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Genomic instability cancer

Chih-Wei Liu, Xu Tian, Hadley J Hartwell, Jiapeng Leng, Liang Chi, Kun Lu, James A Swenberg
Genomic instability caused by DNA-protein crosslink (DPCs)-induced DNA damage is implicated in disease pathogenesis, aging and cancer development. The covalent linkages between DNA and protein are induced by chemical reactions catalyzed by the endogenous metabolic intermediates and exogenous agents such as aldehydes, chemotherapeutic agents, and ionizing radiation. Formaldehyde has been classified as a genotoxic carcinogen. In addition, endogenous formaldehyde-induced DPCs may increase the risks of bone marrow toxicity and leukemia...
April 13, 2018: Chemical Research in Toxicology
Gerd P Pfeifer
Human malignant tumors are characterized by pervasive changes in the patterns of DNA methylation. These changes include a globally hypomethylated tumor cell genome and the focal hypermethylation of numerous 5'-cytosine-phosphate-guanine-3' (CpG) islands, many of them associated with gene promoters. It has been challenging to link specific DNA methylation changes with tumorigenesis in a cause-and-effect relationship. Some evidence suggests that cancer-associated DNA hypomethylation may increase genomic instability...
April 12, 2018: International Journal of Molecular Sciences
Tiphanie Faïs, Julien Delmas, Nicolas Barnich, Richard Bonnet, Guillaume Dalmasso
Cyclomodulins are bacterial toxins that interfere with the eukaryotic cell cycle. A new cyclomodulin called colibactin, which is synthetized by the pks genomic island, was discovered in 2006. Despite many efforts, colibactin has not yet been purified, and its structure remains elusive. Interestingly, the pks island is found in members of the family Enterobacteriaceae (mainly Escherichia coli and Klebsiella pneumoniae ) isolated from different origins, including from intestinal microbiota, septicaemia, newborn meningitis, and urinary tract infections...
April 10, 2018: Toxins
Theodoros Karantanos, Alison R Moliterno
The JAK2V617F-positive myeloproliferative neoplasms (MPN) serve as an excellent model for the study of genomic instability accumulation during cancer progression. Recent studies highlight the implication of JAK2 activating mutations in the development of DNA damage via reactive oxygen species (ROS) production, replication stress induction and the accumulation of genomic instability via the increased degradation of p53 and acquisition of a "mutagenic" phenotype. The accumulation of genomic instability and acquisition of mutations in critical DNA damage repair (DDR) mediators appears to be implicated in the progression of JAK2V617F-positive MPN...
March 30, 2018: Blood Reviews
Altea Targa, Giulia Rancati
Pioneering studies described cancer as an evolutionary process and detailed its intratumor heterogeneity in patients' specimens. The development of unbiased single-cell sequencing technologies confirmed these early observations and neoplasms are now widely recognized as populations of genetically, chromosomally and epigenetically distinct cells in which clones carrying beneficial traits expand in presence of selection factors like chemotherapy treatment. In support of this view, intratumor heterogeneity, by providing a large pool of phenotypically distinct clones, was shown to correlate with poor prognosis, therapy failure and metastasis...
April 3, 2018: Current Opinion in Cell Biology
Takeshi Terabayashi, Katsuhiro Hanada
Maintenance of genome integrity is essential for all organisms because genome information regulates cell proliferation, growth arrest, and vital metabolic processes in cells, tissues, organs, and organisms. Because genomes are constantly exposed to intrinsic and extrinsic genotoxic stress, cellular DNA repair machinery and proper DNA damage responses (DDR) have evolved to quickly eliminate genotoxic DNA lesions, thus maintaining the genome integrity suitably. In human, germline mutations in genes involved not only in cellular DNA repair pathways but also in cellular DDR machinery frequently predispose hereditary diseases associated with chromosome aberrations...
April 5, 2018: Cell Biology and Toxicology
Ganjun Yu, Yanfeng Wu, Wenying Wang, Jia Xu, Xiaoping Lv, Xuetao Cao, Tao Wan
PD-1 blockade has demonstrated impressive clinical outcomes in colorectal cancers that have high microsatellite instability. However, the therapeutic efficacy for patients with tumors with low microsatellite instability or stable microsatellites needs further improvement. Here, we have demonstrated that low-dose decitabine could increase the expression of immune-related genes such as major histocompatibility complex genes and cytokine-related genes as well as the number of lymphocytes at the tumor site in CT26 colorectal cancer-bearing mice...
April 5, 2018: Cellular & Molecular Immunology
Tuo Li, Zhijian J Chen
Detection of microbial DNA is an evolutionarily conserved mechanism that alerts the host immune system to mount a defense response to microbial infections. However, this detection mechanism also poses a challenge to the host as to how to distinguish foreign DNA from abundant self-DNA. Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS) is a DNA sensor that triggers innate immune responses through production of the second messenger cyclic GMP-AMP (cGAMP), which binds and activates the adaptor protein STING...
April 5, 2018: Journal of Experimental Medicine
Yang Liu, Nilay S Sethi, Toshinori Hinoue, Barbara G Schneider, Andrew D Cherniack, Francisco Sanchez-Vega, Jose A Seoane, Farshad Farshidfar, Reanne Bowlby, Mirazul Islam, Jaegil Kim, Walid Chatila, Rehan Akbani, Rupa S Kanchi, Charles S Rabkin, Joseph E Willis, Kenneth K Wang, Shannon J McCall, Lopa Mishra, Akinyemi I Ojesina, Susan Bullman, Chandra Sekhar Pedamallu, Alexander J Lazar, Ryo Sakai, Vésteinn Thorsson, Adam J Bass, Peter W Laird
We analyzed 921 adenocarcinomas of the esophagus, stomach, colon, and rectum to examine shared and distinguishing molecular characteristics of gastrointestinal tract adenocarcinomas (GIACs). Hypermutated tumors were distinct regardless of cancer type and comprised those enriched for insertions/deletions, representing microsatellite instability cases with epigenetic silencing of MLH1 in the context of CpG island methylator phenotype, plus tumors with elevated single-nucleotide variants associated with mutations in POLE...
April 2, 2018: Cancer Cell
Giulia Martina Cavestro, Alessandro Mannucci, Raffaella Alessia Zuppardo, Milena Di Leo, Elena Stoffel, Giovanni Tonon
Early onset colorectal cancers, defined as arising before 50 years of age, are a growing health hazard in western and eastern countries alike. The incidence of colon and rectal cancers in young individuals is projected to increase by as much as 90% and 140%, respectively, by 2030. Although several known cancer risk factors (e.g. smoking, alcohol, dietary habits) have been investigated, there is no single compelling explanation for this epidemiological trend. While some early onset colorectal cancers have been associated with germline mutations in cancer predisposition genes, genetic syndromes are implicated in only a fraction of these cancers (20%) and do not explain the rising incidence...
February 23, 2018: Digestive and Liver Disease
Xiacheng Sun, Lei Zhan, Yibing Chen, Gang Wang, Linjie He, Qian Wang, Feng Zhou, Fang Yang, Jin Wu, Yousheng Wu, Jinliang Xing, Xianli He, Qichao Huang
Colorectal cancer is one of the leading causes of cancer death worldwide. According to global genomic status, colorectal cancer can be classified into two main types: microsatellite-stable and microsatellite-instable tumors. Moreover, the two subtypes also exhibit different responses to chemotherapeutic agents through distinctive molecular mechanisms. Recently, mitochondrial DNA depletion has been shown to induce apoptotic resistance in microsatellite-instable colorectal cancer. However, the effects of altered mitochondrial DNA copy number on the progression of microsatellite-stable colorectal cancer, which accounts for the majority of colorectal cancer, remain unclear...
2018: Signal Transduction and Targeted Therapy
Erich A Nigg, Dominik Schnerch, Olivier Ganier
Centrosomes determine the disposition of microtubule networks and thereby contribute to regulate cell shape, polarity, and motility, as well as chromosome segregation during cell division. Additionally, centrioles, the core components of centrosomes, are required for the formation of cilia and flagella. Mutations in genes coding for centrosomal and centriolar proteins are responsible for several human diseases, foremost ciliopathies and developmental disorders resulting in small brains (primary microcephaly) or small body size (dwarfism)...
April 2, 2018: Cold Spring Harbor Symposia on Quantitative Biology
Erlyana K Clarke, Katherine A Rivera Gomez, Zaki Mustachi, Mikaela C Murph, Mara Schvarzstein
Mechanisms that involve whole genome polyploidy play important roles in development and evolution; also, an abnormal generation of tetraploid cells has been associated with both the progression of cancer and the development of drug resistance. Until now, it has not been feasible to easily manipulate the ploidy of a multicellular animal without generating mostly sterile progeny. Presented here is a simple and rapid protocol for generating tetraploid Caenorhabditis elegans animals from any diploid strain. This method allows the user to create a bias in chromosome segregation during meiosis, ultimately increasing ploidy in C...
March 15, 2018: Journal of Visualized Experiments: JoVE
Ryan P Barnes, Elise Fouquerel, Patricia L Opresko
Telomeres are dynamic nucleoprotein-DNA structures that cap and protect linear chromosome ends. Because telomeres shorten progressively with each replication, they impose a functional limit on the number of times a cell can divide. Critically short telomeres trigger cellular senescence in normal cells, or genomic instability in pre-malignant cells, which contribute to numerous degenerative and aging-related diseases including cancer. Therefore, a detailed understanding of the mechanisms of telomere loss and preservation is important for human health...
March 28, 2018: Mechanisms of Ageing and Development
Daniel Temko, Inge C Van Gool, Emily Rayner, Mark Glaire, Seiko Makino, Matthew Brown, Laura Chegwidden, Claire Palles, Jeroen Depreeuw, Andrew Beggs, Chaido Stathopoulou, John Mason, Ann-Marie Baker, Marc Williams, Vincenzo Cerundolo, Margarida Rei, Jenny C Taylor, Anna Schuh, Ahmed Ahmed, Frédéric Amant, Diether Lambrechts, Vincent Thbm Smit, Tjalling Bosse, Trevor A Graham, David N Church, Ian Tomlinson
Genomic instability, a hallmark of cancer, is generally thought to occur in the mid to late stages of tumorigenesis, following the acquisition of permissive molecular aberrations such as TP53 mutation or whole genome doubling. Tumours with somatic POLE exonuclease domain mutations are notable for their extreme genomic instability (their mutation burden is among the highest in human cancer), distinct mutational signature, lymphocytic infiltrate and excellent prognosis. To what extent these characteristics are determined by the timing of POLE mutations in oncogenesis is unknown...
March 31, 2018: Journal of Pathology
Juan Ni, Xihan Guo, Han Wang, Tao Zhou, Xu Wang
The tea catechin epigallocatechin-3-gallate (EGCG) proved to be the most potent physiologically active tea compound in vitro. It possesses antioxidant as well as pro-oxidant properties. EGCG has the effect of inducing apoptosis of tumor cells and inhibiting cell proliferation. Whether this effect is associated with the antioxidant or pro-oxidative effects of EGCG affecting the genome stability of normal and cancer cells has not been confirmed. Here, we selected Human normal colon epithelial cells NCM460 and colon adenocarcinoma cells COLO205 to investigate the effects of EGCG (0–40 μg/mL) on the genome stability and cell growth status...
March 29, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Nadine Schuler, Jan Palm, Sabine Schmitz, Yvonne Lorat, Claudia E Rübe
Background: Li-Fraumeni syndrome (LFS) is a cancer predisposition disorder characterized by germline mutations of the p53 tumor-suppressor gene. In response to DNA damage, p53 stimulates protective cellular processes including cell-cycle arrest and apoptosis to prevent aberrant cell proliferation. Current cancer therapies involve agents that damage DNA, which also affect non-cancerous hematopoietic stem/progenitor cells. Here, we report on a child with LFS who developed genomic instability during craniospinal irradiation for metastatic choroid plexus carcinoma (CPC)...
December 2017: Clinical and Translational Radiation Oncology
Vered Domankevich, Hossam Eddini, Amani Odeh, Imad Shams
The blind mole rat, Spalax , is the only mammalian species, to date, for which spontaneous cancer was never reported and resistance to carcinogens- induced cancers was demonstrated. However, the underlying mechanisms are still poorly understood. The fact that Spalax is also a hypoxia-tolerant and a long-lived species implies for molecular adaptations to prevent genomic instability, which underlies both cancer and aging. We previously demonstrated the up-regulation of transcripts related to DNA replication and repair pathways in Spalax Yet, to date, no direct experimental evidence for improved genomic maintenance was demonstrated for this species...
March 28, 2018: Journal of Experimental Biology
Sanne Ten Hoorn, Anne Trinh, Joan de Jong, Lianne Koens, Louis Vermeulen
Colorectal cancer (CRC) is a heterogeneous disease, which can be categorized into distinct consensus molecular subtypes (CMSs). These subtypes differ in both clinical as well as biological properties. The gold-standard classification strategy relies on genome-wide expression data, which hampers widespread implementation. Here we describe an immunohistochemical (IHC) Mini Classifier, a practical tool that, in combination with microsatellite instability testing, delivers objective and accurate scoring to classify CRC patients into the main molecular disease subtypes...
2018: Methods in Molecular Biology
Shigeo Yamaguchi, Shin Takahashi, Kaoru Mogushi, Yuki Izumi, Yumi Nozaki, Tadashi Nomizu, Yoichiro Kakugawa, Takanori Ishida, Noriaki Ohuchi, Chikashi Ishioka, Shunsuke Kato
Purpose: TP53 signature has a robust predictive performance for prognosis in early-stage breast cancer, but the experiment that reported this relied on public microarray data and fresh-frozen samples. Before TP53 signature can be used in a clinical setting, a simple and low-cost diagnostic system using formalin-fixed paraffin-embedded (FFPE) samples is needed. New treatments based on the biological characteristics of TP53 signature are expected to follow. Experimental Design: TP53 signature was evaluated in 174 FFPE early breast cancer specimens using digital quantification via the nCounter technique (NanoString)...
March 6, 2018: Oncotarget
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