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TP53 disruption

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https://www.readbyqxmd.com/read/28533818/a-novel-bcr-abl1-fusion-gene-with-genetic-heterogeneity-indicates-a-good-prognosis-in-a-chronic-myeloid-leukemia-case
#1
Fen Zhou, Runming Jin, Yu Hu, Heng Mei
BACKGROUND: Chronic myelogenous leukemia (CML) is a pluripotent hematopoietic stem cell disorder caused by the fusion of the BCR and ABL1 genes. Quantitative RT-PCR (qRT-PCR) is a routinely performed screening technique to identify BCR-ABL1 fusion genes, but a limitation of this method is its inability to recognize novel fusions that have not been previously characterized. Next-generation sequencing (NGS) is an effective and sensitive detection method for the determination of novel BCR-ABL1 fusion genes as well as previously characterized ones...
2017: Molecular Cytogenetics
https://www.readbyqxmd.com/read/28527674/analysis-of-full-coding-sequence-of-the-tp53-gene-in-invasive-vulvar-cancers-implications-for-therapy
#2
Karl Kashofer, Sigrid Regauer
OBJECTIVE: This study evaluates the frequency and type of TP53 gene mutations and HPV status in 72 consecutively diagnosed primary invasive vulvar squamous cell carcinomas (SCC) during the past 5years. METHODS: DNA of formalin-fixed and paraffin embedded tumour tissue was analysed for 32 HPV subtypes and the full coding sequence of the TP53 gene, and correlated with results of p53 immunohistochemistry. RESULTS: 13/72 (18%) cancers were HPV-induced squamous cell carcinomas, of which 1/13 (8%) carcinoma harboured a somatic TP53 mutation...
May 17, 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/28523248/the-keap1-nrf2-system-in-cancer
#3
REVIEW
Keiko Taguchi, Masayuki Yamamoto
Cancer cells first adapt to the microenvironment and then propagate. Mutations in tumor suppressor genes or oncogenes are frequently found in cancer cells. Comprehensive genomic analyses have identified somatic mutations and other alterations in the KEAP1 or NRF2 genes and in well-known tumor suppressor genes or oncogenes, such as TP53, CDKN2A, PTEN, and PIK3CA, in various types of cancer. Aberrant NRF2 activation in cancer cells occurs through somatic mutations in the KEAP1 or NRF2 gene as well as through other mechanisms that disrupt the binding of KEAP1 to NRF2...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28497579/modulation-of-basal-cell-fate-during-productive-and-transforming-hpv16-infection-is-mediated-by-progressive-e6-driven-depletion-of-notch
#4
Christian Kranjec, Christina Holleywood, Diane Libert, Heather Griffin, Radma Mahmood, Erin Isaacson, John Doorbar
In stratified epithelia such as the epidermis, homeostasis is maintained by the proliferation of cells in the lower epithelial layers, and the concomitant loss of differentiated cells from the epithelial surface. These differentiating keratinocytes progressively stratify, and form a self-regenerating multi-layered barrier that protects the underlying dermis. In such tissue, the continual loss and replacement of differentiated cells also limits the accumulation of oncogenic mutations within the tissue. Inactivating mutations in key driver genes, such as TP53 and NOTCH1, reduce the proportion of differentiating cells allowing for the long-term persistence of expanding mutant clones in the tissue...
May 12, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28482147/1-4-5-trisubstituted-imidazole-based-p53-mdm2-mdmx-antagonists-with-aliphatic-linkers-for-conjugation-with-biological-carriers
#5
Aleksandra Twarda-Clapa, Sylwia Krzanik, Katarzyna Kubica, Katarzyna Guzik, Beata Labuzek, Constantinos G Neochoritis, Kareem Khoury, Kaja Kowalska, Miroslawa Czub, Grzegorz Dubin, Alexander Dömling, Lukasz Skalniak, Tad A Holak
The tumor suppressor protein p53, the "guardian of the genome", is inactivated in nearly all cancer types by mutations in the TP53 gene or by overexpression of its negative regulators, oncoproteins MDM2/MDMX. Recovery of p53 function by disrupting the p53-MDM2/MDMX interaction using small-molecule antagonists could provide an efficient nongenotoxic anticancer therapy. Here we present the syntheses, activities, and crystal structures of the p53-MDM2/MDMX inhibitors based on the 1,4,5-trisubstituted imidazole scaffold which are appended with aliphatic linkers that enable coupling to bioactive carriers...
May 16, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28475293/synonymous-mutation-in-tp53-results-in-a-cryptic-splice-site-affecting-its-dna-binding-site-in-an-adolescent-with-two-primary-sarcomas
#6
Frances Austin, Usua Oyarbide, Gita Massey, Margaret Grimes, Seth J Corey
Pathologic variants in TP53 are known risk factors for the development of cancer. We report a 17-year-old male who presented with two primary sarcomas. Germline sequencing revealed a novel TP53 c.672 G>A mutation. Sequencing revealed wild-type TP53 in the parents, and there was no history of cancer in first-degree relatives. This de novo synonymous germline mutation results in a 5' cryptic splice site that is bound by U1, resulting in a shift of the splice site by 5 base pairs. The frame shift results in a truncated protein at residue 246, which disrupts the DNA-binding domain of p53...
May 5, 2017: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/28467829/whole-genome-landscapes-of-major-melanoma-subtypes
#7
Nicholas K Hayward, James S Wilmott, Nicola Waddell, Peter A Johansson, Matthew A Field, Katia Nones, Ann-Marie Patch, Hojabr Kakavand, Ludmil B Alexandrov, Hazel Burke, Valerie Jakrot, Stephen Kazakoff, Oliver Holmes, Conrad Leonard, Radhakrishnan Sabarinathan, Loris Mularoni, Scott Wood, Qinying Xu, Nick Waddell, Varsha Tembe, Gulietta M Pupo, Ricardo De Paoli-Iseppi, Ricardo E Vilain, Ping Shang, Loretta M S Lau, Rebecca A Dagg, Sarah-Jane Schramm, Antonia Pritchard, Ken Dutton-Regester, Felicity Newell, Anna Fitzgerald, Catherine A Shang, Sean M Grimmond, Hilda A Pickett, Jean Y Yang, Jonathan R Stretch, Andreas Behren, Richard F Kefford, Peter Hersey, Georgina V Long, Jonathan Cebon, Mark Shackleton, Andrew J Spillane, Robyn P M Saw, Núria López-Bigas, John V Pearson, John F Thompson, Richard A Scolyer, Graham J Mann
Melanoma of the skin is a common cancer only in Europeans, whereas it arises in internal body surfaces (mucosal sites) and on the hands and feet (acral sites) in people throughout the world. Here we report analysis of whole-genome sequences from cutaneous, acral and mucosal subtypes of melanoma. The heavily mutated landscape of coding and non-coding mutations in cutaneous melanoma resolved novel signatures of mutagenesis attributable to ultraviolet radiation. However, acral and mucosal melanomas were dominated by structural changes and mutation signatures of unknown aetiology, not previously identified in melanoma...
May 11, 2017: Nature
https://www.readbyqxmd.com/read/28435028/antagonistic-effects-of-p53-and-hif1a-on-microrna-34a-regulation-of-ppp1r11-and-stat3-and-hypoxia-induced-epithelial-to-mesenchymal-transition-in-colorectal-cancer-cells
#8
Huihui Li, Matjaz Rokavec, Longchang Jiang, David Horst, Heiko Hermeking
BACKGROUND & AIMS: In colorectal tumors, hypoxia causes resistance to therapy and promotes metastasis. Loss of the tumor suppressor p53 (encoded by TP53) provides cancer cells with a selective advantage under conditions of hypoxia, but little is known about the mediators of this effect. METHODS: Isogenic CRC cell lines with different TP53 genotypes were placed under conditions of hypoxia. We examined the effects on levels and activity of microRNA-34 a (MIR34A) in CRC cells...
April 20, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28427204/an-extensive-molecular-cytogenetic-characterization-in-high-risk-chronic-lymphocytic-leukemia-identifies-karyotype-aberrations-and-tp53-disruption-as-predictors-of-outcome-and-chemorefractoriness
#9
Gian Matteo Rigolin, Luca Formigaro, Maurizio Cavallari, Francesca Maria Quaglia, Enrico Lista, Antonio Urso, Emanuele Guardalben, Sara Martinelli, Elena Saccenti, Cristian Bassi, Laura Lupini, Maria Antonella Bardi, Eleonora Volta, Elisa Tammiso, Aurora Melandri, Massimo Negrini, Francesco Cavazzini, Antonio Cuneo
We investigated whether karyotype analysis and mutational screening by next generation sequencing could predict outcome in 101 newly diagnosed chronic lymphocytic leukemia patients with high-risk features, as defined by the presence of unmutated IGHV gene and/or 11q22/17p13 deletion by FISH and/or TP53 mutations. Cytogenetic analysis showed favorable findings (normal karyotype and isolated 13q14 deletion) in 30 patients, unfavorable (complex karyotype and/or 17p13/11q22 deletion) in 34 cases and intermediate (all other abnormalities) in 36 cases...
April 25, 2017: Oncotarget
https://www.readbyqxmd.com/read/28427187/rita-displays-anti-tumor-activity-in-medulloblastomas-independent-of-tp53-status
#10
Aline Gottlieb, Kristina Althoff, Laura Grunewald, Theresa Thor, Andrea Odersky, Marc Schulte, Hedwig E Deubzer, Lukas Heukamp, Angelika Eggert, Alexander Schramm, Johannes H Schulte, Annette Künkele
Current therapy of medulloblastoma, the most common malignant brain tumor of childhood, achieves 40-70% survival. Secondary chemotherapy resistance contributes to treatment failure, where TP53 pathway dysfunction plays a key role. MDM2 interaction with TP53 leads to its degradation. Reactivating TP53 functionality using small-molecule inhibitors, such as RITA, to disrupt TP53-MDM2 binding may have therapeutic potential. We show here that RITA decreased viability of all 4 analyzed medulloblastoma cell lines, regardless of TP53 functional status...
April 25, 2017: Oncotarget
https://www.readbyqxmd.com/read/28394340/selective-targeting-p53-wt-lung-cancer-cells-harboring-homozygous-p53-arg72-by-an-inhibitor-of-cypa
#11
W Lu, F Cheng, W Yan, X Li, X Yao, W Song, M Liu, X Shen, H Jiang, J Chen, J Li, J Huang
TP53 plays essential roles in tumor initiation and progression, and is frequently mutated in cancer. However, pharmacological stabilization and reactivation of p53 have not been actively explored for targeted cancer therapies. Herein, we identify a novel Cyclophilin A (CypA) small molecule inhibitor (HL001) that induces non-small cell lung cancer (NSCLC) cell cycle arrest and apoptosis via restoring p53 expression. We find that HL001 stabilizes p53 through inhibiting the MDM2-mediated p53 ubiquitination. Further mechanistic studies reveal that the downregulation of G3BP1 and the induction of reactive oxygen species and DNA damage by HL001 contribute to p53 stabilization...
April 10, 2017: Oncogene
https://www.readbyqxmd.com/read/28387325/hpv-negative-penile-squamous-cell-carcinoma-disruptive-mutations-in-the-tp53-gene-are-common
#12
Karl Kashofer, Elke Winter, Iris Halbwedl, Andrea Thueringer, Marisa Kreiner, Stefan Sauer, Sigrid Regauer
The majority of penile squamous cell carcinomas is caused by transforming human papilloma virus (HPV) infection. The etiology of HPV-negative cancers is unclear, but TP53 mutations have been implicated. Archival tissues of 108 invasive squamous cell carcinoma from a single pathology institution in a low-incidence area were analyzed for HPV-DNA and p16(ink4a) overexpression and for TP53 mutations by ion torrent next-generation sequencing. Library preparation failed in 32/108 squamous cell carcinomas. Institutional review board approval was obtained...
April 7, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/28238728/an-integrative-transcriptomic-analysis-reveals-bisphenol-a-exposure-induced-dysregulation-of-microrna-expression-in-human-endometrial-cells
#13
Wei-Chun Chou, Pei-Hsuan Lee, Yan-Yan Tan, Ho-Chen Lin, Chung-Wei Yang, Kuan-Hsueh Chen, Chun-Yu Chuang
Bisphenol A (BPA) are commonly used in the manufacture of polycarbonate plastics. Higher BPA exposure levels have been found in patients with endometrial hyperplasia that is one of risk factors of endometrial cancer (EC). Aberrant microRNAs (miRNAs) regulation has been observed in the development of cancer. Thus, this study investigated whether BPA exposure can disrupt miRNA regulation and its gene expression regarding to EC carcinogenic progress. Microarray experiments of miRNA and mRNA were performed in human endometrial cancer RL95-2 cells with treatment of low-to-moderate (10, 10(3) and 10(5)nM) BPA to explore the aberrant genes corresponding to human EC progression...
February 24, 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/28153010/targeting-muc1-c-inhibits-the-akt-s6k1-elf4a-pathway-regulating-tigar-translation-in-colorectal-cancer
#14
Rehan Ahmad, Maroof Alam, Masanori Hasegawa, Yasumitsu Uchida, Omar Al-Obaid, Surender Kharbanda, Donald Kufe
BACKGROUND: Colorectal cancer is third most common malignancy and is the second most common cause of cancer-related death. The MUC1 heterodimeric protein is aberrantly overexpressed in colorectal cancer and has been linked to poor outcomes in this disease. Here, we investigate the effects of the MUC1-C subunit inhibitor (GO-203), which disrupts MUC1-C homo-oligomerization, on human colorectal cancer cells. METHODS: TIGAR mRNA level was determined using qRT-PCR. Western blotting was used to measure TIGAR protein level and AKT-mTOR-S6K1 pathways...
February 2, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/28068922/functional-changes-in-mrna-expression-and-alternative-pre-mrna-splicing-associated-with-the-effects-of-nutrition-on-apoptosis-and-spermatogenesis-in-the-adult-testis
#15
Yongjuan Guan, Guanxiang Liang, Graeme B Martin, Le Luo Guan
BACKGROUND: The effects of nutrition on testis mass in the sexually mature male have long been known, however, the cellular and molecular processes of the testis response to nutrition was not fully understood. METHODS: We tested whether the defects in spermatogenesis and increases in germ cell apoptosis in the testis that are induced by under-nutrition are associated with changes in mRNA expression and pre-mRNA alternative splicing using groups of 8 male sheep fed for a 10% increase or 10% decrease in body mass over 65 days...
January 10, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28000777/bach1-promotes-temozolomide-resistance-in-glioblastoma-through-antagonizing-the-function-of-p53
#16
Er Nie, Xin Jin, Weining Wu, Tianfu Yu, Xu Zhou, Tongle Zhi, Zhumei Shi, Junxia Zhang, Ning Liu, Yongping You
The acquisition of drug resistance is a persistent clinical problem limiting the successful treatment of glioblastoma (GBM). However, the molecular mechanisms by which initially chemoresponsive tumors develop therapeutic resistance remain poorly understood. In this study, we report that BACH1, a heme-binding protein that participates in transcriptional repression or activation, was significantly upregulated in glioblastoma tissues. Overexpression of BACH1 in GBM cells conferred resistance to temozolomide, whereas its inhibition markedly sensitized resistant cells to temozolomide in vitro and in vivo...
December 21, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27959929/histological-transformation-and-progression-in-follicular-lymphoma-a-clonal-evolution-study
#17
Robert Kridel, Fong Chun Chan, Anja Mottok, Merrill Boyle, Pedro Farinha, King Tan, Barbara Meissner, Ali Bashashati, Andrew McPherson, Andrew Roth, Karey Shumansky, Damian Yap, Susana Ben-Neriah, Jamie Rosner, Maia A Smith, Cydney Nielsen, Eva Giné, Adele Telenius, Daisuke Ennishi, Andrew Mungall, Richard Moore, Ryan D Morin, Nathalie A Johnson, Laurie H Sehn, Thomas Tousseyn, Ahmet Dogan, Joseph M Connors, David W Scott, Christian Steidl, Marco A Marra, Randy D Gascoyne, Sohrab P Shah
BACKGROUND: Follicular lymphoma (FL) is an indolent, yet incurable B cell malignancy. A subset of patients experience an increased mortality rate driven by two distinct clinical end points: histological transformation and early progression after immunochemotherapy. The nature of tumor clonal dynamics leading to these clinical end points is poorly understood, and previously determined genetic alterations do not explain the majority of transformed cases or accurately predict early progressive disease...
December 2016: PLoS Medicine
https://www.readbyqxmd.com/read/27869650/inhibiting-mitochondrial-respiration-prevents-cancer-in-a-mouse-model-of-li-fraumeni-syndrome
#18
Ping-Yuan Wang, Jie Li, Farzana L Walcott, Ju-Gyeong Kang, Matthew F Starost, S Lalith Talagala, Jie Zhuang, Ji-Hoon Park, Rebecca D Huffstutler, Christina M Bryla, Phuong L Mai, Michael Pollak, Christina M Annunziata, Sharon A Savage, Antonio Tito Fojo, Paul M Hwang
Li-Fraumeni syndrome (LFS) is a cancer predisposition disorder caused by germline mutations in TP53 that can lead to increased mitochondrial metabolism in patients. However, the implications of altered mitochondrial function for tumorigenesis in LFS are unclear. Here, we have reported that genetic or pharmacologic disruption of mitochondrial respiration improves cancer-free survival in a mouse model of LFS that expresses mutant p53. Mechanistically, inhibition of mitochondrial function increased autophagy and decreased the aberrant proliferation signaling caused by mutant p53...
January 3, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27866339/recurrent-tp53-missense-mutation-in-cancer-patients-of-arab-descent
#19
Aviad Zick, Luna Kadouri, Sherri Cohen, Michael Frohlinger, Tamar Hamburger, Naama Zvi, Morasha Plaser, Eilat Avital, Shani Breuier, Firase Elian, Azzam Salah, Yael Goldberg, Tamar Peretz
Hereditary cancer comprises more than 10% of all breast cancer cases. Identification of germinal mutations enables the initiation of a preventive program that can include early detection or preventive treatment and may also have a major impact on cancer therapy. Several recurrent mutations were identified in the BRCA1/2 genes in Jewish populations however, in other ethnic groups in Israel, no recurrent mutations were identified to date. Our group established panel sequencing in cancer patients to identify recurrent, founder, and new mutations in the heterogeneous and diverse populations in Israel, We evaluated five breast cancer patients of Arab descent diagnosed with cancer before the age of 50 years and identified the previously described TP53 mutation, c...
April 2017: Familial Cancer
https://www.readbyqxmd.com/read/27821812/karyotypic-complexity-rather-than-chromosome-8-abnormalities-aggravates-the-outcome-of-chronic-lymphocytic-leukemia-patients-with-tp53-aberrations
#20
Gonzalo Blanco, Anna Puiggros, Panagiotis Baliakas, Anastasia Athanasiadou, MªDolores García-Malo, Rosa Collado, Aliki Xochelli, María Rodríguez-Rivera, Margarita Ortega, Mª José Calasanz, Elisa Luño, MªTeresa Vargas, Javier Grau, Carolina Martínez-Laperche, Alberto Valiente, José Cervera, Achilles Anagnostopoulos, Eva Gimeno, Eugènia Abella, Evangelia Stalika, Jesús Mª Hernández-Rivas, Francisco José Ortuño, Diego Robles, Ana Ferrer, David Ivars, Marcos González, Francesc Bosch, Pau Abrisqueta, Kostas Stamatopoulos, Blanca Espinet
Patients with chronic lymphocytic leukemia (CLL) harboring TP53 aberrations (TP53abs; chromosome 17p deletion and/or TP53 mutation) exhibit an unfavorable clinical outcome. Chromosome 8 abnormalities, namely losses of 8p (8p-) and gains of 8q (8q+) have been suggested to aggravate the outcome of patients with TP53abs. However, the reported series were small, thus hindering definitive conclusions. To gain insight into this issue, we assessed a series of 101 CLL patients harboring TP53 disruption. The frequency of 8p- and 8q+ was 14...
December 6, 2016: Oncotarget
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