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TP53 disruption

Wensheng Zhang, Erik K Flemington, Kun Zhang
Most cancers are driven by somatic mutations in proto-oncogenes and tumor suppressor genes. Genetic changes in a tumor may accumulate in the tissue self-renewal phase prior to neoplasm. The risk of sporadic mutations increases with age. In this regard, a positive association between patient age and the accumulated mutation burden in tumors exists for many cancer types. However, the reported lines of evidence for such a connection are still limited. TP53 is the most frequently mutated cancer gene. The encoded p53 protein plays crucial roles in DNA repair...
September 2016: Cancer Genetics
Peter Broderick, Sara E Dobbins, Daniel Chubb, Ben Kinnersley, Malcolm G Dunlop, Ian Tomlinson, Richard S Houlston
High-throughput sequencing analysis has accelerated searches for genes associated with risk for colorectal cancer (CRC); germline mutations in NTHL1, RPS20, FANCM, FAN1, TP53, BUB1, BUB3, LRP6, and PTPN12 have been recently proposed to increase CRC risk. We attempted to validate the association between variants in these genes and development of CRC in a systematic review of 11 publications, using sequence data from 863 familial CRC cases and 1604 individuals without CRC (controls). All cases were diagnosed at an age of 55 years or younger and did not carry mutations in an established CRC predisposition gene...
October 3, 2016: Gastroenterology
Yannick Le Bris, Stéphanie Struski, Romain Guièze, Caroline Rouvellat, Naïs Prade, Xavier Troussard, Olivier Tournilhac, Marie C Béné, Eric Delabesse, Loïc Ysebaert
Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder of remarkable heterogeneity as demonstrated by cytogenetics and molecular analyses. Complex karyotype (CK), TP53 deletions and/or mutations (TP53 disruption), IGVH mutational status, and, more recently, recurrent somatic mutations have been identified as prognostic markers in CLL. On a cohort of 110 patients with CLL treated with first-line fludarabin, cyclophosphamide, and rituximab treatment compared with 33 untreated (watch and wait) patients with CLL, we report more frequent complex karyotypes (34 vs 15%; P = ...
September 28, 2016: Hematological Oncology
Gian Matteo Rigolin, Elena Saccenti, Cristian Bassi, Laura Lupini, Francesca Maria Quaglia, Maurizio Cavallari, Sara Martinelli, Luca Formigaro, Enrico Lista, Maria Antonella Bardi, Eleonora Volta, Elisa Tammiso, Aurora Melandri, Antonio Urso, Francesco Cavazzini, Massimo Negrini, Antonio Cuneo
BACKGROUND: In chronic lymphocytic leukemia (CLL), next-generation sequencing (NGS) analysis represents a sensitive, reproducible, and resource-efficient technique for routine screening of gene mutations. METHODS: We performed an extensive biologic characterization of newly diagnosed CLL, including NGS analysis of 20 genes frequently mutated in CLL and karyotype analysis to assess whether NGS and karyotype results could be of clinical relevance in the refinement of prognosis and assessment of risk of progression...
September 15, 2016: Journal of Hematology & Oncology
Xin Liu, Jason R Pitarresi, Maria C Cuitiño, Raleigh D Kladney, Sarah A Woelke, Gina M Sizemore, Sunayana G Nayak, Onur Egriboz, Patrick G Schweickert, Lianbo Yu, Stefan Trela, Daniel J Schilling, Shannon K Halloran, Maokun Li, Shourik Dutta, Soledad A Fernandez, Thomas J Rosol, Gregory B Lesinski, Reena Shakya, Thomas Ludwig, Stephen F Konieczny, Gustavo Leone, Jinghai Wu, Michael C Ostrowski
The contribution of the microenvironment to pancreatic acinar-to-ductal metaplasia (ADM), a preneoplastic transition in oncogenic Kras-driven pancreatic cancer progression, is currently unclear. Here we show that disruption of paracrine Hedgehog signaling via genetic ablation of Smoothened (Smo) in stromal fibroblasts in a Kras(G12D) mouse model increased ADM. Smo-deleted fibroblasts had higher expression of transforming growth factor-α (Tgfa) mRNA and secreted higher levels of TGFα, leading to activation of EGFR signaling in acinar cells and increased ADM...
September 1, 2016: Genes & Development
Walid Sabri Hamadou, Sawsen Besbes, Violaine Bourdon, Yosra Ben Youssef, Mohamed Adnène Laatiri, Testsuro Noguchi, Abderrahim Khélif, Hagay Sobol, Zohra Soua
Mutations are responsible for familial cancer syndromes which account for approximately 5-10 % of all types of cancers. Familial cancers are often caused by genetic alterations occurring either in tumor suppressor or genomic stability genes such as TP53. In this study, we have analyzed the TP53 gene by direct sequencing approach, in a panel of 18 Tunisian familial hematological malignancies cases including several forms of leukemia, lymphoma and myeloid syndrome and 22 cases of sporadic acute leukemia. In one familial case diagnosed with acute lymphoblastic leukemia, we reported an intronic substitution 559+1 G>A which may disrupt the splice site and impact the normal protein function...
September 12, 2016: Familial Cancer
A Hashimoto, S Hashimoto, H Sugino, A Yoshikawa, Y Onodera, H Handa, T Oikawa, H Sabe
Onset of the cancer mesenchymal program is closely associated with cancer malignancy and drug resistance. Among the different epithelial-mesenchymal transition (EMT)-associated transcriptional factors, ZEB1 has a key role in inducing the mesenchymal phenotypes and stem cell-like properties of different breast cancer cells. ARF6 and its effector AMAP1 are frequently overexpressed in breast cancer cells, and promote invasion, metastasis and drug resistance. EPB41L5 is induced during EMT, and mediates the disruption of E-cadherin-based cell-cell adhesion and the promotion of focal adhesion dynamics...
2016: Oncogenesis
Jana Zemanova, Ondrej Hylse, Jana Collakova, Pavel Vesely, Alexandra Oltova, Marek Borsky, Kristina Zaprazna, Marie Kasparkova, Pavlina Janovska, Jan Verner, Jiri Kohoutek, Marta Dzimkova, Vitezslav Bryja, Zuzana Jaskova, Yvona Brychtova, Kamil Paruch, Martin Trbusek
Treatment options for TP53-mutated lymphoid tumors are very limited. In experimental models, TP53-mutated lymphomas were sensitive to direct inhibition of checkpoint kinase 1 (Chk1), a pivotal regulator of replication. We initially tested the potential of the highly specific Chk1 inhibitor SCH900776 to synergize with nucleoside analogs (NAs) fludarabine, cytarabine and gemcitabine in cell lines derived from B-cell malignancies. In p53-proficient NALM-6 cells, SCH900776 added to NAs enhanced signaling towards Chk1 (pSer317/pSer345), effectively blocked Chk1 activation (Ser296 autophosphorylation), increased replication stress (p53 and γ-H2AX accumulation) and temporarily potentiated apoptosis...
August 19, 2016: Oncotarget
Nisar Amin, Sriram Balasubramanian, Kamlai Saiya-Cork, Kerby Shedden, Nan Hu, Sami Malek
PURPOSE: Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, is approved for the treatment of relapsed CLL and CLL with del17p. Mechanistically, ibrutinib interferes with BCR signaling as well as multiple CLL cell to microenvironment interactions. Given the importance of ibrutinib in the management of CLL, a deeper understanding of factors governing sensitivity and resistance is warranted. EXPERIMENTAL DESIGN: We studied 48 longitudinally sampled paired CLL samples, 42 of which were procured before and after standard CLL chemotherapies, and characterized them for well-studied CLL molecular traits as well as by whole exome sequencing and SNP 6...
August 17, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Mariia Patyka, Zeinab Sharifi, Kevin Petrecca, Jose Mansure, Bertrand Jean-Claude, Siham Sabri
Alterations of the TP53 tumor suppressor gene occur in ~30% of primary glioblastoma (GBM) with a high frequency of missense mutations associated with the acquisition of oncogenic "gain-of-function" (GOF) mutant (mut)p53 activities. PRIMA-1MET/APR-246, emerged as a promising compound to rescue wild-type (wt)p53 function in different cancer types. Previous studies suggested the role of wtp53 in the negative regulation of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT), a major determinant in resistance to therapy in GBM treatment...
August 11, 2016: Oncotarget
Romain Guièze, Mélanie Pages, Lauren Véronèse, Patricia Combes, Richard Lemal, Mathilde Gay-Bellile, Martine Chauvet, Mary Callanan, Fabrice Kwiatkowski, Bruno Pereira, Philippe Vago, Jacques-Olivier Bay, Olivier Tournilhac, Andreï Tchirkov
In chronic lymphocytic leukemia (CLL), telomere dysfunction is associated with poor outcomes. TP53 is involved in cellular responses to dysfunctional telomeres, and its inactivation is the strongest adverse prognostic factor for CLL. Given the biological relationship between TP53 and telomeres, and their prognostic value, it is important to improve our understanding of the impact of TP53 alterations on telomeres. We performed a comprehensive study of the deletions and mutations of the TP53 gene and telomere parameters, including hTERT and the shelterin complex, in 115 CLL patients...
July 29, 2016: Oncotarget
Genki Tanaka, Ken-Ichi Inoue, Takayuki Shimizu, Kazumi Akimoto, Keiichi Kubota
NRF2 stabilizes redox potential through genes for glutathione and thioredoxin antioxidant systems. Whether blockade of glutathione and thioredoxin is useful in eliminating cancer stem cells remain unknown. We used xenografts derived from colorectal carcinoma patients to investigate the pharmacological inhibition of glutathione and thioredoxin systems. Higher expression of five glutathione S-transferase isoforms (GSTA1, A2, M4, O2, and P1) was observed in xenograft-derived spheroids than in fibroblasts. Piperlongumine (2...
September 2016: Cancer Medicine
Makhdum Ahmed, Leo Zhang, Krystle Nomie, Laura Lam, Michael Wang
Mutations and epigenetic alterations are key events in transforming normal cells to cancer cells. Mantle cell lymphoma (MCL), a non-Hodgkin's lymphoma of the B-cell, is an aggressive malignancy with poor prognosis especially for those patients who are resistant to the frontline drugs. There is a great need to describe the molecular basis and mechanism of drug resistance in MCL to develop new strategies for treatment. We reviewed frequent somatic mutations and mutations involving the B-cell pathways in MCL and discussed clinical trials that attempted to disrupt these gene pathways and/or epigenetic events...
July 19, 2016: Oncotarget
Nina Lapke, Yen-Jung Lu, Chun-Ta Liao, Li-Yu Lee, Chien-Yu Lin, Hung-Ming Wang, Shu-Hang Ng, Shu-Jen Chen, Tzu-Chen Yen
TP53 mutations have been linked to reduced survival in patients with oral cavity squamous cell carcinoma (OSCC). However, the impact of different types of TP53 mutations remains unclear. Here, we demonstrate that the carriage of missense mutations in the TP53 DNA binding domain (DBD missense mutations) is associated with decreased disease-specific survival (DSS) compared with wild-type TP53 (P=0.002) in a cohort of 345 OSCC patients. In contrast, DSS of patients bearing all of the remaining TP53 mutations did not differ from that observed in wild-type TP53 patients (P=0...
June 8, 2016: Oncotarget
H Parker, M J J Rose-Zerilli, M Larrayoz, R Clifford, J Edelmann, S Blakemore, J Gibson, J Wang, V Ljungström, T K Wojdacz, T Chaplin, A Roghanian, Z Davis, A Parker, E Tausch, S Ntoufa, S Ramos, P Robbe, R Alsolami, A J Steele, G Packham, A E Rodríguez-Vicente, L Brown, F McNicholl, F Forconi, A Pettitt, P Hillmen, M Dyer, M S Cragg, C Chelala, C C Oakes, R Rosenquist, K Stamatopoulos, S Stilgenbauer, S Knight, A Schuh, D G Oscier, J C Strefford
Histone methyltransferases (HMTs) are important epigenetic regulators of gene transcription and are disrupted at the genomic level in a spectrum of human tumours including haematological malignancies. Using high-resolution single nucleotide polymorphism (SNP) arrays, we identified recurrent deletions of the SETD2 locus in 3% (8/261) of chronic lymphocytic leukaemia (CLL) patients. Further validation in two independent cohorts showed that SETD2 deletions were associated with loss of TP53, genomic complexity and chromothripsis...
June 10, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
(no author information available yet)
TP53-altered HCC tumors become addicted to MYC stabilization.
July 2016: Cancer Discovery
D Rossi, S Rasi, V Spina, A Bruscaggin, S Monti, S Cresta, R Famà, C Deambrogi, M Greco, M Fangazio, C Ciardullo, D Piranda, G M Casaluci, M Messina, I D Giudice, S Chiaretti, M Marinelli, A Guarini, R Foà, G Gaidano
Next-generation whole-exome sequencing has revealed two novel genes, namely NOTCH1 and SF3B1, whose mutations predict poor outcome and preferentially associate with chemorefractory chronic lymphocytic leukemia (CLL). Analysis of 539 CLL cases documents that NOTCH1 mutations i) represent one of the most frequent cancer gene mutations involved at presentation; ii) cluster with cases harboring trisomy 12 and tend to be mutually exclusive with TP53 disruption among genetic subgroups; iii) identify high-risk patients showing poor survival similar to that associated with TP53 abnormalities; and iv) exert a prognostic role independent of widely accepted clinical and genetic risk factors...
August 2012: Leukemia Supplements
Jeroen den Hertog
Zebrafish are increasingly being used to study cancer. Almost all tumor types have been found in zebrafish. However, tumor incidence is relatively low and tumors develop late in life. Functional inactivation of tumor suppressors is a crucial step in cancer progression and more and more tumor suppressor genes are being studied in zebrafish. Most often tumor suppressors have been inactivated by reverse genetics approaches using targeted disruption. However, some tumor suppressor mutants were identified by forward genetic screens for mutants with a particular phenotype...
2016: Advances in Experimental Medicine and Biology
Eyad Alhourani, Moneeb A K Othman, Joana B Melo, Isabel M Carreira, Beata Grygalewicz, Dragana Vujić, Zeljko Zecević, Gordana Joksić, Anita Glaser, Beate Pohle, Cordula Schlie, Sven Hauke, Thomas Liehr
Deletions within chromosome 11q22-23, are considered among the most common chromosomal aberrations in chronic lymphocytic leukemia (CLL), and are associated with a poor outcome. In addition to the ataxia telangiectasia mutated (ATM) gene, the baculoviral IAP repeat-containing 3 (BIRC3) gene is also located in the region. BIRC3 encodes a negative regulator of the non-canonical nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) protein. Disruption of BIRC3 is known to be restricted to CLL fludarabine-refractory patients...
May 2016: Oncology Letters
M Dal Bo, P Bulian, R Bomben, A Zucchetto, F Maria Rossi, F Pozzo, E Tissino, D Benedetti, T Bittolo, P Nanni, I Cattarossi, E Zaina, H Chivilò, M Degan, F Zaja, G Pozzato, A Chiarenza, F Di Raimondo, M I Del Principe, G Del Poeta, D Rossi, G Gaidano, V Gattei
CD49d, the alpha-chain of the integrin heterodimer α4β1, was identified among the strongest predictors of overall survival (OS) in chronic lymphocytic leukemia (CLL), along with IGHV mutational status and deletion of the 17p chromosome involving TP53. In addition to TP53, the clinical relevance of NOTCH1, SF3B1 and BIRC3 gene mutations has been recently emphasized. By analyzing a cohort of 778 unselected CLL patients, we assessed the clinical relevance of CD49d as OS predictor in subgroups defined by mutation/deletion of the TP53, NOTCH1, SF3B1 and BIRC3 genes...
April 25, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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