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TP53 mutation

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https://www.readbyqxmd.com/read/29904909/inactivation-of-tp53-and-pten-drives-rapid-development-of-pleural-and-peritoneal-malignant-mesotheliomas
#1
Eleonora Sementino, Craig W Menges, Yuwaraj Kadariya, Suraj Peri, Jinfei Xu, Zemin Liu, Richard G Wilkes, Kathy Q Cai, Frank J Rauscher, Andres J Klein-Szanto, Joseph R Testa
Malignant mesothelioma (MM) is a therapy-resistant cancer arising primarily from the lining of the pleural and peritoneal cavities. The most frequently altered genes in human MM are cyclin-dependent kinase inhibitor 2A (CDKN2A), which encodes components of the p53 (p14ARF) and RB (p16INK4A) pathways, BRCA1-associated protein 1 (BAP1), and neurofibromatosis 2 (NF2). Furthermore, the p53 gene (TP53) itself is mutated in ~15% of MMs. In many MMs, the PI3K-PTEN-AKT-mTOR signaling node is hyperactivated, which contributes to tumor cell survival and therapeutic resistance...
June 15, 2018: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29902286/association-of-somatic-driver-alterations-with-prognosis-in-postmenopausal-hormone-receptor-positive-her2-negative-early-breast-cancer-a-secondary-analysis-of-the-big-1-98-randomized-clinical-trial
#2
Stephen J Luen, Rebecca Asher, Chee Khoon Lee, Peter Savas, Roswitha Kammler, Patrizia Dell'Orto, Olivia Maria Biasi, David Demanse, Lellean JeBailey, Sinead Dolan, Wolfgang Hackl, Beat Thuerlimann, Giuseppe Viale, Marco Colleoni, Meredith M Regan, Sherene Loi
Importance: A range of somatic driver alterations has been described in estrogen receptor-positive, HER2-negative (ER+/HER2-) early breast cancer (BC); however, the clinical relevance is unknown. Objective: To investigate associations of driver alterations with prognosis and the role of PIK3CA mutations in prediction of benefit associated with endocrine therapy in postmenopausal patients with ER+/HER2- early BC treated with tamoxifen or letrozole. Design, Setting, and Participants: The Breast International Group (BIG) 1-98 trial randomized 8010 postmenopausal patients with hormone receptor-positive, operable, invasive BC to monotherapy with letrozole, tamoxifen, or a sequential strategy for 5 years...
June 14, 2018: JAMA Oncology
https://www.readbyqxmd.com/read/29901519/evidence-of-a-monoclonal-origin-for-bilateral-serous-tubal-intraepithelial-neoplasia
#3
Emily E Meserve, Kyle C Strickland, Alexander Miron, Thing R Soong, Frank Campbell, Brooke E Howitt, Christopher P Crum
Serous tubal intraepithelial carcinoma (STIC) is found in 10% to 60% of cases of tuboovarian high-grade serous carcinoma (HGSC) and is presumed to be the site of origin, linking many HGSCs to the fallopian tube. Bilateral STIC is present in ∼20% of cases. Because clonal Tp53 mutations are a defining feature of HGSC, including their associated STICs, we analyzed 4 cases of bilateral serous tubal intraepithelial neoplasia (STIN), including STIC and Tp53-mutated serous tubal intraepithelial lesions (STILs), associated with HGSC to determine whether they contained the same or different p53 mutations...
June 12, 2018: International Journal of Gynecological Pathology
https://www.readbyqxmd.com/read/29901149/diagnostic-value-and-lymph-node-metastasis-prediction-of-a-custom%C3%A2-made-panel-thyroline-in-thyroid-cancer
#4
Zunfu Ke, Yihao Liu, Yunjian Zhang, Jie Li, Ming Kuang, Sui Peng, Jinyu Liang, Shuang Yu, Lei Su, Lili Chen, Cong Sun, Bin Li, Jessica Cao, Weiming Lv, Haipeng Xiao
Differentiation of benign and malignant thyroid nodules is crucial for clinical management. Here, we explored the efficacy of next‑generation sequencing (NGS) in predicting the classification of benign and malignant thyroid nodules and lymph node metastasis status, and simultaneously compared the results with ultrasound (US). Thyroline was designed to detect 15 target gene mutations and 2 fusions in 98 formalin‑fixed, paraffin‑embedded (FFPE) tissues, including those from 82 thyroid cancer (TC) patients and 16 patients with benign nodules...
June 14, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29900037/nanocomplex-based-tp53-gene-therapy-promotes-anti-tumor-immunity-through-tp53-and-sting-dependent-mechanisms
#5
Ellen C Moore, Lillian Sun, Paul E Clavijo, Jay Friedman, Joe B Harford, Anthony D Saleh, Carter Van Waes, Esther H Chang, Clint T Allen
Loss or mutation of TP53 has been linked to alterations in anti-tumor immunity as well as dysregulation of cell cycle and apoptosis. We explored immunologic effects and mechanisms following restoration of wild-type human TP53 cDNA in murine oral cancer cells using the therapeutic nanocomplex scL-53. We demonstrated scL-53 induces dose-dependent expression of TP53 and induction of apoptosis and immunogenic cell death. We further demonstrated both TP53-dependent and independent induction of tumor cell immunogenicity through the use of blocking mAbs, nanocomplex loaded with DNA plasmid with or without TP53 cDNA, empty nanocomplex and siRNA knockdown techniques...
2018: Oncoimmunology
https://www.readbyqxmd.com/read/29899852/concomitant-driver-mutations-in-advanced-egfr-mutated-non-small-cell-lung-cancer-and-their-impact-on-erlotinib-treatment
#6
Jan Nyrop Jakobsen, Eric Santoni-Rugiu, Morten Grauslund, Linea Melchior, Jens Benn Sørensen
Background: Patients with EGFR -mutated non-small-cell lung cancer benefit from EGFR tyrosine kinase inhibitors (TKIs) like erlotinib. However, the efficacy may be impaired by driver mutations in other genes. Methods: Five hundred and fourteen consecutive patients with NSCLC of all stages were tested for EGFR -mutations by cobas® EGFR Mutation Test. Fluorescent in situ hybridization (FISH) for MET -amplification, immunohistochemistry (IHC) for MET- and ALK-expression, and Next Generation Sequencing (NGS) for concomitant driver mutations were performed on EGFR -mutated tumor samples from erlotinib-treated patients...
May 25, 2018: Oncotarget
https://www.readbyqxmd.com/read/29896680/ebv-in-t-nk-cell-tumorigenesis
#7
Hiroshi Kimura
Epstein-Barr virus (EBV), which is associated with B-cell proliferative disorders, also transforms T- or natural killer (NK)-lineage cells and has been connected with various T- or NK (T/NK)-cell malignancies, such as extranodal NK/T-cell lymphoma-nasal type and aggressive NK-cell leukemia. Chronic active EBV (CAEBV) disease , which occurs most often in children and young adults in East Asia, is an EBV-associated T-/NK-cell lymphoproliferative disease. Patients with CAEBV often progress to overt lymphoma or leukemia over a long-term clinical course...
2018: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29895933/molecular-profiles-and-tumor-mutational-burden-analysis-in-chinese-patients-with-gynecologic-cancers
#8
Min Wang, Wensheng Fan, Mingxia Ye, Chen Tian, Lili Zhao, Jianfei Wang, Wenbo Han, Wen Yang, Chenglei Gu, Mingxia Li, Zhe Zhang, Yongjun Wang, Henghui Zhang, Yuanguang Meng
The goal of this work was to investigate the tumor mutational burden (TMB) in Chinese patients with gynecologic cancer. In total, 117 patients with gynecologic cancers were included in this study. Both tumor DNA and paired blood cell genomic DNA were isolated from formalin-fixed paraffin-embedded (FFPE) specimens and blood samples, and next-generation sequencing was performed to identify somatic mutations. TP53, PTEN, ARID1A, and PIK3CA alterations were significantly different in various types of gynecologic cancers (p = 0...
June 12, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29895903/integrated-dna-rna-targeted-genomic-profiling-of-diffuse-large-b-cell-lymphoma-using-a-clinical-assay
#9
Andrew M Intlekofer, Erel Joffe, Connie L Batlevi, Patrick Hilden, Jie He, Venkatraman E Seshan, Andrew D Zelenetz, M Lia Palomba, Craig H Moskowitz, Carol Portlock, David J Straus, Ariela Noy, Steven M Horwitz, John F Gerecitano, Alison Moskowitz, Paul Hamlin, Matthew J Matasar, Anita Kumar, Marcel R van den Brink, Kristina M Knapp, Janine D Pichardo, Michelle K Nahas, Sally E Trabucco, Tariq Mughal, Amanda R Copeland, Elli Papaemmanuil, Mathai Moarii, Ross L Levine, Ahmet Dogan, Vincent A Miller, Anas Younes
We sought to define the genomic landscape of diffuse large B-cell lymphoma (DLBCL) by using formalin-fixed paraffin-embedded (FFPE) biopsy specimens. We used targeted sequencing of genes altered in hematologic malignancies, including DNA coding sequence for 405 genes, noncoding sequence for 31 genes, and RNA coding sequence for 265 genes (FoundationOne-Heme). Short variants, rearrangements, and copy number alterations were determined. We studied 198 samples (114 de novo, 58 previously treated, and 26 large-cell transformation from follicular lymphoma)...
June 12, 2018: Blood Cancer Journal
https://www.readbyqxmd.com/read/29895132/lymphoepithelioma-like-carcinoma-of-the-endometrium-case-report-of-a-rare-tumour-with-comprehensive-immunohistochemical-and-molecular-analysis
#10
Kristýna Němejcová, Nikola Hájková, Ivana Tichá, Michaela Bártů, Dagmar Dolínská, Vladimír Kalist, Pavel Dundr
We are reporting a case of endometrial lymphoepithelioma-like carcinoma (LELC) in a 63-year-old female. Microscopically, the tumor consisted of groups of tumor cells surrounded by dense lymphoplasmacytic infiltrate. Immunohistochemically, the tumour cells were positive for cytokeratins AE1/AE3, EMA, PAX8, p16, and estrogen receptors. Protein p53 showed an aberrant type of expression. Molecular genetic analysis revealed mutations in the TP53 and PIKP53CA genes. Based on our results, we believe that the tumor represents an unusual morphological variant of endometrial serous carcinoma...
2018: Polish Journal of Pathology: Official Journal of the Polish Society of Pathologists
https://www.readbyqxmd.com/read/29893337/a-correlation-of-immunohistochemical-expression-of-tp53-and-cdkn1a-in-oral-epithelial-dysplasia-and-oral-squamous-cell-carcinoma
#11
Jay Ashokkumar Pandya, Karen Boaz, Srikant Natarajan, Nidhi Manaktala, K P Nandita, Amitha J Lewis
Purpose: Oral epithelial dysplasia (OED) occurs on exposure of epithelial cells to carcinogens and genetic alteration. Once the reversible cell damage is surpassed, cells either undergo apoptosis or transform into malignancy, chiefly oral squamous cell carcinoma (OSCC). Progressive accumulation of genetic errors (including mutations in TP53 and CDKN1A) is associated with the initiation and progression of potentially malignant oral lesions toward frank malignancy. The present study attempted to correlate the immunohistochemical expression of CDKN1A and TP53 with increasing severity of OED along with increased aggressiveness of OSCC as reflected in the clinicopathologic variables...
April 2018: Journal of Cancer Research and Therapeutics
https://www.readbyqxmd.com/read/29892687/clonal-lineage-of-high-grade-serous-ovarian-cancer-in-a-patient-with-neurofibromatosis-type-1
#12
Eric J Norris, Wendell D Jones, Marius D Surleac, Andrei J Petrescu, Darla Destephanis, Qing Zhang, Issam Hamadeh, Jeffrey S Kneisl, Chad A Livasy, Ram N Ganapathi, David L Tait, Mahrukh K Ganapathi
Neurofibromatosis type 1 (NF1) is caused by mutations in the NF1 gene encoding neurofibromin, which negatively regulates Ras signaling. NF1 patients have an increased risk of developing early onset breast cancer, however, the association between NF1 and high grade serous ovarian cancer (HGSOC) is unclear. Since most NF1-related tumors exhibit early biallelic inactivation of NF1 , we evaluated the evolution of genetic alterations in HGSOC in an NF1 patient. Somatic variation analysis of whole exome sequencing of tumor samples from both ovaries and a peritoneal metastasis showed a clonal lineage originating from an ancestral clone within the left adnexa, which exhibited copy number (CN) loss of heterozygosity (LOH) in the region of chromosome 17 containing TP53, NF1 , and BRC A1 and mutation of the other TP53 allele...
February 2018: Gynecologic Oncology Reports
https://www.readbyqxmd.com/read/29892062/p53-inhibits-crispr-cas9-engineering-in-human-pluripotent-stem-cells
#13
Robert J Ihry, Kathleen A Worringer, Max R Salick, Elizabeth Frias, Daniel Ho, Kraig Theriault, Sravya Kommineni, Julie Chen, Marie Sondey, Chaoyang Ye, Ranjit Randhawa, Tripti Kulkarni, Zinger Yang, Gregory McAllister, Carsten Russ, John Reece-Hoyes, William Forrester, Gregory R Hoffman, Ricardo Dolmetsch, Ajamete Kaykas
CRISPR/Cas9 has revolutionized our ability to engineer genomes and conduct genome-wide screens in human cells1-3 . Whereas some cell types are amenable to genome engineering, genomes of human pluripotent stem cells (hPSCs) have been difficult to engineer, with reduced efficiencies relative to tumour cell lines or mouse embryonic stem cells3-13 . Here, using hPSC lines with stable integration of Cas9 or transient delivery of Cas9-ribonucleoproteins (RNPs), we achieved an average insertion or deletion (indel) efficiency greater than 80%...
June 11, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29888503/elevation-of-the-tp53-isoform-%C3%AE-133p53%C3%AE-in-glioblastomas-an-alternative-to-mutant-p53-in-promoting-tumour-development
#14
Marina Kazantseva, Ramona A Eiholzer, Sunali Mehta, Ahmad Taha, Sara Bowie, Imogen Roth, Jean Zhou, Sebastien M Joruiz, Janice A Royds, Noelyn A Hung, Tania L Slatter, Antony W Braithwaite
As tumour protein 53 (p53) isoforms have tumour promoting, migration and inflammatory properties, this study investigated whether p53 isoforms contributed to glioblastoma progression. The expression levels of full-length TP53α (TAp53α) and six TP53 isoforms were quantitated by RT-qPCR in 89 glioblastomas and correlated with TP53 mutation status, tumour-associated macrophage content and various immune cell markers. Elevated levels of Δ133p53β mRNA characterised glioblastomas with increased CD163-positive macrophages and wild-type TP53...
June 10, 2018: Journal of Pathology
https://www.readbyqxmd.com/read/29885407/tp53-mutations-in-peripheral-mature-t-and-nk-cell-lymphomas-a-whole-exome-sequencing-study-with-correlation-to-p53-expression
#15
Hui-Shan Huang, Chun-Kai Liao, Ting-Ting Liu, Huey-Ling You, Ming-Chung Wang, Wan-Ting Huang
Peripheral mature T and NK cell lymphomas consist of a heterogeneous group of neoplasms with cytogenetic and molecular diversities. TP53 mutation is involved in the events of tumorigenesis and present in a variety of cancer subtypes. However, TP53 mutation in peripheral mature T and NK cell lymphomas has not been extensively investigated. In this study, fifty-seven formalin-fixed paraffin-embedded samples were collected for whole-exome sequencing and immunohistochemical study. Ten cases had TP53 mutation variant allele frequency (VAF) of more than 5%, predominantly in intestinal T-cell lymphoma (60%), peripheral T-cell lymphoma, not otherwise specified (22...
June 6, 2018: Human Pathology
https://www.readbyqxmd.com/read/29885057/genetic-instability-and-recurrent-myc-amplification-in-alk-translocated-nsclc-a-central-role-of-tp53-mutations
#16
Christina Alidousty, Till Baar, Luciano G Martelotto, Carina Heydt, Svenja Wagener, Jana Fassunke, Nicolai Duerbaum, Andreas H Scheel, Sandra Frank, Barbara Holz, Elke Binot, Anna Kron, Sabine Merkelbach-Bruse, Michaela A Ihle, Jürgen Wolf, Reinhard Buettner, Anne Maria Schultheis
The anaplastic lymphoma kinase (ALK) rearrangement defines a distinct molecular subtype of non-small cell lung cancer (NSCLC). Despite the excellent initial efficacy of ALK inhibitors in patients with ALK+ lung cancer, resistance occurs almost inevitably. To date, there is no reliable biomarker allowing the identification of patients at higher risk of relapse. Here, we analysed a subset of 53 ALK+ tumours with and without TP53 mutation and ALK+ NSCLC cell lines by NanoString nCounter technology. We found that the co-occurrence of early TP53 mutations in ALK+ NSCLC can lead to chromosomal instability: 24% of TP53-mutated patients showed amplifications of known cancer genes such as MYC (14%), CCND1 (10%), TERT (5%), BIRC2 (5%), ORAOV1 (5%) and YAP1 (5%)...
June 9, 2018: Journal of Pathology
https://www.readbyqxmd.com/read/29884457/distinct-activities-of-glycolytic-enzymes-identify-chronic-lymphocytic-leukemia-patients-with-a-more-aggressive-course-and-resistance-to-chemo-immunotherapy
#17
Georg Gdynia, Tadeusz Robak, Jürgen Kopitz, Anette Heller, Svetlana Grekova, Katarina Duglova, Gloria Laukemper, Monika Heinzel-Gutenbrunner, Cornelius Gutenbrunner, Wilfried Roth, Anthony D Ho, Peter Schirmacher, Michael Schmitt, Peter Dreger, Leopold Sellner
A higher capacity to grow under hypoxic conditions can lead to a more aggressive behavior of tumor cells. Determining tumor activity under hypoxia may identify chronic lymphocytic leukemia (CLL) with aggressive clinical course and predict response to chemo-immunotherapy (CIT). A metabolic score was generated by determining pyruvate kinase and lactate dehydrogenase, key enzymes of glycolysis, ex vivo in primary CLL samples under normoxic and hypoxic conditions. This score was further correlated with clinical endpoints and response to CIT in 96 CLL patients...
June 5, 2018: EBioMedicine
https://www.readbyqxmd.com/read/29884406/integrated-genomic-characterization-of-oral-carcinomas-in-post-hematopoietic-stem-cell-transplantation-survivors
#18
Glenn J Hanna, Eric R Kofman, Muhammad Ali Shazib, Sook-Bin Woo, Brendan Reardon, Nathaniel S Treister, Robert I Haddad, Corey S Cutler, Joseph H Antin, Eliezer M Van Allen, Ravindra Uppaluri, Robert J Soiffer
OBJECTIVES: Secondary oral squamous cell carcinoma (OSCC) is a late complication in allogeneic hematopoietic stem cell transplantation (HSCT) patients, but little is known about long-term outcomes and prognostication. Additionally, molecular alterations and immunologic insights unique to this disease remain largely unexplored. METHODS: We present a cohort of 31 patients with post-HSCT OSCC and reported on clinicopathologic predictors of survival. Whole-exome sequencing was performed on 6 (19%) matched pairs of peripheral blood (post-conditioning, pre-HSCT) and tumor samples...
June 2018: Oral Oncology
https://www.readbyqxmd.com/read/29882679/ramp3-is-a-prognostic-indicator-of-liver-cancer-and-might-reduce-the-adverse-effect-of-tp53-mutation-on-survival
#19
Aiping Fang, Shijie Zhou, Xiaolan Su, Chuang Liu, Xiaoxin Chen, Yang Wan, Xiaohong Lei, Linshen Xie, Yiping Jia, Wenzhi Wang, Luo Yang, Xuejiao Song, Yuqin Yao
AIM: To assess the prognostic value of RAMP3 expression in terms of overall survival (OS) and recurrence-free survival (RFS) in hepatocellular carcinoma (HCC) patients. MATERIALS & METHODS: Immunochemistry staining was performed to detect RAMP3 expression. Data in the Cancer Genome Atlas-Liver Hepatocellular Cancer were used for secondary analysis. RESULTS: RAMP3 expression was significantly downregulated in HCC tissues than in normal liver tissues...
June 8, 2018: Future Oncology
https://www.readbyqxmd.com/read/29881993/primary-intracranial-spindle-cell-sarcoma-with-rhabdomyosarcoma-like-features-share-a-highly-distinct-methylation-profile-and-dicer1-mutations
#20
Christian Koelsche, Martin Mynarek, Daniel Schrimpf, Luca Bertero, Jonathan Serrano, Felix Sahm, David E Reuss, Yanghao Hou, Daniel Baumhoer, Christian Vokuhl, Uta Flucke, Iver Petersen, Wolfgang Brück, Stefan Rutkowski, Sandro Casavilca Zambrano, Juan Luis Garcia Leon, Rosdali Yesenia Diaz Coronado, Manfred Gessler, Oscar M Tirado, Jaume Mora, Javier Alonso, Xavier Garcia Del Muro, Manel Esteller, Dominik Sturm, Jonas Ecker, Till Milde, Stefan M Pfister, Andrey Korshunov, Matija Snuderl, Gunhild Mechtersheimer, Ulrich Schüller, David T W Jones, Andreas von Deimling
Patients with DICER1 predisposition syndrome have an increased risk to develop pleuropulmonary blastoma, cystic nephroma, embryonal rhabdomyosarcoma, and several other rare tumor entities. In this study, we identified 22 primary intracranial sarcomas, including 18 in pediatric patients, with a distinct methylation signature detected by array-based DNA-methylation profiling. In addition, two uterine rhabdomyosarcomas sharing identical features were identified. Gene panel sequencing of the 22 intracranial sarcomas revealed the almost unifying feature of DICER1 hotspot mutations (21/22; 95%) and a high frequency of co-occurring TP53 mutations (12/22; 55%)...
June 7, 2018: Acta Neuropathologica
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