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https://www.readbyqxmd.com/read/28324749/a-phase-i-study-of-sar405838-a-novel-human-double-minute-2-hdm2-antagonist-in-patients-with-solid-tumours
#1
Maja de Jonge, Vincent A de Weger, Mark A Dickson, Marlies Langenberg, Axel Le Cesne, Andrew J Wagner, Karl Hsu, Wei Zheng, Sandrine Macé, Gilles Tuffal, Koruth Thomas, Jan H M Schellens
PURPOSE: In tumours with wild-type TP53, the tumour-suppressive function of p53 is frequently inhibited by HDM2. This phase I, dose-escalating study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics and pharmacodynamics of SAR405838, an HDM2 inhibitor, in patients with advanced solid tumours (NCT01636479). METHODS: In dose escalation, patients with any locally advanced/metastatic solid tumour with TP53 mutation prevalence below 40%, or documented as TP53 wild-type, were eligible...
March 16, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28319526/anaplastic-variant-of-diffuse-large-b-cell-lymphoma-displays-intricate-genetic-alterations-and-distinct-biological-features
#2
Mingyang Li, Yixiong Liu, Yingmei Wang, Gang Chen, Qiongrong Chen, Hualiang Xiao, Fang Liu, Chubo Qi, Zhou Yu, Xia Li, Linni Fan, Ying Guo, Qingguo Yan, Shuangping Guo, Zhe Wang
Anaplastic diffuse large B-cell lymphoma (A-DLBCL) is a rare morphologic variant characterized by the presence of polygonal, bizarre-shaped tumor cells. However, the clinicopathologic and genetic features of this variant are largely unknown. In this study, we investigated 35 cases of A-DLBCL with regard to their clinical, pathologic, and genetic characteristics. The age of the patients ranged from 23 to 89 years (median age, 62 y) with a male to female ratio of 23:12. Twenty-two of 26 (85%) patients had Ann Arbor stage III or IV disease, and 17/26 (65%) patients had a high-intermediate or high International Prognostic Index score...
March 17, 2017: American Journal of Surgical Pathology
https://www.readbyqxmd.com/read/28315738/pulmonary-sarcomatoid-carcinomas-commonly-harbor-either-potentially-targetable-genomic-alterations-or-high-tumor-mutational-burden-as-observed-by-comprehensive-genomic-profiling
#3
Alexa B Schrock, Shuyu D Li, Garrett M Frampton, James Suh, Eduardo Braun, Ranee Mehra, Steven Buck, Jose A Bufill, Nir Peled, Nagla Abdel Karim, Cynthia Hsieh, Manuel Doria, James Knost, Rong Chen, Sai-Hong Ignatius Ou, Jeffrey S Ross, Philip J Stephens, Paul Fishkin, Vincent A Miller, Siraj M Ali, Balazs Halmos, Jane J Liu
BACKGROUND: Pulmonary sarcomatoid carcinoma (PSC) is a high-grade non-small cell lung carcinoma (NSCLC) characterized by poor prognosis and resistance to chemotherapy. Development of targeted therapeutic strategies for PSC has been hampered due to limited and inconsistent molecular characterization. METHODS: Hybrid-capture based comprehensive genomic profiling (CGP) was performed on DNA from 15,867 FFPE NSCLCs including 125 PSCs (0.8%). Tumor mutational burden (TMB) was calculated from 1...
March 15, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28306358/the-genetics-of-gastroesophageal-adenocarcinoma-and-the-use-of-circulating-cell-free-dna-for-disease-detection-and-monitoring
#4
Mark R Openshaw, Catherine J Richards, David S Guttery, Jacqueline A Shaw, Anne L Thomas
Gastroesophageal adenocarcinoma (GOA) is a frequently occurring cancer worldwide with a poor clinical outcome. Adenocarcinomas of the oesophagus and gastroesophageal junction have shown a recent increase in frequency, therefore there is need to increase our understanding of GOA in order to improve our ability to detect, monitor and treat the disease. Areas covered: The authors discuss the current classification of GOA in the context of recent changes in incidence. The authors also discuss developments in the understanding of disease biology and recent discoveries from whole genome and whole exome sequencing, and studies in immunotherapy...
March 17, 2017: Expert Review of Molecular Diagnostics
https://www.readbyqxmd.com/read/28304377/establishment-of-a-novel-cellular-model-for-myxofibrosarcoma-heterogeneity
#5
Birgit Lohberger, Nicole Stuendl, Andreas Leithner, Beate Rinner, Stefan Sauer, Karl Kashofer, Bernadette Liegl-Atzwanger
Human cancers frequently display substantial intra-tumoural heterogeneity in virtually all distinguishable phenotypic features, such as cellular morphology, gene expression, and metastatic potential. In order to investigate tumour heterogeneity in myxofibrosarcoma, we established a novel myxofibrosarcoma cell line with two well defined sub-clones named MUG-Myx2a and MUG-Myx2b. The parental tumour tissue and both MUG-Myx2 cell lines showed the same STR profile. The fact that MUG-Myx2a showed higher proliferation activity, faster migration and enhanced tumourigenicity was of particular interest...
March 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28304071/erratum-screening-for-germline-brca1-brca2-tp53-and-chek2-mutations-in-families-at-risk-for-hereditary-breast-cancer-identified-in-a-population-based-study-from-southern-brazil
#6
(no author information available yet)
[This corrects the article doi: 10.1590/1678-4685-GMB-2014-0363].
March 16, 2017: Genetics and Molecular Biology
https://www.readbyqxmd.com/read/28302680/genomic-and-epigenomic-heterogeneity-of-hepatocellular-carcinoma
#7
De-Chen Lin, Anand Mayakonda, Huy Q Dinh, Pinbo Huang, Lehang Lin, Xiaoping Liu, Ling-Wen Ding, Jie Wang, Benjamin Berman, Erwei Song, Dong Yin, H Phillip Koeffler
Understanding the intratumoral heterogeneity of hepatocellular carcinoma (HCC) is instructive for developing personalized therapy and identifying molecular biomarkers. Here we applied whole-exome sequencing to 69 samples from 11 patients to resolve the genetic architecture of subclonal diversification. Spatial genomic diversity was found in all 11 HCC cases, with 29% of driver mutations being heterogeneous, including TERT, ARID1A, NOTCH2, and STAG2. Similar with other cancer types, TP53 mutations were always shared between all tumor regions i...
February 20, 2017: Cancer Research
https://www.readbyqxmd.com/read/28301507/tp53-alterations-in-primary-and-secondary-s%C3%A3-zary-syndrome-a-diagnostic-tool-for-the-assessment-of-malignancy-in-patients-with-erythroderma
#8
Audrey Gros, Elodie Laharanne, Marie Vergier, Martina Prochazkova-Carlotti, Anne Pham-Ledard, Thomas Bandres, Sandrine Poglio, Sabine Berhouet, Béatrice Vergier, Jean-Philippe Vial, Edith Chevret, Marie Beylot-Barry, Jean-Philippe Merlio
Recent massive parallel sequencing data have evidenced the genetic diversity and complexity of Sézary syndrome mutational landscape with TP53 alterations being the most prevalent genetic abnormality. We analyzed a cohort of 35 patients with SS and a control group of 8 patients with chronic inflammatory dermatoses. TP53 status was analyzed at different clinical stages especially in 9 patients with a past-history of mycosis fungoides (MF), coined secondary SS. TP53 mutations were only detected in 10 patients with either primary or secondary SS (29%) corresponding to point mutations, small insertions and deletions which were unique in each case...
2017: PloS One
https://www.readbyqxmd.com/read/28297660/progesterone-prevents-high-grade-serous-ovarian-cancer-by-inducing-necroptosis-of-p53-defective-fallopian-tube-epithelial-cells
#9
Na-Yiyuan Wu, Hsuan-Shun Huang, Tung Hui Chao, Hsien Ming Chou, Chao Fang, Chong-Zhen Qin, Chueh-Yu Lin, Tang-Yuan Chu, Hong Hao Zhou
High-grade serous ovarian carcinoma (HGSOC) originates mainly from the fallopian tube (FT) epithelium and always carries early TP53 mutations. We previously reported that tumors initiate in the FT fimbria epithelium because of apoptotic failure and the expansion of cells with DNA double-strand breaks (DSB) caused by bathing of the FT epithelial cells in reactive oxygen species (ROSs) and hemoglobin-rich follicular fluid (FF) after ovulation. Because ovulation is frequent and HGSOC is rare, we hypothesized that luteal-phase progesterone (P4) could eliminate p53-defective FT cells...
March 14, 2017: Cell Reports
https://www.readbyqxmd.com/read/28297624/genomics-of-acute-myeloid-leukemia-diagnosis-and-pathways
#10
Lars Bullinger, Konstanze Döhner, Hartmut Döhner
In recent years, our understanding of the molecular pathogenesis of myeloid neoplasms, including acute myeloid leukemia (AML), has been greatly advanced by genomics discovery studies that use novel high-throughput sequencing techniques. AML, similar to most other cancers, is characterized by multiple somatically acquired mutations that affect genes of different functional categories, a complex clonal architecture, and disease evolution over time. Patterns of mutations seem to follow specific and temporally ordered trajectories...
March 20, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28296509/tp53-and-atm-mrna-expression-in-skin-and-skeletal-muscle-after-low-level-laser-exposure
#11
Luciana Guedes de Almeida, Luiz Philippe da Silva Sergio, Flavia de Paoli, Andre Luiz Mencalha, Adenilson de Souza da Fonseca
Low-level lasers are widespread in regenerative medicine, but the molecular mechanisms involved in their biological effects are not fully understood, particularly those on DNA stability. Therefore, this study aimed to investigate mRNA expression of genes related to DNA genomic stability in skin and skeletal muscle tissue from Wistar rats exposed to low-level red and infrared lasers. For this, TP53 (Tumor Protein 53) and ATM (Ataxia Telangiectasia Mutated gene) mRNA expressions were evaluated by real-time quantitative PCR (RT-qPCR) technique 24 hours after low-level red and infrared laser exposure...
February 16, 2017: Journal of Cosmetic and Laser Therapy: Official Publication of the European Society for Laser Dermatology
https://www.readbyqxmd.com/read/28293485/a-long-term-survivor-of-metastatic-pancreatic-adenocarcinoma-free-of-recurrence-12-years-after-treatment-of-oligometastatic-disease
#12
John M Stahl, Zenta Walther, Bryan W Chang, Howard S Hochster, Kimberly L Johung
Aggressive local therapy for patients with oligometastatic pancreatic ductal adenocarcinoma (PDAC) has traditionally not been pursued due to high rates of distant progression. We describe a 62-year-old male initially presenting with resectable PDAC who underwent the Whipple procedure but developed multiple liver metastases within two months of starting adjuvant gemcitabine. Oxaliplatin was added to the regimen and complete resolution of the liver lesions resulted. He remained disease-free for five years until re-staging revealed a small lung nodule...
February 2, 2017: Curēus
https://www.readbyqxmd.com/read/28292439/integrated-molecular-characterization-of-uterine-carcinosarcoma
#13
Andrew D Cherniack, Hui Shen, Vonn Walter, Chip Stewart, Bradley A Murray, Reanne Bowlby, Xin Hu, Shiyun Ling, Robert A Soslow, Russell R Broaddus, Rosemary E Zuna, Gordon Robertson, Peter W Laird, Raju Kucherlapati, Gordon B Mills, John N Weinstein, Jiashan Zhang, Rehan Akbani, Douglas A Levine
We performed genomic, epigenomic, transcriptomic, and proteomic characterizations of uterine carcinosarcomas (UCSs). Cohort samples had extensive copy-number alterations and highly recurrent somatic mutations. Frequent mutations were found in TP53, PTEN, PIK3CA, PPP2R1A, FBXW7, and KRAS, similar to endometrioid and serous uterine carcinomas. Transcriptome sequencing identified a strong epithelial-to-mesenchymal transition (EMT) gene signature in a subset of cases that was attributable to epigenetic alterations at microRNA promoters...
March 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28289221/gentamicin-b1-is-a-minor-gentamicin-component-with-major-nonsense-mutation-suppression-activity
#14
Alireza Baradaran-Heravi, Jürgen Niesser, Aruna D Balgi, Kunho Choi, Carla Zimmerman, Andrew P South, Hilary J Anderson, Natalie C Strynadka, Marcel B Bally, Michel Roberge
Nonsense mutations underlie about 10% of rare genetic disease cases. They introduce a premature termination codon (PTC) and prevent the formation of full-length protein. Pharmaceutical gentamicin, a mixture of several related aminoglycosides, is a frequently used antibiotic in humans that can induce PTC readthrough and suppress nonsense mutations at high concentrations. However, testing of gentamicin in clinical trials has shown that safe doses of this drug produce weak and variable readthrough activity that is insufficient for use as therapy...
March 13, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28288132/census-and-evaluation-of-p53-target-genes
#15
REVIEW
M Fischer
The tumor suppressor p53 functions primarily as a transcription factor. Mutation of the TP53 gene alters its response pathway, and is central to the development of many cancers. The discovery of a large number of p53 target genes, which confer p53's tumor suppressor function, has led to increasingly complex models of p53 function. Recent meta-analysis approaches, however, are simplifying our understanding of how p53 functions as a transcription factor. In the survey presented here, a total set of 3661 direct p53 target genes is identified that comprise 3509 potential targets from 13 high-throughput studies, and 346 target genes from individual gene analyses...
March 13, 2017: Oncogene
https://www.readbyqxmd.com/read/28285689/mutations-in-tp53-pik3ca-pten-and-other-genes-in-egfr-mutated-lung-cancers-correlation-with-clinical-outcomes
#16
Paul A VanderLaan, Deepa Rangachari, Susan M Mockus, Vanessa Spotlow, Honey V Reddi, Joan Malcolm, Mark S Huberman, Loren J Joseph, Susumu S Kobayashi, Daniel B Costa
INTRODUCTION: The degree and duration of response to epidermal growth factor receptor (EGFR) inhibitors in EGFR mutated lung cancer are heterogeneous. We hypothesized that the concurrent genomic landscape of these tumors, which is currently unknown in view of the prevailing single gene assay diagnostic paradigm in clinical practice, could play a role in clinical outcomes and/or mechanisms of resistance. METHODS: We retrospectively probed our institutional lung cancer database for tumors with EGFR kinase domain mutations that were also evaluated by more comprehensive molecular profiling, and evaluated tumor response to EGFR tyrosine kinase inhibitors (TKIs)...
April 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28284458/p53-dysregulation-in-b-cell-malignancies-more-than-a-single-gene-in-the-pathway-to-hell
#17
REVIEW
B Tessoulin, M Eveillard, A Lok, D Chiron, P Moreau, M Amiot, A Moreau-Aubry, S Le Gouill, C Pellat-Deceunynck
TP53 deletion or mutation is frequent in B-cell malignancies and is associated with a low response rate. We describe here the p53 landscape in B-cell malignancies, from B-Acute Lymphoblastic Leukemia to Plasma Cell Leukemia, by analyzing incidence of gain or loss of function of actors both upstream and within the p53 pathway, namely MYC, RAS, ARF, MDM2, ATM and TP53. Abnormalities are not equally distributed and their incidence is highly variable among malignancies. Deletion and mutation, usually associated, of ATM or TP53 are frequent in Diffuse Large B-Cell Lymphoma and Mantle Cell Lymphoma...
March 4, 2017: Blood Reviews
https://www.readbyqxmd.com/read/28281555/nf-%C3%AE%C2%BAb-p50-activation-associated-with-immune-dysregulation-confers-poorer-survival-for-diffuse-large-b-cell-lymphoma-patients-with-wild-type-p53
#18
Qingqing Cai, Meifeng Tu, Zijun Y Xu-Monette, Ruifang Sun, Ganiraju C Manyam, Xiaolu Xu, Alexander Tzankov, Eric D Hsi, Michael B Møller, L Jeffrey Medeiros, Chi Young Ok, Ken H Young
Dysregulated NF-κB signaling is critical for lymphomagenesis, however, the expression and clinical relevance of NF-κB subunit p50 in diffuse large B-cell lymphoma have not been evaluated. In this study, we analyzed the prognostic significance and gene expression signatures of p50 nuclear expression as a surrogate for p50 activation in 465 patients with de novo diffuse large B-cell lymphoma. We found that p50(+) nuclear expression, observed in 34.6% of diffuse large B-cell lymphoma, predominantly composed of activated B-cell-like subtype, was an independent adverse prognostic factor in patients with activated B-cell-like diffuse large B-cell lymphoma...
March 10, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/28281553/ctnnb1-beta-catenin-mutation-identifies-low-grade-early-stage-endometrial-cancer-patients-at-increased-risk-of-recurrence
#19
Katherine C Kurnit, Grace N Kim, Bryan M Fellman, Diana L Urbauer, Gordon B Mills, Wei Zhang, Russell R Broaddus
Although the majority of low grade, early stage endometrial cancer patients will have good survival outcomes with surgery alone, those patients who do recur tend to do poorly. Optimal identification of the subset of patients who are at high risk of recurrence and would benefit from adjuvant treatment has been difficult. The purpose of this study was to evaluate the impact of somatic tumor mutation on survival outcomes in this patient population. For this study, low grade was defined as endometrioid FIGO grades 1 or 2, while early stage was defined as endometrioid stages I or II (disease confined to the uterus)...
March 10, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/28280605/next-generation-sequencing-identifies-interactome-signatures-in-relapsed-and-refractory-metastatic-colorectal-cancer
#20
Benny Johnson, Laurence Cooke, Daruka Mahadevan
BACKGROUND: In the management of metastatic colorectal cancer (mCRC), KRAS, NRAS and BRAF mutational status individualizes therapeutic options and identify a cohort of patients (pts) with an aggressive clinical course. We hypothesized that relapsed and refractory mCRC pts develop unique mutational signatures that may guide therapy, predict for a response and highlight key signaling pathways important for clinical decision making. METHODS: Relapsed and refractory mCRC pts (N=32) were molecularly profiled utilizing commercially available next generation sequencing (NGS) platforms...
February 2017: Journal of Gastrointestinal Oncology
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