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p53 cancer mutation

Kenya Kobayashi, Seiichi Yoshimoto, Fumihiko Matsumoto, Mizuo Ando, Naoya Murakami, Go Omura, Masahiko Fukasawa, Yoshifumi Matsumoto, Satoko Matsumura, Maki Akamatsu, Nobuyoshi Hiraoka, Ryo Eigitsu, Taisuke Mori
BACKGROUND: This study elucidates the clinical impact of surgical treatment of head and neck squamous cell carcinoma (HNSCC) based on a detailed search of all exons of the TP53 gene and p53 protein phenotypic analysis using formalin-fixed paraffin-embedded (FFPE) specimens. METHODS: Clinically well-annotated FFPE specimens from 317 patients with HNSCC treated by surgery were examined by all-exon TP53 sequencing using a next-generation sequencer and p53 protein phenotype by immunohistochemistry...
March 21, 2019: Annals of Surgical Oncology
Chiao-En Wu, Tsin Shue Koay, Yi-Hsuan Ho, Penny Lovat, John Lunec
Background: Emergence of resistance to molecular targeted therapy constitutes a limitation to clinical benefits in cancer treatment. Cross-resistance commonly happens with chemotherapeutic agents but might not with targeted agents. Methods: In the current study, TP53 wild-type cell lines with druggable MAPK pathway mutations [ BRAF V600E (WM35) or NRAS Q61K (SJSA-1)] were compared with their TP53 mutant sublines (WM35-R, SN40R2) derived by selection for resistance to MDM2/p53 binding antagonists...
2019: Cancer Cell International
Benoit Tessoulin, Geraldine Descamps, Christelle Dousset, Martine Amiot, Catherine Pellat-Deceunynck
Prima-1Met (APR-246) was previously shown to be dependent on glutathione inhibition and on ROS induction in cancer cells with mutated or deleted TP53 . Because this ROS induction was, at least in part, due to a direct interference with the thioredoxin reductase enzyme, we investigated whether activity of Prima-1Met could be mimicked by auranofin, an inhibitor of the thioredoxin reductase. We thus compared the activity of auranofin and Prima-1Met in 18 myeloma cell lines and in 10 samples from patients with multiple myeloma or plasma cell leukemia...
2019: Frontiers in Oncology
Hyeon Jeong Oh, Jeong Mo Bae, Xianyu Wen, Seorin Jung, Younghoon Kim, Kyung Ju Kim, Nam-Yun Cho, Jung Ho Kim, Sae-Won Han, Tae-You Kim, Gyeong Hoon Kang
BACKGROUND: We attempted to elucidate whether p53 expression or TP53 mutation status was associated with cancer-specific survival in adjuvant FOLFOX-treated patients with stage III or high-risk stage II colorectal cancer (CRC). METHODS: We analysed CRCs (N = 621) for the presence of TP53 alterations and for p53 expression, using targeted resequencing and immunohistochemistry. CRCs were grouped into four subsets according to the p53 expression status, which included p53-no, mild, moderate and strong expression...
March 21, 2019: British Journal of Cancer
Paula Kurtz, Amanda E Jones, Bhavana Tiwari, Nichole Link, Annika Wylie, Charles Tracy, Helmut Krämer, John M Abrams
TP53 is the most frequently mutated gene in human cancers, and despite intensive research efforts, genome-scale studies of p53 function in whole animal models are rare. The need for such in vivo studies is underscored by recent challenges to established paradigms, indicating that unappreciated p53 functions contribute to cancer prevention. Here we leveraged the Drosophila system to interrogate p53 function in a postmitotic context. In the developing embryo, p53 robustly activates important apoptotic genes in response to radiation-induced DNA damage...
March 20, 2019: Molecular Biology of the Cell
Sofi E Eriksson, Sophia Ceder, Vladimir J N Bykov, Klas G Wiman
The TP53 tumor suppressor gene encodes a DNA-binding transcription factor that regulates multiple cellular processes including cell growth and cell death. The ability of p53 to bind to DNA and activate transcription is tightly regulated by post-translational modifications and is dependent on a reducing cellular environment. Some p53 transcriptional target genes are involved in regulation of the cellular redox homeostasis, e.g. TIGAR and GLS2. A large fraction of human tumors carry TP53 mutations, most commonly missense mutations that lead to single amino acid substitutions in the core domain...
February 14, 2019: Journal of Molecular Cell Biology
Fuyan Hu, Yuxuan Zhou, Qing Wang, Zhiyuan Yang, Yu Shi, Qingjia Chi
As one of the most common malignancies in the world, lung adenocarcinoma (LUAD) is currently difficult to cure. However, the advent of precision medicine provides an opportunity to improve the treatment of lung cancer. Subtyping lung cancer plays an important role in performing a specific treatment. Here, we developed a framework that combines k-means clustering, t-test, sensitivity analysis, self-organizing map (SOM) neural network, and hierarchical clustering methods to classify LUAD into four subtypes. We determined that 24 differentially expressed genes could be used as therapeutic targets, and five genes (i...
March 18, 2019: IEEE/ACM Transactions on Computational Biology and Bioinformatics
Lev M Berstein, Aglaya G Iyevleva, Alexander O Ivantsov, Dmitry A Vasilyev, Tatyana E Poroshina, Igor V Berlev
AIM: To compare endocrine characteristics of  endometrial cancer (EC) patients based on recent molecular EC types classification. MATERIALS & METHODS:  A total of 234 treatment-naive EC patients as well their tumors were studied. RESULTS: Patients with POLE mutations demonstrated tendency to lower body mass index (BMI) and higher serum estradiol. Patients with p53 overexpression were older and had higher diabetes incidence. In the without characteristic molecular profile group there was no difference in fasting serum insulin, estradiol and testosterone levels between women with BMI ≥30...
March 19, 2019: Future Oncology
Saad Saffo, Tamar H Taddei
Hepatocellular carcinoma (HCC) arises from a number of cirrhosis-related and non-cirrhosis-related exposures and is one of the leading causes of cancer-related deaths worldwide. Achieving a durable cure currently relies on either resection or transplantation, but since most patients will be diagnosed with inoperable disease, there is great interest in achieving more effective systemic therapies. At a molecular level, HCC is heterogeneous, but initial treatment strategies, including the use of multi-targeted tyrosine kinase inhibitors and checkpoint inhibitors, have been fairly homogenous, depending on general host factors and overall tumor burden rather than specific molecular signatures...
March 18, 2019: Digestive Diseases and Sciences
Suyong Choi, Mo Chen, Vincent L Cryns, Richard A Anderson
The tumour suppressor p53 (encoded by TP53) protects the genome against cellular stress and is frequently mutated in cancer. Mutant p53 acquires gain-of-function oncogenic activities that are dependent on its enhanced stability. However, the mechanisms by which nuclear p53 is stabilized are poorly understood. Here, we demonstrate that the stability of stress-induced wild-type and mutant p53 is regulated by the type I phosphatidylinositol phosphate kinase (PIPKI-α (also known as PIP5K1A)) and its product phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2 )...
March 18, 2019: Nature Cell Biology
Emily A Quinn, Jamie L Maciaszek, Emilia M Pinto, Aaron H Phillips, David Berdy, Mohammad Khandwala, Santhosh A Upadhyaya, Gerard P Zambetti, Richard W Kriwacki, David W Ellison, Kim E Nichols, Chimene Kesserwan
Li-Fraumeni syndrome (LFS) is a highly penetrant cancer predisposition syndrome caused by heterozygous germline mutations in the TP53 gene. Although several missense and null TP53 mutations are well established as disease-causing, little is known about the pathogenicity and cancer risks associated with small in-frame deletions. This leads to challenges in variant classification and subsequent difficulty making a molecular diagnosis. We report the genetic testing process for a pediatric patient diagnosed with an undifferentiated high-grade brain tumor following his mother's diagnosis of early-onset bilateral breast cancer...
March 18, 2019: Cold Spring Harbor Molecular Case Studies
Tarun Karthik Kumar Mamidi, Jiande Wu, Chindo Hicks
BACKGROUND: Prostate cancer (PCa) is the most common diagnosed malignancy and the second leading cause of cancer-related deaths among men in the United States. High-throughput genotyping has enabled discovery of germline genetic susceptibility variants (herein referred to as germline mutations) associated with an increased risk of developing PCa. However, germline mutation information has not been leveraged and integrated with information on acquired somatic mutations to link genetic susceptibility to tumorigenesis...
March 14, 2019: BMC Cancer
Norman G Nicolson, Reju Korah, Tobias Carling
Adrenocortical carcinomas are rare tumors with poor prognosis and limited treatment options. Although widely used as in vitro models to test novel therapeutic strategies, the adrenocortical carcinoma-derived cell lines NCI-H295R and SW-13 have been only partially described genetically. Our aim was to characterize the mutational landscape of these cells to improve their experimental utility and map them to clinical sub-types of adrenocortical carcinoma. Genomic DNA from NCI-H295R and SW-13 cells was subjected to whole-exome sequencing...
March 1, 2019: Journal of Molecular Endocrinology
Dan Sun, Meng Yu, Yuanyuan Li, Haotian Xing, Ying Gao, Zhihong Huang, Wenjun Hao, Kaining Lu, Chuize Kong, Osamu Shimozato, Toshinori Ozaki, Yuyan Zhu
Tumor suppressor p53 is a short-lived nuclear transcription factor, which becomes stabilized and activated in response to a wide variety of cellular stresses. Around 50% of human cancer tissues carry p53 mutations, and certain p53 mutations contribute to chemoresistance. In the present study, we found that histone deacetylase 2 (HDAC2) acts as a co-activator of tumor suppressor p53 and participates in the early molecular events following DNA damage. Anti-cancer drug adriamycin (ADR) treatment induced cell death in p53 -wild-type human osteosarcoma U2OS cells, and this was accompanied by a remarkable accumulation of p53 and γH2AX...
March 2019: FEBS Open Bio
Di Jiang, James F Rusling
The chemistry of DNA and its repair selectivity control the influence of genomic oxidative stress on the development of serious disorders such as cancer and heart diseases. DNA is oxidized by endogenous reactive oxygen species (ROS) in vivo or in vitro as a result of high energy radiation, non-radiative metabolic processes, and other consequences of oxidative stress. Some oxidations of DNA and tumor suppressor gene p53 are thought to be mutagenic when not repaired. For example, site-specific oxidations of p53 tumor suppressor gene may lead to cancer-related mutations at the oxidation site codon...
March 2019: ChemistryOpen
Xiaofei Zhang, Zihao Qi, Huijing Yin, Gong Yang
The interplay between p53 and RAS signaling regulates cancer chemoresistance, but the detailed mechanism is unclear. In this study, we investigated the interactive effects of p53 and RAS on ovarian cancer cisplatin resistance to explore the potential therapeutic targets. Methods : An inducible p53 and RAS mutants active in either MAPK/ERK (S35 and E38) or PI3K/AKT (C40) or both (V12) were sequentially introduced into a p53-null ovarian cancer cell line-SKOV3. Comparative microarray analysis was performed using Gene Chip Prime View Human Gene Expression arrays (Affymetrix)...
2019: Theranostics
You-Cai Zhu, Xin-Gen Zhang, Xue-Ping Lin, Wen-Xian Wang, Xiao-Feng Li, Li-Xin Wu, Hua-Fei Chen, Chun-Wei Xu, Kai-Qi Du
C-ros oncogene 1 receptor tyrosine kinase ( ROS1 ) rearrangement forms a novel molecular subgroup of non-small cell lung cancer (NSCLC). The present study explored the clinicopathological features and clinical efficacy of crizotinib in patients with ROS1 -positive NSCLC. A retrospective analysis of 2,617 cases of NSCLC diagnosed between January 2013 and December 2016 was performed. ROS1 fusion genes were detected by reverse transcription-quantitative polymerase chain reaction, fluorescence in situ hybridization or next-generation sequencing techniques, and patients positive for the ROS1 fusion gene received oral treatment with crizotinib...
March 2019: Oncology Letters
Jiayi Zhao, Yiping Han, Jiamei Li, Rong Chai, Chong Bai
The present study explored the association between KRAS proto-oncogene GTPase (KRAS), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) and tumor protein p53 (TP53) mutations, and the clinical features and survival prognosis in 50 patients with non-small cell lung cancer (NSCLC). The most common concurrent single gene mutation was TP53, followed by KRAS and PIK3CA . Co-existing mutations were found in 17 patients. KRAS, PIK3CA and TP53 mutations were associated with carbohydrate antigen 19-9 expression, invasive growth, vacuolar signs and margin lobulation on chest CT...
March 2019: Oncology Letters
Changlong Liu, Carolyn E Banister, Phillip J Buckhaults
TP53 mutations are common in most human cancers, but few therapeutic options for TP53-mutant tumors exist. To identify potential therapeutic options for cancer patients with TP53 mutations, we profiled 127 FDA approved chemotherapy drugs against human embryonic stem cells (hESC) in which we engineered TP53 deletion by genome editing. We identified twenty-seven cancer therapeutic drugs for which TP53 mutations conferred resistance; most of these drugs target DNA synthesis or topoisomerase and cause DNA damage...
March 12, 2019: Cancer Research
Georg Richtig, Alena Maria Aigelsreiter, Martin Asslaber, Thomas Weiland, Martin Pichler, Katharina Eberhard, Stephan Sygulla, Silvia Schauer, Gerald Hoefler, Ariane Aigelsreiter
BACKGROUND: Since the hedgehog signaling pathway plays a major role in many types of cancer and can nowadays be targeted by specific compounds, we aimed to investigate the role of this pathway in squamous cell carcinoma of the head and neck. MATERIALS AND METHODS: Ninety-eight treatment naïve head and neck cancer specimens were immunohistologically stained for SMO, GLI-1, p53 and p16 expression and correlated with clinico-pathological factors. RESULTS: Immunoreactivity for SMO and GLI-1 was found in 20 (20...
March 12, 2019: Histopathology
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