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atm mutated

Li-Yun Fann, Ying Chen, Da-Chen Chu, Shao-Ju Weng, Heng-Cheng Chu, Alexander T H Wu, Jiann-Fong Lee, Ahmed Atef Ahmed Ali, Tsung-Chih Chen, Hsu-Shan Huang, Kuo-Hsing Ma
The small-molecule naphtha [2,3-f]quinoxaline-7,12-dione (NSC745887) can effectively inhibit the proliferation of various cancers by trapping DNA-topoisomerase cleavage. The aim of this study was to elucidate cellular responses of NSC745887 in human glioblastoma multiforme (GBM, U118MG and U87MG cells) and investigate the underlying molecular mechanisms. NSC745887 reduced the cell survival rate and increased the sub-G1 population in dose- and time-dependent manners in GBM cells. Moreover, NSC745887 increased expression of γH2AX and caused DNA fragmentation leading to DNA damage...
February 23, 2018: Oncotarget
Jinyu Wang, Haitao Zhang, Mohammed Al Shibar, Belinda Willard, Alo Ray, Kurt W Runge
Telomeres, the ends of eukaryotic chromosomes, consist of repetitive DNA sequences and their bound proteins that protect the end from the DNA damage response. Short telomeres with fewer repeats are preferentially elongated by telomerase. Tel1, the yeast homolog of human ATM kinase, is preferentially recruited to short telomeres and Tel1 kinase activity is required for telomere elongation. Rif1, a telomere-binding protein, negatively regulates telomere length by forming a complex with two other telomere binding proteins, Rap1 and Rif2, to block telomerase recruitment...
March 7, 2018: DNA Repair
Justin Stebbing, Kalpit Shah, Lei Cheng Lit, Teresa Gagliano, Angeliki Ditsiou, Tingting Wang, Franz Wendler, Thomas Simon, Krisztina Sára Szabó, Timothy O'Hanlon, Michael Dean, April Camilla Roslani, Swee Hung Cheah, Soo-Chin Lee, Georgios Giamas
Lemur tyrosine kinase 3 (LMTK3) is an oncogenic kinase that is involved in different types of cancer (breast, lung, gastric, colorectal) and biological processes including proliferation, invasion, migration, chromatin remodeling as well as innate and acquired endocrine resistance. However, the role of LMTK3 in response to cytotoxic chemotherapy has not been investigated thus far. Using both 2D and 3D tissue culture models, we found that overexpression of LMTK3 decreased the sensitivity of breast cancer cell lines to cytotoxic (doxorubicin) treatment...
March 15, 2018: Oncogene
Paula Gutierrez-Martinez, Leah Hogdal, Manavi Nagai, Miriama Kruta, Rumani Singh, Kristopher Sarosiek, Andre Nussenzweig, Isabel Beerman, Anthony Letai, Derrick J Rossi
Ageing of haematopoietic stem cells (HSCs) contributes to deficits in the aged haematopoietic system. HSC decline is driven in part by DNA damage accumulation; yet, how ageing impacts the acute DNA damage response (DDR) of HSCs is poorly understood. We show that old HSCs exhibit diminished ATM activity and attenuated DDR, leading to elevated clonal survival in response to a range of genotoxins that was underwritten by diminished apoptotic priming. Distinct HSC subsets exhibited ageing-dependent and subtype-dependent differences in apoptotic priming and survival in response to DNA damage...
March 12, 2018: Nature Cell Biology
Tatsuo Miyamoto, Silvia Natsuko Akutsu, Hiroshi Tauchi, Yoshiki Kudo, Satoshi Tashiro, Takashi Yamamoto, Shinya Matsuura
DNA double-strand breaks (DSBs) induced by ionizing radiation (IR) are the initial and critical step in major alteration of genetic information and cell death. To prevent deleterious effects, DNA repair systems recognize and re-join DNA DSBs in human cells. It has been suggested that there are individual differences in radiosensitivity within human populations, and that variations in DNA repair genes might contribute to this heterogeneity. Because confounding factors, including age, gender, smoking, and diverse genetic backgrounds within human populations, also influence the cellular radiosensitivity, to accurately measure the effect of candidate genetic variations on radiosensitivity, it is necessary to use human cultured cells with a uniform genetic background...
March 8, 2018: Journal of Radiation Research
Dehong Huang, Lei Jin, Zhengkang Li, Ji Wu, Ni Zhang, Dianrong Zhou, Xiaorong Ni, Tieying Hou
Hepatoblastoma (HB) is the most common malignant liver tumor in children. DNA and DNA-associated processes are one of the most important targets of chemotherapeutic agents. Isoorientin (Iso), a natural flavonoid compound, can be extracted from several plant species. The effects of Iso and its molecular mechanisms on hepatic malignancies remain unclear. Herein, the anti-tumor effects of Iso in HB and its underlying mechanisms were explored. We found that Iso significantly inhibited the proliferation of HB cells both in vitro and in vivo...
March 7, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Diana A Olszewska, Terri McVeigh, Emer M Fallon, Gregory M Pastores, Tim Lynch
Genetics is the backbone of Neurology, where a number of disorders have a genetic aetiology and are complex, requiring a dedicated Neurogenetics clinic. Genetics in the Republic of Ireland is under-resourced, with the lowest number of consultants per million of population in Europe. In November 2014, we established the monthly adult Neurogenetics clinic in Ireland, staffed by 2 consultants and 2 registrars from each speciality. We see patients with complex rare neurological conditions that may potentially have an underlying genetic basis, in the presence or absence of a family history...
March 9, 2018: Irish Journal of Medical Science
Vivek Tripathi, Himanshi Agarwal, Swati Priya, Harish Batra, Priyanka Modi, Monica Pandey, Dhurjhoti Saha, Sathees C Raghavan, Sagar Sengupta
Mutations in BLM in Bloom Syndrome patients predispose them to multiple types of cancers. Here we report that BLM is recruited in a biphasic manner to annotated DSBs. BLM recruitment is dependent on the presence of NBS1, MRE11 and ATM. While ATM activity is essential for BLM recruitment in early phase, it is dispensable in late phase when MRE11 exonuclease activity and RNF8-mediated ubiquitylation of BLM are the key determinants. Interaction between polyubiquitylated BLM and NBS1 is essential for the helicase to be retained at the DSBs...
March 9, 2018: Nature Communications
Ulrika A Hänninen, Riku Katainen, Tomas Tanskanen, Roosa-Maria Plaketti, Riku Laine, Jiri Hamberg, Ari Ristimäki, Eero Pukkala, Minna Taipale, Jukka-Pekka Mecklin, Linda M Forsström, Esa Pitkänen, Kimmo Palin, Niko Välimäki, Netta Mäkinen, Lauri A Aaltonen
Small bowel adenocarcinoma (SBA) is an aggressive disease with limited treatment options. Despite previous studies, its molecular genetic background has remained somewhat elusive. To comprehensively characterize the mutational landscape of this tumor type, and to identify possible targets of treatment, we conducted the first large exome sequencing study on a population-based set of SBA samples from all three small bowel segments. Archival tissue from 106 primary tumors with appropriate clinical information were available for exome sequencing from a patient series consisting of a majority of confirmed SBA cases diagnosed in Finland between the years 2003-2011...
March 9, 2018: PLoS Genetics
Jan Hauke, Judit Horvath, Eva Groß, Andrea Gehrig, Ellen Honisch, Karl Hackmann, Gunnar Schmidt, Norbert Arnold, Ulrike Faust, Christian Sutter, Julia Hentschel, Shan Wang-Gohrke, Mateja Smogavec, Bernhard H F Weber, Nana Weber-Lassalle, Konstantin Weber-Lassalle, Julika Borde, Corinna Ernst, Janine Altmüller, Alexander E Volk, Holger Thiele, Verena Hübbel, Peter Nürnberg, Katharina Keupp, Beatrix Versmold, Esther Pohl, Christian Kubisch, Sabine Grill, Victoria Paul, Natalie Herold, Nadine Lichey, Kerstin Rhiem, Nina Ditsch, Christian Ruckert, Barbara Wappenschmidt, Bernd Auber, Andreas Rump, Dieter Niederacher, Thomas Haaf, Juliane Ramser, Bernd Dworniczak, Christoph Engel, Alfons Meindl, Rita K Schmutzler, Eric Hahnen
The prevalence of germ line mutations in non-BRCA1/2 genes associated with hereditary breast cancer (BC) is low, and the role of some of these genes in BC predisposition and pathogenesis is conflicting. In this study, 5589 consecutive BC index patients negative for pathogenic BRCA1/2 mutations and 2189 female controls were screened for germ line mutations in eight cancer predisposition genes (ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D, and TP53). All patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germ line testing...
March 9, 2018: Cancer Medicine
Enrico Mini, Ida Landini, Laura Lucarini, Andrea Lapucci, Cristina Napoli, Gabriele Perrone, Renato Tassi, Emanuela Masini, Flavio Moroni, Stefania Nobili
The poly(ADP-ribose) polymerase (PARP) enzymes play a key role in the regulation of cellular processes (e.g., DNA damage repair, genomic stability). It has been shown that PARP inhibitors (PARPIs) are selectively cytotoxic against cells having dysfunctions in genes involved in DNA repair mechanisms (synthetic lethality). Drug-induced PARP inhibition potentiates the activity of anticancer drugs such as 5-fluorouracil in enhancing DNA damage, whose repair involves PARP-1 activity. The aim of this study was to evaluate the inhibitory effects of a novel PARPI, HYDAMTIQ, on growth in human tumor cell lines characterized by different features with regard to DNA damage response pathways (BRCA mutational status, microsatellite status, and ATM expression level) and degree of sensitivity/resistance to 5-fluorouracil...
March 5, 2018: Oncology Research
Qi Liu, Liliana Gheorghiu, Michael Drumm, Rebecca Clayman, Alec Eidelman, Matthew F Wszolek, Aria Olumi, Adam Feldman, Meng Wang, Lynnette Marcar, Deborah E Citrin, Chin-Lee Wu, Cyril H Benes, Jason A Efstathiou, Henning Willers
Biomarkers and mechanisms of poly (ADP-ribose) polymerase (PARP) inhibitor-mediated cytotoxicity in tumor cells lacking a BRCA-mutant or BRCA-like phenotype are poorly defined. We sought to explore the utility of PARP-1 inhibitor (PARPi) treatment with/without ionizing radiation in muscle-invasive bladder cancer (MIBC), which has poor therapeutic outcomes. We assessed the DNA damaging and cytotoxic effects of the PARPi olaparib in nine bladder cancer cell lines. Olaparib radiosensitized all cell lines with dose enhancement factors from 1...
March 7, 2018: Oncogene
Yusuke Yamamoto, Kohkichi Hosoda, Taichiro Imahori, Jun Tanaka, Kazuya Matsuo, Tomoaki Nakai, Yasuhiro Irino, Masakazu Shinohara, Naoko Sato, Takashi Sasayama, Kazuhiro Tanaka, Hiroaki Nagashima, Masaaki Kohta, Eiji Kohmura
Molecular mechanism underlying ischemic stroke remains poorly understood. We previously reported glucose 6-phosphate dehydrogenase (G6PD) activity in pentose phosphate pathway (PPP) is activated via heat shock protein 27 (HSP27) phosphorylation at serine 85 (S85) by ataxia telangiectasia mutated (ATM) kinase during cerebral ischemia. This mechanism seems to be endogenous antioxidative system. To determine whether this system also works during reperfusion, we performed comparative metabolic analysis of reperfusion effect on metabolism in rat cortex using middle cerebral artery occlusion (MCAO)...
March 3, 2018: Brain Research
Britta Weigelt, Rui Bi, Rahul Kumar, Pedro Blecua, Diana L Mandelker, Felipe C Geyer, Fresia Pareja, Paul A James, Fergus J Couch, Diana M Eccles, Fiona Blows, Paul Pharoah, Anqi Li, Pier Selenica, Raymond S Lim, Gowtham Jayakumaran, Nic Waddell, Ronglai Shen, Larry Norton, Hannah Y Wen, Simon N Powell, Nadeem Riaz, Mark E Robson, Jorge S Reis-Filho, Georgia Chenevix-Trench
Pathogenic germline variants in ataxia-telangiectasia mutated (ATM), a gene that plays a role in DNA damage response and cell cycle checkpoints, confer an increased breast cancer (BC) risk. Here, we investigated the phenotypic characteristics and landscape of somatic genetic alterations in 24 BCs from ATM germline mutation carriers by whole-exome and targeted sequencing. ATM-associated BCs were consistently hormone receptor positive and largely displayed minimal immune infiltrate. Although 79.2% of these tumors exhibited loss of heterozygosity of the ATM wild-type allele, none displayed high activity of mutational signature 3 associated with defective homologous recombination DNA (HRD) repair...
February 28, 2018: Journal of the National Cancer Institute
Svetlana O Sharapova, Alena V Valochnik, Irina E Guryanova, Inga S Sakovich, Olga V Aleinikova
Ataxia-telangiectasia (AT) is a rare neurodegenerative disease characterized by an early onset ataxia, oculocutaneous telangiectasia, immunodeficiency, recurrent infections, radio-sensitivity, and a predisposition to malignancy. We present the case of a child with coexistent AT and trisomy X (47,XXX). We used fluorescent in situ hybridization (FISH) to confirm that this person had 47,XXX karyotype in blood cells, bone marrow, fibroblasts, and buccal smear. Standard cytogenetic studies (not banded) were conducted on blood cells...
February 28, 2018: Immunogenetics
Eleftheria Alexopoulou, Theodora Katsila, Maria Tolia, Nikolaos Tsoukalas, Michael Leontsinidis, George Kyrgias, Vasilios Kouloulias, George P Patrinos, Despoina Spyropoulou, Dimitrios Kardamakis
BACKGROUND/AIM: Radiation dermatitis is observed in 95% of breast cancer patients receiving radiotherapy. The aim of this study was to explore the correlation between protein expression in tumor cells and the risk of developing radiation dermatitis. PATIENTS AND METHODS: Breast cancer patients receiving postoperative radiotherapy were included in this study. Tumor specimens from 122 patients were examined by immunohistochemistry for the expression of Ki67, ataxia telangiectasia mutated (ATM) kinase, hypoxia-inducible factor-1-alpha (HIF-1a), inducible nitric oxide synthase (iNOS), and a-glucosidase (aGluc)...
March 2018: Anticancer Research
A Lindemann, H Takahashi, A A Patel, A A Osman, J N Myers
Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer worldwide and in the United States. OSCC remains a major cause of morbidity and mortality in patients with head and neck cancers. Tobacco and alcohol consumption alone or with chewing betel nut are potential risk factors contributing to the high prevalence of OSCC. Multimodality therapies, including surgery, chemotherapy, biologic therapy, and radiotherapy, particularly intensity-modulated radiotherapy (IMRT), are the current treatments for OSCC patients...
February 1, 2018: Journal of Dental Research
E Cirillo, E Del Giudice, R Micheli, A M Cappellari, A Soresina, R M Dellepiane, M C Pietrogrande, L Dell'Era, F Specchia, A Pession, A Plebani, C Pignata
BACKGROUND AND PURPOSE: Ataxia-Telangiectasia (A-T) is a rare neurodegenerative disease, due to A-T Mutated (ATM) gene mutations, which typically presents with signs of progressive neurological dysfunction, cerebellar ataxia and uncoordinated movements. A-T severely affects patients' quality of life (QoL). Successful treatment options are still not available. Aim of this multicenter study, performed with a blind evaluation procedure, was to define the minimal effective dosage of oral betamethasone, thus preventing the occurrence of side effects...
February 28, 2018: European Journal of Neurology: the Official Journal of the European Federation of Neurological Societies
Mitra Mehrad, Somak Roy, William A LaFramboise, Patti Petrosko, Caitlyn Miller, Pimpin Incharoen, Sanja Dacic
Pulmonary Sarcomatoid Carcinoma (PSC) is a poorly-differentiated non-small cell lung carcinoma (NSCLC) with aggressive behavior. This study aimed to evaluate the prognostic clinicopathologic and genetic characteristics of PSCs. Fifty-three cases of surgically treated PSCs were selected, of which 23 were subjected to mutation and copy number variation analysis using 50-gene Ion AmpliSeq Cancer Panel. Majority of the patients were male (32/53, 60.3%) and smoker (51/53, 96.2%). Overall, 25 (47.1%) patients died within 2 to 105 months (mean 22...
February 28, 2018: Histopathology
David A Barrington, Macie L Champion, Teresa K L Boitano, Christen L Walters-Haygood, Meagan B Farmer, Ronald D Alvarez, Jacob M Estes, Charles A Leath
OBJECTIVES: Describe patient characteristics in African American (AA) women seen for gynecologic cancer related genetic counseling at a large southeastern comprehensive cancer center. METHODS: We reviewed an IRB approved, prospective observational cohort of patients from a Gynecologic Cancer Risk Assessment Clinic. Data evaluated included personal cancer history, family history, frequency of genetic testing, frequency/type of genetic mutations, and frequency of surgical intervention...
February 24, 2018: Gynecologic Oncology
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