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TP53 disruption

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https://www.readbyqxmd.com/read/29025288/-state-of-the-art-molecular-diagnostics-and-therapy-of-chronic-lymphocytic-leukaemia-in-the-era-of-new-targeted-therapies
#1
Tímea Gurbity Pálfi, Viktória Fésüs, Csaba Bödör, Zita Borbényi
Chronic lymphoid leukaemia (CLL) has a heterogeneous clinical course depending on many clinical and molecular prognostic markers, which play an important role in the selection of the best treatment option. So far, TP53 disruption is the key prognostic and predictive factor assisting treatment decisions, especially in the era of novel therapies. Asymptomatic patients in early stages of the disease will still benefit from watchful waiting. In the frontline setting, chemoimmunotherapy is still the standard care in the majority of standard risk CLL patients...
October 2017: Orvosi Hetilap
https://www.readbyqxmd.com/read/28994094/novel-prognostic-molecular-factors-a-quantum-leap-in-the-field-of-chronic-lymphocytic-leukemia
#2
Ewelina Zakrzewska, Marta Pirog, Joanna Purkot, Krzysztof Giannopoulos
Cytogenetic lesions do not completely explain clinical heterogeneity of chronic lymphocytic leukemia (CLL). The 2016 revision of the World Health Organization classification 2008 introduced that molecular lesions of TP53, NOTCH1, SF3B1 and BIRC3 have potential clinical relevance and could be integrated into an updated risk profile. The negative clinical implications of TP53 disruptions are well constituted and patients with these mutations should be considered for novel, small molecule signal transduction inhibitors therapies...
October 10, 2017: Folia Histochemica et Cytobiologica
https://www.readbyqxmd.com/read/28973975/identification-of-linkages-between-edcs-in-personal-care-products-and-breast-cancer-through-data-integration-combined-with-gene-network-analysis
#3
Hyeri Jeong, Jongwoon Kim, Youngjun Kim
Approximately 1000 chemicals have been reported to possibly have endocrine disrupting effects, some of which are used in consumer products, such as personal care products (PCPs) and cosmetics. We conducted data integration combined with gene network analysis to: (i) identify causal molecular mechanisms between endocrine disrupting chemicals (EDCs) used in PCPs and breast cancer; and (ii) screen candidate EDCs associated with breast cancer. Among EDCs used in PCPs, four EDCs having correlation with breast cancer were selected, and we curated 27 common interacting genes between those EDCs and breast cancer to perform the gene network analysis...
September 30, 2017: International Journal of Environmental Research and Public Health
https://www.readbyqxmd.com/read/28911001/whole-exome-analysis-of-a-li-fraumeni-family-trio-with-a-novel-tp53-prd-mutation-and-anticipation-profile
#4
Sara Franceschi, Laura Spugnesi, Paolo Aretini, Francesca Lessi, Rosa Scarpitta, Alvaro Galli, Caterina Congregati, Maria Adelaide Caligo, Chiara Maria Mazzanti
Li-Fraumeni syndrome is a clinically heterogeneous familial cancer predisposition syndrome with autosomal-dominant inheritance caused by heterozygous germline mutations in the TP53 gene. We here analyze the genetic background of a family with a 4-year-proband presented with a Li-Fraumeni tumor. The mother developed breast cancer at age 37 and the proband died at age 8. We performed Sanger sequencing and whole-exome sequencing on peripheral blood DNA from proband and relatives. Data analysis selected only high-quality score and depth reads, rare variants and protein impact involving missense, non-sense, frameshift and splice disrupt mutations...
September 1, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/28814964/milk-disrupts-p53-and-dnmt1-the-guardians-of-the-genome-implications-for-acne-vulgaris-and-prostate-cancer
#5
Bodo C Melnik
There is accumulating evidence that milk shapes the postnatal metabolic environment of the newborn infant. Based on translational research, this perspective article provides a novel mechanistic link between milk intake and milk miRNA-regulated gene expression of the transcription factor p53 and DNA methyltransferase 1 (DNMT1), two guardians of the human genome, that control transcriptional activity, cell survival, and apoptosis. Major miRNAs of milk, especially miRNA-125b, directly target TP53 and complex p53-dependent gene regulatory networks...
2017: Nutrition & Metabolism
https://www.readbyqxmd.com/read/28790111/amiloride-an-old-diuretic-drug-is-a-potential-therapeutic-agent-for-multiple-myeloma
#6
Elizabeta Rojas, Luis Corchete, Laura San Segundo, Juan F Martínez-Blanch, Francisco M Codoñer, Teresa Paíno, Noemi Puig, Ramón García-Sanz, Maria Victoria Mateos, Enrique M Ocio, Irena Misiewicz-Krzeminska, Norma C Gutiérrez
PURPOSE: The search for new drugs that control the continuous relapses of multiple myeloma is still required. Here, we report for the first time the potent anti-myeloma activity of amiloride, an old potassium-sparing diuretic approved for the treatment of hypertension and edema due to heart failure. EXPERIMENTAL DESIGN:  Myeloma cell lines and primary samples were used to evaluate cytotoxicity of amiloride. In vivo studies were carried out in a xenograft mouse model...
August 8, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28776759/melatonin-ameliorates-hypoglycemic-stress-induced-brain-endothelial-tight-junction-injury-by-inhibiting-protein-nitration-of-tp53-induced-glycolysis-and-apoptosis-regulator
#7
Cheng-Kun Wang, Muhammad Masood Ahmed, Quan Jiang, Nan-Nan Lu, Chao Tan, Yin-Ping Gao, Qaisar Mahmood, Dan-Yang Chen, Kohji Fukunaga, Mei Li, Zhong Chen, Christopher S Wilcox, Ying-Mei Lu, Zheng-Hong Qin, Feng Han
Severe hypoglycemia has a detrimental impact on the cerebrovasculature, but the molecular events that lead to the disruption of the integrity of the tight junctions remain unclear. Here, we report that the microvessel integrity was dramatically compromised (59.41% of wild-type mice) in TP53-induced glycolysis and apoptosis regulator (TIGAR) transgenic mice stressed by hypoglycemia. Melatonin, a potent antioxidant, protects against hypoglycemic stress-induced brain endothelial tight junction injury in the dosage of 400 nmol/L in vitro...
August 4, 2017: Journal of Pineal Research
https://www.readbyqxmd.com/read/28760909/-span-style-font-weight-400-circulating-tumor-dna-reveals-clinically-actionable-somatic-genome-of-metastatic-bladder-cancer-span
#8
Gillian R Vandekerkhove, Tilman Todenhöfer, Matti Annala, Werner J Struss, Amanda Wong, Kevin Beja, Elie Ritch, Sonal Brahmbhatt, Stas Volik, Jörg Hennenlotter, Matti Nykter, Kim N Chi, Scott North, Arnulf Stenzl, Colin C Collins, Bernhard J Eigl, Peter C Black, Alexander W Wyatt
Targeted agents and immunotherapies promise to transform the treatment of metastatic bladder cancer (BCa), but therapy selection will depend on practical tumor molecular stratification. Circulating tumor DNA (ctDNA) is established in several solid malignancies as a minimally-invasive tool to profile the tumor genome in real-time, but is critically under-explored in BCa. <p>Experimental Design: We applied a combination of whole exome sequencing and targeted sequencing across 50 BCa driver genes to plasma cell-free DNA (cfDNA) from 51 patients with aggressive BCa, including 37 with metastatic disease...
July 31, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28718729/the-novel-autophagy-inhibitor-elaiophylin-exerts-antitumor-activity-against-multiple-myeloma-with-mutant-tp53-in-part-through-endoplasmic-reticulum-stress-induced-apoptosis
#9
Gaoxiang Wang, Pan Zhou, Xing Chen, Lei Zhao, Jiaqi Tan, Yang Yang, Yong Fang, Jianfeng Zhou
Elaiophylin is a natural compound and a novel and potent inhibitor of late stage autophagy with outstanding antitumor activity in human ovarian cancer cells. However, the possible biologic effects and functional linkage between elaiophylin and multiple myeloma (MM) have not been explored. This study aimed to assess the effect of elaiophylin on MM cells with mutant TP53 and the possible molecular mechanism. The results suggested that elaiophylin exerted anti-myeloma activity by inducing apoptosis and proliferation arrest...
July 18, 2017: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/28664506/prevalence-and-spectrum-of-germline-rare-variants-in-brca1-2-and-palb2-among-breast-cancer-cases-in-sarawak-malaysia
#10
Xiaohong R Yang, Beena C R Devi, Hyuna Sung, Jennifer Guida, Eliseos J Mucaki, Yanzi Xiao, Ana Best, Lisa Garland, Yi Xie, Nan Hu, Maria Rodriguez-Herrera, Chaoyu Wang, Kristine Jones, Wen Luo, Belynda Hicks, Tieng Swee Tang, Karobi Moitra, Peter K Rogan, Michael Dean
PURPOSE: To characterize the spectrum of germline mutations in BRCA1, BRCA2, and PALB2 in population-based unselected breast cancer cases in an Asian population. METHODS: Germline DNA from 467 breast cancer patients in Sarawak General Hospital, Malaysia, where 93% of the breast cancer patients in Sarawak are treated, was sequenced for the entire coding region of BRCA1; BRCA2; PALB2; Exons 6, 7, and 8 of TP53; and Exons 7 and 8 of PTEN. Pathogenic variants included known pathogenic variants in ClinVar, loss of function variants, and variants that disrupt splice site...
June 29, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/28620865/involvement-of-atm-and-trp53-in-neural-cell-loss-due-to-terf2-inactivation-during-mouse-brain-development
#11
Jusik Kim, Inseo Choi, Youngsoo Lee
Maintenance of genomic integrity is one of the critical features for proper neurodevelopment and inhibition of neurological diseases. The signals from both ATM and ATR to TP53 are well-known mechanisms to remove neural cells with DNA damage during neurogenesis. Here we examined the involvement of Atm and Atr in genomic instability due to Terf2 inactivation during mouse brain development. Selective inactivation of Terf2 in neural progenitors induced apoptosis, resulting in a complete loss of the brain structure...
June 15, 2017: Histochemistry and Cell Biology
https://www.readbyqxmd.com/read/28537240/-point-mutations-in-the-dna-binding-domain-of-p53-contribute-to-glioma-progression-and-poor-prognosis
#12
P P Sarma, D Dutta, Z Mirza, K Kr Saikia, B Kr Baishya
TP53 mutations play a significant role in glioma tumorigenesis. When located in in the DNA binding domain, these mutations can perturb p53 protein conformation and its function, often culminating in altered downstream signaling. Here we describe prevalent pattern of TP53 point mutations in a cohort of 40 glioma patients and show their relevance to gliomagenesis. Point mutations in exon 5-9 of TP53 gene were detected by DNA sequencing. Possible influence of identified mutations at the function of p53 was studied computationally and correlated with the survival...
March 2017: Molekuliarnaia Biologiia
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
#13
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
#14
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...
August 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/28523248/the-keap1-nrf2-system-in-cancer
#15
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-hpv-16-infection-is-mediated-by-progressive-e6-driven-depletion-of-notch
#16
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...
August 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
#17
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 25, 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
#18
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...
November 2017: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/28467829/whole-genome-landscapes-of-major-melanoma-subtypes
#19
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
#20
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 colorectal cancer (CRC) cell lines with different TP53 genotypes were placed under conditions of hypoxia. We examined the effects on levels and activity of microRNA-34a (MIR34A) in CRC cells...
August 2017: Gastroenterology
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