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TP53 disruption

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https://www.readbyqxmd.com/read/29661169/rna-seq-reveals-the-existence-of-a-cdkn1c-e2f1-tp53-axis-that-is-altered-in-human-t-cell-lymphoblastic-lymphomas
#1
Pilar López-Nieva, Pablo Fernández-Navarro, Concepción Vaquero-Lorenzo, María Villa-Morales, Osvaldo Graña-Castro, María Ángeles Cobos-Fernández, José Luis López-Lorenzo, Pilar Llamas, Laura González-Sanchez, Isabel Sastre, Marina Pollan, Marcos Malumbres, Javier Santos, José Fernández-Piqueras
BACKGROUND: Precursor T-cell lymphoblastic lymphomas (T-LBL) are rare aggressive hematological malignancies that mainly develop in children. As in other cancers, the loss of cell cycle control plays a prominent role in the pathogenesis in these malignancies that is primarily attributed to loss of CDKN2A (encoding protein p16INK4A). However, the impact of the deregulation of other genes such as CDKN1C, E2F1, and TP53 remains to be clarified. Interestingly, experiments in mouse models have proven that conditional T-cell specific deletion of Cdkn1c gene may induce a differentiation block at the DN3 to DN4 transition, and that the loss of this gene in the absence of Tp53 led to aggressive thymic lymphomas...
April 16, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29617666/systematic-analysis-of-splice-site-creating-mutations-in-cancer
#2
Reyka G Jayasinghe, Song Cao, Qingsong Gao, Michael C Wendl, Nam Sy Vo, Sheila M Reynolds, Yanyan Zhao, Héctor Climente-González, Shengjie Chai, Fang Wang, Rajees Varghese, Mo Huang, Wen-Wei Liang, Matthew A Wyczalkowski, Sohini Sengupta, Zhi Li, Samuel H Payne, David Fenyö, Jeffrey H Miner, Matthew J Walter, Benjamin Vincent, Eduardo Eyras, Ken Chen, Ilya Shmulevich, Feng Chen, Li Ding
For the past decade, cancer genomic studies have focused on mutations leading to splice-site disruption, overlooking those having splice-creating potential. Here, we applied a bioinformatic tool, MiSplice, for the large-scale discovery of splice-site-creating mutations (SCMs) across 8,656 TCGA tumors. We report 1,964 originally mis-annotated mutations having clear evidence of creating alternative splice junctions. TP53 and GATA3 have 26 and 18 SCMs, respectively, and ATRX has 5 from lower-grade gliomas. Mutations in 11 genes, including PARP1, BRCA1, and BAP1, were experimentally validated for splice-site-creating function...
April 3, 2018: Cell Reports
https://www.readbyqxmd.com/read/29610288/plasma-dna-and-metastatic-castration-resistant-prostate-cancer-the-odyssey-to-a-clinical-biomarker-test
#3
Anuradha Jayaram, Daniel Wetterskog, Gerhardt Attard
<b/> Comprehensive plasma DNA analysis identifies clinically actionable genomic aberrations. Cancers harboring disruption of TP53 or BRCA2 or ATM detected in plasma have significantly worse outcomes on novel AR targeting. Cancer Discov; 8(4); 392-4. ©2018 AACR. See related article by Annala et al., p. 444 .
April 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29561706/potential-of-bcl2-as-a-target-for-chronic-lymphocytic-leukemia-treatment
#4
Riccardo Moia, Fary Diop, Chiara Favini, Ahad Ahmed Kodipad, Gianluca Gaidano
Chronic lymphocytic leukemia (CLL) is a highly heterogeneous disease. Deregulation of apoptosis is a major pathogenetic feature, and represents a therapeutic target. TP53 disrupted patients are categorized as high risk patients and are treated with novel target therapies. Among these new drugs, venetoclax, an orally bioavailable BCL2 inhibitor, has shown high efficacy also in relapsed/refractory CLL with TP53 disruption. Venetoclax has also been tested in combination with other drugs without compromising venetoclax dose and with a good safety profile...
March 21, 2018: Expert Review of Hematology
https://www.readbyqxmd.com/read/29522758/c9orf72-is-essential-for-neurodevelopment-and-motility-mediated-by-cyclin-g1
#5
Tu-Hsueh Yeh, Han-Fang Liu, Yu-Wen Li, Chin-Song Lu, Hung-Yu Shih, Ching-Chi Chiu, Sheng-Jia Lin, Yin-Cheng Huang, Yi-Chuan Cheng
Hexanucleotide repeat expansions in the C9orf72 gene are a common genetic cause of familial and sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the function of C9orf72 in neural development and the pathogenic mechanism underlying neurodegeneration are unknown. We found that disrupting C9orf72 expression by using C9orf72 constructs that lack the complete DENN domain result in reduced GTPase activity in zebrafish embryos, demonstrating the indispensability of the complete DENN domain...
March 6, 2018: Experimental Neurology
https://www.readbyqxmd.com/read/29472722/chromothripsis-in-acute-myeloid-leukemia-biological-features-and-impact-on-survival
#6
Maria Chiara Fontana, Giovanni Marconi, Jelena D Milosevic Feenstra, Eugenio Fonzi, Cristina Papayannidis, Andrea Ghelli Luserna di Rorá, Antonella Padella, Vincenza Solli, Eugenia Franchini, Emanuela Ottaviani, Anna Ferrari, Carmen Baldazzi, Nicoletta Testoni, Ilaria Iacobucci, Simona Soverini, Torsten Haferlach, Viviana Guadagnuolo, Lukas Semerad, Michael Doubek, Michael Steurer, Zdenek Racil, Stefania Paolini, Marco Manfrini, Michele Cavo, Giorgia Simonetti, Robert Kralovics, Giovanni Martinelli
Chromothripsis is a one-step genome-shattering catastrophe resulting from disruption of one or few chromosomes in multiple fragments and consequent random rejoining and repair. This study defines incidence of chromothripsis in 395 newly diagnosed adult acute myeloid leukemia (AML) patients from three institutions, its impact on survival and its genomic background. SNP 6.0 or CytoscanHD Array (Affymetrix® ) were performed on all samples. We detected chromothripsis with a custom algorithm in 26/395 patients...
February 23, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29452455/complex-hur-function-in-pancreatic-cancer-cells
#7
REVIEW
Jonathan R Brody, Dan A Dixon
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with dismal patient outcomes. The underlying core genetic drivers of disease have been identified in human tumor specimens and described in genetically engineered mouse models. These genetic drivers of PDAC include KRAS signaling, TP53 mutations, and genetic loss of the SMAD4 tumor suppressor protein. Beyond the known mutational landscape of PDAC genomes, alternative disrupted targets that extend beyond conventional genetic mutations have been elusive and understudied in the context of PDAC cell therapeutic resistance and survival...
February 16, 2018: Wiley Interdisciplinary Reviews. RNA
https://www.readbyqxmd.com/read/29449315/metaplastic-breast-cancer-in-a-patient-with-neurofibromatosis-type-1-and-somatic-loss-of-heterozygosity
#8
Lorena Suarez-Kelly, Keiko Akagi, Julie W Reeser, Eric Samorodnitsky, Matthew Reeder, Amy Smith, Sameek Roychowdhury, David E Symer, William E Carson
Metaplastic breast carcinoma (MBC) is rare and has a poor prognosis. Here we describe genetic analysis of a 41-year-old female patient with MBC and neurofibromatosis type I (NF1). She initially presented with pT3N1a, grade 3 MBC, but lung metastases were discovered subsequently. To identify the molecular cause of her NF1, we screened for germline mutations disrupting NF1 or SPRED1, revealing a heterozygous germline single nucleotide variant (SNV) in exon 21 of NF1 at c.2709G>A, chr17: 29556342. By report, this variant disrupts pre-mRNA splicing of NF1 transcripts...
February 15, 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29448954/new-therapeutic-strategies-to-treat-human-cancers-expressing-mutant-p53-proteins
#9
REVIEW
Giovanni Blandino, Silvia Di Agostino
The tumor suppressor p53 plays a critical role to preserve DNA fidelity from diverse insults through the regulation of cell-cycle checkpoints, DNA repair, senescence and apoptosis. The TP53 is the most frequently inactivated gene in human cancers. This leads to the production of mutant p53 proteins that loose wild-type p53 tumor suppression functions and concomitantly acquire new oncogenic properties among which deregulated cell proliferation, increased chemoresistance, disruption of tissue architecture, promotion of migration, invasion and metastasis and several other pro-oncogenic activities...
February 15, 2018: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/29374752/photocarcinogenesis-and-skin-cancer-prevention-strategies-an-update
#10
REVIEW
Marie Christine Martens, Christina Seebode, Janin Lehmann, Steffen Emmert
UV radiation is acknowledged as the primary cause of photocarcinogenesis and therefore contributes to the development of skin cancer entities such as squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and melanoma. Typical DNA photoproducts and indirect DNA damage caused by reactive oxygen species are the result of UV radiation. UV-induced DNA damage is repaired by nucleotide excision repair, which consequently counteracts the development of mutations and skin carcinogenesis. Tumour-suppressor genes are inactivated by mutation and growth-promoting pathways are activated leading to disruption of cell-cycle progression...
February 2018: Anticancer Research
https://www.readbyqxmd.com/read/29325031/use-of-deep-whole-genome-sequencing-data-to-identify-structure-risk-variants-in-breast-cancer-susceptibility-genes
#11
Xingyi Guo, Jiajun Shi, Qiuyin Cai, Xiao-Ou Shu, Jing He, Wanqing Wen, Jamie Allen, Paul Pharoah, Alison Dunning, David J Hunter, Peter Kraft, Douglas F Easton, Wei Zheng, Jirong Long
Functional disruptions of susceptibility genes by large genomic structure variant (SV) deletions in germlines are known to be associated with cancer risk. However, few studies have been conducted to systematically search for SV deletions in breast cancer susceptibility genes. We analysed deep (> 30x) whole-genome sequencing (WGS) data generated in blood samples from 128 breast cancer patients of Asian and European descent with either a strong family history of breast cancer or early cancer onset disease...
March 1, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29280516/suppression-of-stat3-nh-2-terminal-domain-chemosensitizes-medulloblastoma-cells-by-activation-of-protein-inhibitor-of-activated-stat3-via-de-repression-by-microrna-21
#12
Sutapa Ray, Don W Coulter, Shawn D Gray, Jason A Sughroue, Shrabasti Roychoudhury, Erin M McIntyre, Nagendra K Chaturvedi, Kishor K Bhakat, Shantaram S Joshi, Timothy R McGuire, John G Sharp
Medulloblastoma (MB) is a malignant pediatric brain tumor with poor prognosis. Signal transducers and activators of transcription-3 (STAT3) is constitutively activated in MB where it functions as an oncoprotein, mediating cancer progression and metastasis. Here, we have delineated the functional role of activated STAT3 in MB, by using a cell permeable STAT3-NH2 terminal domain inhibitor (S3-NTDi) that specifically perturbs the structure/function of STAT3. We have implemented several biochemical experiments using human MB tumor microarray (TMA) and pediatric MB cell lines, derived from high-risk SHH-TP53-mutated and MYC-amplified Non-WNT/SHH tumors...
April 2018: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/29275106/clinical-significance-of-the-wild-type-p53-induced-phosphatase-1-expression-in-invasive-breast-cancer
#13
Yuka Inoue, Nami Yamashita, Hiroyuki Kitao, Kimihiro Tanaka, Hiroshi Saeki, Eiji Oki, Yoshinao Oda, Eriko Tokunaga, Yoshihiko Maehara
BACKGROUND: Wild type p53-induced phosphatase 1 (Wip1), encoded by the protein phosphatase magnesium dependent 1 delta (PPM1D), inhibits p53. PPM1D amplification has been reported in breast cancer. Breast cancer can sometimes develop without a tumor protein 53 (TP53) mutation. In these cases, the p53 pathway might be disrupted by alternative mechanisms, and Wip1 is reported to be a key molecule involved. MATERIALS AND METHODS: Primary invasive ductal carcinoma specimens were obtained from 201 cases, for which archival tissue samples for immunohistochemistry were available...
November 21, 2017: Clinical Breast Cancer
https://www.readbyqxmd.com/read/29249819/chromothripsis-in-acute-myeloid-leukemia-biological-features-and-impact-on-survival
#14
M C Fontana, G Marconi, J D M Feenstra, E Fonzi, C Papayannidis, A G L di Rorá, A Padella, V Solli, E Franchini, E Ottaviani, A Ferrari, C Baldazzi, N Testoni, I Iacobucci, S Soverini, T Haferlach, V Guadagnuolo, L Semerad, M Doubek, M Steurer, Z Racil, S Paolini, M Manfrini, M Cavo, G Simonetti, R Kralovics, G Martinelli
Chromothripsis is a one-step genome-shattering catastrophe resulting from disruption of one or few chromosomes in multiple fragments and consequent random rejoining and repair. This study define incidence of chromothripsis in 395 newly-diagnosed adult acute myeloid leukemia (AML) patients from three institutions, its impact on survival and its genomic background. SNP 6.0 or CytoscanHD Array (Affymetrix®) were performed on all samples. We detected chromothripsis with a custom algorithm in 26/395 patients. Patients harboring chromothripsis had higher age (P=0...
December 18, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29238899/induction-of-apoptosis-in-human-glioma-cell-lines-of-various-grades-through-the-ros-mediated-mitochondrial-pathway-and-caspase-activation-by-rhaponticum-carthamoides-transformed-root-extract
#15
Ewa Skała, Tomasz Kowalczyk, Monika Toma, Janusz Szemraj, Maciej Radek, Dariusz Pytel, Joanna Wieczfinska, Halina Wysokińska, Tomasz Śliwiński, Przemysław Sitarek
The present study is the first investigation of the inhibitory effect of Rhaponticum carthamoides transformed roots (TR) extract on the proliferation of grade II and III human glioma cells. TR extract showed the cytotoxic effect and inhibited the colony formation of both glioma cell lines in dose-dependent manner. The root extract induced apoptosis by increasing of the reactive oxygen species (about threefold compared to the control cells) leading to a disruption of mitochondrial membrane potential. Additionally, the mRNA levels of the apoptotic factors such as Bax, Tp53, caspase-3, and caspase-9 were observed to increase...
December 14, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/29228154/comparative-transcriptomic-analysis-of-human-placentae-at-term-and-preterm-delivery
#16
Alison G Paquette, Heather M Brockway, Nathan D Price, Louis J Muglia
Preterm birth affects 1 out of every 10 infants in the United States, resulting in substantial neonatal morbidity and mortality. Currently, there are few predictive markers and few treatment options to prevent preterm birth. A healthy, functioning placenta is essential to positive pregnancy outcomes. Previous studies have suggested that placental pathology may play a role in preterm birth etiology. Therefore, we tested the hypothesis that preterm placentae may exhibit unique transcriptomic signatures compared to term samples reflective of their abnormal biology leading to this adverse outcome...
January 1, 2018: Biology of Reproduction
https://www.readbyqxmd.com/read/29222275/the-mutational-landscape-of-chronic-lymphocytic-leukemia-and-its-impact-on-prognosis-and-treatment
#17
REVIEW
Gianluca Gaidano, Davide Rossi
The typical genome of chronic lymphocytic leukemia (CLL) carries ∼2000 molecular lesions. Few mutations recur across patients at a frequency >5%, whereas a large number of biologically and clinically uncharacterized genes are mutated at lower frequency. Approximately 80% of CLL patients carry at least 1 of 4 common chromosomal alterations, namely deletion 13q14, deletion 11q22-23, deletion 17p12, and trisomy 12. Knowledge of the CLL genome has translated into the availability of molecular biomarkers for prognosis and treatment prediction...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/29192272/ribosomal-stress-and-tp53-mediated-neuronal-apoptosis-in-response-to-capsid-protein-of-the-zika-virus
#18
Lukasz P Slomnicki, Dong-Hoon Chung, Austin Parker, Taylor Hermann, Nolan L Boyd, Michal Hetman
We report here that in rat and human neuroprogenitor cells as well as rat embryonic cortical neurons Zika virus (ZIKV) infection leads to ribosomal stress that is characterized by structural disruption of the nucleolus. The anti-nucleolar effects were most pronounced in postmitotic neurons. Moreover, in the latter system, nucleolar presence of ZIKV capsid protein (ZIKV-C) was associated with ribosomal stress and apoptosis. Deletion of 22 C-terminal residues of ZIKV-C prevented nucleolar localization, ribosomal stress and apoptosis...
November 30, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29143255/pcb-exposure-and-potential-future-cancer-incidence-in-slovak-children-an-assessment-from-molecular-finger-printing-by-ingenuity-pathway-analysis-ipa%C3%A2-derived-from-experimental-and-epidemiological-investigations
#19
Somiranjan Ghosh, Christopher A Loffredo, Partha S Mitra, Tomas Trnovec, Lubica Palkovicova Murinova, Eva Sovcikova, Eric P Hoffman, Kepher H Makambi, Sisir K Dutta
The risk of cancer due to PCB exposure in humans is highly debated. In eastern Slovakia, high exposure of the population to organochlorines (especially PCBs) was associated with various disease and disorder pathways, viz., endocrine disruption, metabolic disorder & diabetes, and cancer, thereby disturbing several cellular processes, including protein synthesis, stress response, and apoptosis. We have evaluated a Slovak cohort (45-month children, at lower and higher levels of PCB exposure from the environment) for disease and disorder development to develop early disease cancer biomarkers that could shed new light on possible mechanisms for the genesis of cancers under such chemical exposures, and identify potential avenues for prevention...
November 15, 2017: Environmental Science and Pollution Research International
https://www.readbyqxmd.com/read/29100379/gambogic-acid-inhibits-thioredoxin-activity-and-induces-ros-mediated-cell-death-in-castration-resistant-prostate-cancer
#20
Hong Pan, Keith H Jansson, Michael L Beshiri, JuanJuan Yin, Lei Fang, Supreet Agarwal, Holly Nguyen, Eva Corey, Ying Zhang, Jie Liu, HuiTing Fan, HongSheng Lin, Kathleen Kelly
Advanced prostate cancer (PrCa) is treated with androgen deprivation therapy, and although there is usually a significant initial response, recurrence arises as castrate resistant prostate cancer (CRPC). New approaches are needed to treat this genetically heterogeneous, phenotypically plastic disease. CRPC with combined homozygous alterations to PTEN and TP53 comprise about 30% of clinical samples. We screened eleven traditional Chinese medicines against a panel of androgen-independent Pten/Tp53 null PrCa-derived cell lines and identified gambogic acid (GA) as a highly potent growth inhibitor...
September 29, 2017: Oncotarget
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