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Genomic instability

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https://www.readbyqxmd.com/read/28213433/chromosomal-instability-as-a-driver-of-tumor-heterogeneity-and-evolution
#1
Samuel F Bakhoum, Dan Avi Landau
Large-scale, massively parallel sequencing of human cancer samples has revealed tremendous genetic heterogeneity within individual tumors. Indeed, tumors are composed of an admixture of diverse subpopulations-subclones-that vary in space and time. Here, we discuss a principal driver of clonal diversification in cancer known as chromosomal instability (CIN), which complements other modes of genetic diversification creating the multilayered genomic instability often seen in human cancer. Cancer cells have evolved to fine-tune chromosome missegregation rates to balance the acquisition of heterogeneity while preserving favorable genotypes, a dependence that can be exploited for a therapeutic benefit...
February 17, 2017: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/28212810/chromosomal-instability-analysis-and-regional-tumor-heterogeneity-in-colon-cancer
#2
Vincenza Barresi, Sergio Castorina, Nicolò Musso, Carmela Capizzi, Tonia Luca, Giovanna Privitera, Daniele Filippo Condorelli
Chromosomal instability (CIN) is classically defined as an increase in the rate at which numerical or structural chromosomal aberrations are acquired in a cancer cell. The number of somatic copy number abnormalities (CNAs) revealed by high resolution genomic array can be considered as a surrogate marker for CIN, but several points, related to sample processing and data analysis, need to be standardized. In this work we analyzed 51 CRC samples and matched normal mucosae by whole genome SNP arrays and compared different bioinformatics tools in order to identify broad (>25% of a chromosomal arm) and focal somatic copy number abnormalities (BCNAs and FCNAs respectively)...
January 2017: Cancer Genetics
https://www.readbyqxmd.com/read/28203566/increased-spontaneous-recombination-in-rnase-h2-deficient-cells-arises-from-multiple-contiguous-rnmps-and-not-from-single-rnmp-residues-incorporated-by-dna-polymerase-epsilon
#3
Anastasiya Epshtein, Catherine J Potenski, Hannah L Klein
Ribonucleotides can become embedded in DNA from insertion by DNA polymerases, failure to remove Okazaki fragment primers, R-loops that can prime replication, and RNA/cDNA-mediated recombination. RNA:DNA hybrids are removed by RNase H enzymes. Single rNMPs in DNA are removed by RNase H2 and if they remain on the leading strand, can lead to mutagenesis in a Top1-dependent pathway. rNMPs in DNA can also stimulate genome instability, among which are homologous recombination gene conversion events. We previously found that, similar to the rNMP-stimulated mutagenesis, rNMP-stimulated recombination was also Top1-dependent...
June 2016: Microbial Cell
https://www.readbyqxmd.com/read/28202506/recurrent-patterns-of-dna-copy-number-alterations-in-tumors-reflect-metabolic-selection-pressures
#4
Nicholas A Graham, Aspram Minasyan, Anastasia Lomova, Ashley Cass, Nikolas G Balanis, Michael Friedman, Shawna Chan, Sophie Zhao, Adrian Delgado, James Go, Lillie Beck, Christian Hurtz, Carina Ng, Rong Qiao, Johanna Ten Hoeve, Nicolaos Palaskas, Hong Wu, Markus Müschen, Asha S Multani, Elisa Port, Steven M Larson, Nikolaus Schultz, Daniel Braas, Heather R Christofk, Ingo K Mellinghoff, Thomas G Graeber
Copy number alteration (CNA) profiling of human tumors has revealed recurrent patterns of DNA amplifications and deletions across diverse cancer types. These patterns are suggestive of conserved selection pressures during tumor evolution but cannot be fully explained by known oncogenes and tumor suppressor genes. Using a pan-cancer analysis of CNA data from patient tumors and experimental systems, here we show that principal component analysis-defined CNA signatures are predictive of glycolytic phenotypes, including (18)F-fluorodeoxy-glucose (FDG) avidity of patient tumors, and increased proliferation...
February 15, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28202223/filtration-based-enrichment-of-circulating-tumor-cells-from-all-prostate-cancer-risk-groups
#5
Julius Adebayo Awe, Jeff Saranchuk, Darrel Drachenberg, Sabine Mai
OBJECTIVE: To combine circulating tumor cell (CTC) isolation by filtration and immunohistochemistry to investigate the presence of CTCs in low, intermediate, and high-risk prostate cancer (PCa). CTCs isolated from these risk groups stained positive for both cytokeratin and androgen receptors, but negative for CD45. PATIENTS AND METHODS: Blood samples from 41 biopsy confirmed patients with PCa at different clinical stages such as low, intermediate, and high risk were analyzed...
February 12, 2017: Urologic Oncology
https://www.readbyqxmd.com/read/28199992/fragile-genes-that-are-frequently-altered-in-cancer-players-not-passengers
#6
Jenna R Karras, Morgan S Schrock, Bahadir Batar, Kay Huebner
FHIT, located at FRA3B, is one of the most commonly deleted genes in human cancers, and loss of FHIT protein is one of the earliest events in cancer initiation. However, location of FHIT at a chromosomal fragile site, a locus prone to breakage and gap formation under even mild replication stress, has encouraged claims that FHIT loss is a passenger event in cancers. We summarize accumulated evidence that FHIT protein functions as a genome "caretaker" required to protect the stability of genomes of normal cells of most tissues from agents causing intrinsic and extrinsic DNA damage...
February 16, 2017: Cytogenetic and Genome Research
https://www.readbyqxmd.com/read/28199840/citron-kinase-deficiency-leads-to-chromosomal-instability-and-tp53-sensitive-microcephaly
#7
Federico Tommaso Bianchi, Chiara Tocco, Gianmarco Pallavicini, Yifan Liu, Fiammetta Vernì, Chiara Merigliano, Silvia Bonaccorsi, Nadia El-Assawy, Lorenzo Priano, Marta Gai, Gaia Elena Berto, Alessandra Maria Adelaide Chiotto, Francesco Sgrò, Alessia Caramello, Laura Tasca, Ugo Ala, Francesco Neri, Salvatore Oliviero, Alessandro Mauro, Stephan Geley, Maurizio Gatti, Ferdinando Di Cunto
Mutations in citron (CIT), leading to loss or inactivation of the citron kinase protein (CITK), cause primary microcephaly in humans and rodents, associated with cytokinesis failure and apoptosis in neural progenitors. We show that CITK loss induces DNA damage accumulation and chromosomal instability in both mammals and Drosophila. CITK-deficient cells display "spontaneous" DNA damage, increased sensitivity to ionizing radiation, and defective recovery from radiation-induced DNA lesions. In CITK-deficient cells, DNA double-strand breaks increase independently of cytokinesis failure...
February 14, 2017: Cell Reports
https://www.readbyqxmd.com/read/28199309/phosphatidylinositol-3-kinase-%C3%AE-blockade-increases-genomic-instability-in-b-cells
#8
Mara Compagno, Qi Wang, Chiara Pighi, Taek-Chin Cheong, Fei-Long Meng, Teresa Poggio, Leng-Siew Yeap, Elif Karaca, Rafael B Blasco, Fernanda Langellotto, Chiara Ambrogio, Claudia Voena, Adrian Wiestner, Siddha N Kasar, Jennifer R Brown, Jing Sun, Catherine J Wu, Monica Gostissa, Frederick W Alt, Roberto Chiarle
Activation-induced cytidine deaminase (AID) is a B-cell-specific enzyme that targets immunoglobulin genes to initiate class switch recombination and somatic hypermutation. In addition, through off-target activity, AID has a much broader effect on genomic instability by initiating oncogenic chromosomal translocations and mutations involved in the development and progression of lymphoma. AID expression is tightly regulated in B cells and its overexpression leads to enhanced genomic instability and lymphoma formation...
February 15, 2017: Nature
https://www.readbyqxmd.com/read/28198347/natural-escherichia-coli-isolates-rapidly-acquire-genetic-changes-upon-laboratory-domestication
#9
Bin Liu, Gustavo Eydallin, Ram P Maharjan, Lu Feng, Lei Wang, Thomas Ferenci
The adaptation of environmental bacteria to laboratory conditions was analysed through the exploration of genomic changes in four strains of Escherichia coli freshly isolated from their natural habitats and belonging to different taxonomic clusters. Up to 25 mutations were present in all cultures of natural isolates within 10 days of transfer in rich media or with a single growth cycle involving an extended stationary phase. Among numerous individual mutations, two genes were affected in parallel in distinct backgrounds...
January 2017: Microbiology
https://www.readbyqxmd.com/read/28197627/copy-number-analysis-identifies-tumor-suppressive-lncrnas-in-human-osteosarcoma
#10
Jianjun Xie, Dechen Lin, Dhong Hyun Tony Lee, Jennifer Akunowicz, Marc Hansen, Carl Miller, Masashi Sanada, Motohiro Kato, Tadayuki Akagi, Norihiko Kawamata, Seishi Ogawa, H Phillip Koeffler
Osteosarcoma (OS) has a high degree of chromosomal instability and total copy number (CN) changes. We examined 58 human OS samples including 40 primary tumors, 11 explants, and 7 cell lines using single nucleotide polymorphism (SNP) arrays, and revealed that 70% of the samples had one or more recurrent CN-neutral loss of heterozygosity (CNN‑LOH) also known as uniparental disomy (UPD). Importantly, 17% of the samples showed prominent homozygous deletion of 3q13.31, suggesting its role in tumorigenesis. We identified and characterized two novel lncRNAs, LOC285194 and BC040587, within this genomic locus, strongly suggesting their tumor suppressor activity...
March 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28197541/way-out-way-in-how-the-relationship-between-wrn-and-cdk1-may-change-the-fate-of-collapsed-replication-forks
#11
Valentina Palermo, Sara Rinalducci, Massimo Sanchez, Francesca Grillini, Annapaola Franchitto, Pietro Pichierri
Replication-dependent double-strand breaks (DSBs) are the main source of genomic instability as their inaccurate repair stimulates chromosomal rearrangements. In a recent work, we uncover a novel regulatory circuit that involves the Werner's syndrome helicase and CDK1, and that is essential for repair pathway choice at replication-dependent DSBs.
2017: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/28196983/genomic-profiling-of-acute-lymphoblastic-leukemia-in-ataxia-telangiectasia-patients-reveals-tight-link-between-atm-mutations-and-chromothripsis
#12
M Ratnaparkhe, M Hlevnjak, T Kolb, A Jauch, K K Maass, F Devens, A Rode, V Hovestadt, A Korshunov, A Pastorczak, W Mlynarski, S Sungalee, J Korbel, J Hoell, U Fischer, T Milde, C Kramm, M Nathrath, K Chrzanowska, E Tausch, M Takagi, T Taga, S Constantini, J Loeffen, J Meijerink, S Zielen, G Gohring, B Schlegelberger, E Maass, R Siebert, J Kunz, A E Kulozik, B Worst, D T Jones, S M Pfister, M Zapatka, P Lichter, A Ernst
Recent developments in sequencing technologies led to the discovery of a novel form of genomic instability, termed chromothripsis. This catastrophic genomic event, involved in tumorigenesis, is characterized by tens to hundreds of simultaneously acquired locally clustered rearrangements on one chromosome. We hypothesized that leukemias developing in individuals with Ataxia Telangiectasia, who are born with two mutated copies of the ATM gene, an essential guardian of genome stability, would show a higher prevalence of chromothripsis due to the associated defect in DNA double-strand break repair...
February 15, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28196964/fancd2-binds-human-papillomavirus-genomes-and-associates-with-a-distinct-set-of-dna-repair-proteins-to-regulate-viral-replication
#13
Chelsey C Spriggs, Laimonis A Laimins
The life cycle of human papillomavirus (HPV) is dependent on the differentiation state of its host cell. HPV genomes are maintained as low-copy episomes in basal epithelial cells and amplified to thousands of copies per cell in differentiated layers. Replication of high-risk HPVs requires the activation of the ataxia telangiectasia-mutated (ATM) and ATM and Rad3-related (ATR) DNA repair pathways. The Fanconi anemia (FA) pathway is a part of the DNA damage response and mediates cross talk between the ATM and ATR pathways...
February 14, 2017: MBio
https://www.readbyqxmd.com/read/28196590/singling-out-chromosome-gains-in-tumor-evolution
#14
Ryan M Naylor, Jan M van Deursen
In this issue of Cancer Cell, Sheltzer et al. shed new light on Theodor Boveri's century-old hypothesis by demonstrating that aneuploidy characterized by single-chromosome gains acts to suppress tumorigenesis and that aneuploidy itself is a nidus for genomic instability.
February 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28195122/integrated-genomic-analyses-of-de-novo-pathways-underlying-atypical-meningiomas
#15
Akdes Serin Harmancı, Mark W Youngblood, Victoria E Clark, Süleyman Coşkun, Octavian Henegariu, Daniel Duran, E Zeynep Erson-Omay, Leon D Kaulen, Tong Ihn Lee, Brian J Abraham, Matthias Simon, Boris Krischek, Marco Timmer, Roland Goldbrunner, S Bülent Omay, Jacob Baranoski, Burçin Baran, Geneive Carrión-Grant, Hanwen Bai, Ketu Mishra-Gorur, Johannes Schramm, Jennifer Moliterno, Alexander O Vortmeyer, Kaya Bilgüvar, Katsuhito Yasuno, Richard A Young, Murat Günel
Meningiomas are mostly benign brain tumours, with a potential for becoming atypical or malignant. On the basis of comprehensive genomic, transcriptomic and epigenomic analyses, we compared benign meningiomas to atypical ones. Here, we show that the majority of primary (de novo) atypical meningiomas display loss of NF2, which co-occurs either with genomic instability or recurrent SMARCB1 mutations. These tumours harbour increased H3K27me3 signal and a hypermethylated phenotype, mainly occupying the polycomb repressive complex 2 (PRC2) binding sites in human embryonic stem cells, thereby phenocopying a more primitive cellular state...
February 14, 2017: Nature Communications
https://www.readbyqxmd.com/read/28193203/first-insight-into-the-somatic-mutation-burden-of-neurofibromatosis-type-2-associated-grade-i-and-grade-ii-meningiomas-a-case-report-comprehensive-genomic-study-of-two-cranial-meningiomas-with-vastly-different-clinical-presentation
#16
Ramita Dewan, Alexander Pemov, Amalia S Dutra, Evgenia D Pak, Nancy A Edwards, Abhik Ray-Chaudhury, Nancy F Hansen, Settara C Chandrasekharappa, James C Mullikin, Ashok R Asthagiri, John D Heiss, Douglas R Stewart, Anand V Germanwala
BACKGROUND: Neurofibromatosis type 2 (NF2) is a rare autosomal dominant nervous system tumor predisposition disorder caused by constitutive inactivation of one of the two copies of NF2. Meningiomas affect about one half of NF2 patients, and are associated with a higher disease burden. Currently, the somatic mutation landscape in NF2-associated meningiomas remains largely unexamined. CASE PRESENTATION: Here, we present an in-depth genomic study of benign and atypical meningiomas, both from a single NF2 patient...
February 13, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28192779/chromosome-imbalances-in-cancer-molecular-cytogenetics-meets-genomics
#17
Elisa Palumbo, Antonella Russo
Genomic instability is a hallmark of cancer, and it is well-known that in several cancers the karyotype is unstable and rapidly evolving. Molecular cytogenetics has contributed to the description and interpretation of cancer karyotypes, in particular through multicolor FISH approaches which can define even complex chromosome rearrangements. The introduction of genome-wide methods has made available a powerful set of tools with higher resolution than cytogenetics, thus appropriate to comprehend the huge variability of cancer cells...
February 14, 2017: Cytogenetic and Genome Research
https://www.readbyqxmd.com/read/28192398/cyclind-cdk4-6-complexes-phosphorylate-cdc25a-and-regulate-its-stability
#18
C Dozier, L Mazzolini, C Cénac, C Froment, O Burlet-Schiltz, A Besson, S Manenti
The phosphatase CDC25A is a key regulator of cell cycle progression by dephosphorylating and activating cyclin-CDK complexes. CDC25A is an unstable protein expressed from G1 until mitosis. CDC25A overexpression, which can be caused by stabilization of the protein, accelerates the G1/S and G2/M transitions, leading to genomic instability and promoting tumorigenesis. Thus, controlling CDC25A protein levels by regulating its stability is a critical mechanism for timing cell cycle progression and to maintain genomic integrity...
February 13, 2017: Oncogene
https://www.readbyqxmd.com/read/28191891/mutations-in-donson-disrupt-replication-fork-stability-and-cause-microcephalic-dwarfism
#19
John J Reynolds, Louise S Bicknell, Paula Carroll, Martin R Higgs, Ranad Shaheen, Jennie E Murray, Dimitrios K Papadopoulos, Andrea Leitch, Olga Murina, Žygimantė Tarnauskaitė, Sarah R Wessel, Anastasia Zlatanou, Audrey Vernet, Alex von Kriegsheim, Rachel M A Mottram, Clare V Logan, Hannah Bye, Yun Li, Alexander Brean, Sateesh Maddirevula, Rachel C Challis, Kassiani Skouloudaki, Agaadir Almoisheer, Hessa S Alsaif, Ariella Amar, Natalie J Prescott, Michael B Bober, Angela Duker, Eissa Faqeih, Mohammed Zain Seidahmed, Saeed Al Tala, Abdulrahman Alswaid, Saleem Ahmed, Jumana Yousuf Al-Aama, Janine Altmüller, Mohammed Al Balwi, Angela F Brady, Luciana Chessa, Helen Cox, Rita Fischetto, Raoul Heller, Bertram D Henderson, Emma Hobson, Peter Nürnberg, E Ferda Percin, Angela Peron, Luigina Spaccini, Alan J Quigley, Seema Thakur, Carol A Wise, Grace Yoon, Maha Alnemer, Pavel Tomancak, Gökhan Yigit, A Malcolm R Taylor, Martin A M Reijns, Michael A Simpson, David Cortez, Fowzan S Alkuraya, Christopher G Mathew, Andrew P Jackson, Grant S Stewart
To ensure efficient genome duplication, cells have evolved numerous factors that promote unperturbed DNA replication and protect, repair and restart damaged forks. Here we identify downstream neighbor of SON (DONSON) as a novel fork protection factor and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a replisome component that stabilizes forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks...
February 13, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28191805/ring-chromosome-may-signal-progression-of-fanconi-anemia
#20
Ream Elzain Abdelgadir, Kulthom Mohamed, Imad Fadl Elmula
BACKGROUND: Fanconi anemia (FA) is a genomic instability disorder associated with high risk of AML. Ring chromosomes are results of genomic instability and observed in many human neoplasias. The present study aimed to assess the role of ring chromosome in the progression of FA. MATERIAL AND METHODS: The study included 60 patients with provisional diagnosis of FA. A total of 5 ml of venous blood was collected and processed for complete hemogram, peripheral blood film, and breakage test...
September 2016: Gulf Journal of Oncology
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