. DDR gene mutations and APOBEC mutagenesis drive mutations in HG-NMIBC and MIBC. UTUC has a distinct mutation profile from bladder cancer.

Publication
Journal: Journal of applied physiology (Bethesda, Md. : 1985)
April/19/2006
Abstract
This study tested the hypothesis that inhibitor of differentiation-2 (Id2), p53, and heat shock proteins (HSP) are responsive to suspension-induced muscle atrophy. Fourteen days of hindlimb suspension were used to unload the hindlimbs and induce atrophy in gastrocnemius muscles of young adult and aged rats. Following suspension, medial gastrocnemius muscle wet weight was reduced by approximately 30%, and the muscle wet weight normalized to the animal body weight decreased by 11 and 15% in young adult and aged animals, respectively. mRNA abundances of Id2, p53, HSP70-2, and HSP27 did not change with suspension, whereas HSP70-1 mRNA content was lower in the suspended muscle compared with the control muscle in both young adult and aged animals. Our immunoblot analyses indicated that protein expressions of HSP70 and HSP60 were not different between suspended and control muscles in both ages, whereas HSP27 protein content was increased in suspended muscle relative to control muscle only in young adult animals. Id2 and p53 protein contents were elevated in the cytosolic fraction of suspended muscle compared with the control muscle in both young and aged animals, but these changes were not found in the nuclear protein fraction. Furthermore, compared with young adult, aged muscles had a lower HSP70-1 mRNA content but higher HSP70-2 mRNA content and protein contents of Id2, p53, HSP70, and HSP27. These findings are consistent with the hypothesis that Id2 and p53 are responsive to unloading-induced muscle atrophy. Moreover, our data indicate that aging is accompanied with altered abundances of HSP70-1 and HSP70-2 mRNA, in addition to Id2, p53, HSP70, and HSP27 protein in rat gastrocnemius muscle.
Publication
Journal: PloS one
December/13/2018
Abstract
Cholinergic Receptor Nicotinic Alpha 5 (CHRNA5) is an important susceptibility locus for nicotine addiction and lung cancer. Depletion of CHRNA5 has been associated with reduced cell viability, increased apoptosis and alterations in cellular motility in different cancers yet not in breast cancer. Herein we first showed the expression of CHRNA5 was variable and positively correlated with the fraction of total genomic alterations in breast cancer cell lines and tumors indicating its potential role in DNA damage response (DDR). Next, we demonstrated that silencing of CHRNA5 expression in MCF7 breast cancer cell line by RNAi affected expression of genes involved in cytoskeleton, TP53 signaling, DNA synthesis and repair, cell cycle, and apoptosis. The transcription profile of CHRNA5 depleted MCF7 cells showed a significant positive correlation with that of A549 lung cancer cell line while exhibiting a negative association with the CHRNA5 co-expression profile obtained from Cancer Cell Line Encylopedia (CCLE). Moreover, it exhibited high similarities with published MCF7 expression profiles obtained from exposure to TP53 inducer nutlin-3a and topoisomerase inhibitors. We then demonstrated that CHRNA5 siRNA treatment reduced cell viability and DNA synthesis indicating G1 arrest while it significantly increased apoptotic sub-G1 cell population. Accordingly, we observed lower levels of phosphorylated RB (Ser807/811) and an increased BAX/BCL2 ratio in RNAi treated MCF7 cells. We also showed that CHRNA5 RNAi transcriptome correlated negatively with DDR relevant gene expression profile in breast cancer gene expression datasets while the coexposure to topoisomerase inhibitors in the presence of CHRNA5 RNAi enhanced chemosensitivity potentially due to reduced DDR. CHRNA5 RNAi consistently lowered total CHEK1 mRNA and protein levels as well as phosphorylated CHEK1 (Ser345) in MCF7 cells. We also detected a significant positive correlation between the expression levels of CHRNA5 and CHEK1 in CCLE, TCGA and METABRIC breast cancer datasets. Our study suggests CHRNA5 RNAi is associated with cell cycle inhibition, apoptosis as well as reduced DDR and increased drug sensitivity in breast cancer yet future studies are warranted since dose- and cell line-specific differences exist in response to CHRNA5 depletion. Gene expression microarray data can be accessed from GEO database under the accession number GSE89333.
Publication
Journal: Advances in medical sciences
December/16/2018
Abstract
The main scope of this study was to evaluate the importance of selected DNA variants for developing inflammation of gastric mucosa and carcinogenesis in gastrointestinal diseases in patients infected with Helicobacter pylori.Patients subjected to analysis constituted a group of 131 consecutive cases, with control groups consisting of 100 healthy volunteers and 13 dyspeptic patients. Molecular analysis included the following genes: TP53 (c.743 G > A, c.746 G > A, c.749C > T), MSH2 (c.942 + 3A > T), MLH1 (c.2041 G > A), NOD2/CARD15 (c.3016_3017insC, c.802C > T), IL1A (c.-949C > T) and IL1B (c.315C > T). DNA variants were detected using PCR-RFLP, pyrosequencing and sequencing.Mutations of the analyzed genes were observed more frequently in patients with a higher degree of mucosal lesions (50.9%) than in patients with milder mucosal changes (27.6%). Single mutations and polymorphisms did not affect the course of the disease. Our analysis confirms the influence of the NOD2/CARD15 c.802C > T polymorphism on the development of mucosal changes. A correlation of the frequency of the CT genotype of the NOD2/CARD15 c.802C > T polymorphism with the NOD2/CARD15 c.3016_3017insC mutation was observed. The TT genotype frequency in the c.315C > T IL1B gene polymorphism was statistically significantly higher in patients with mucosa changes.Accumulation of molecular abnormalities may increase the susceptibility to inflammatory response of the gastric mucosa in H. pylori-infected patients and play an important role in the development of chronic active gastritis, atrophy, intestinal metaplasia, dysplasia and the intestinal type of gastric cancer. The severity of gastric mucosal damage correlates with the presence of mutations in the gastric mucosa and the age of patients.
Publication
Journal: International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group
February/8/2009
Abstract
OBJECTIVE
Hyperthermia is useful in the treatment of human head and neck cancers, because it is relatively easy to regulate temperatures when compared to tumors located in deep organs. In this study, attention was focused on p53 as a possible predictive indicator for the efficacy of hyperthermic cancer therapy.
METHODS
Two kinds of cell lines were used. These were derived from a human squamous cell carcinoma (SAS) and had identical genetic backgrounds except for their p53 gene status. It was previously reported that the heat sensitivity and frequency of apoptosis in wild-type p53 cells (SAS/neo) were clearly elevated when compared with mutated p53 cells (SAS/mp53). In order to study the expression of apoptosis related proteins after heat treatment, protein microarray analysis was used.
RESULTS
The expression of apoptosis inhibitory proteins such as Bcl-2, Bcl-xL, NF-kappaB, COX2, STAT3, IL-6, and IKKalpha/1 was seen to increase after heat treatment in SAS/mp53 cells, but not in SAS/neo cells.
CONCLUSIONS
The result of these observations indicates that apoptosis inhibitory proteins (such as Bcl-2, Bcl-xL, IL-6, etc.) were highly induced in SAS/mp53 cells after heat treatment when compared to control SAS/neo cells.
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