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[PMID]:28465371
[Au] Autor:Castellucci E; He T; Goldstein DY; Halmos B; Chuy J
[Ad] Endereço:Department of Medical Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York, USA.
[Ti] Título:DNA Polymerase É› Deficiency Leading to an Ultramutator Phenotype: A Novel Clinically Relevant Entity.
[So] Source:Oncologist;22(5):497-502, 2017 May.
[Is] ISSN:1549-490X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Deficiencies in DNA repair due to mutations in the exonuclease domain of DNA polymerase É› have recently been described in a subset of cancers characterized by an ultramutated and microsatellite stable (MSS) phenotype. This alteration in DNA repair is distinct from the better-known mismatch repair deficiencies which lead to microsatellite instability (MSI) and an increased tumor mutation burden. Instead, mutations in lead to impaired proofreading intrinsic to Pol É› during DNA replication resulting in a dramatically increased mutation rate. Somatic mutations of Pol É› have been found most frequently in endometrial and colorectal cancers (CRC) and can lead to a unique familial syndrome in the case of germline mutations. While other key genomic abnormalities, such as MSI, have known prognostic and treatment implications, in this case it is less clear. As molecular genotyping of tumors becomes routine in the care of cancer patients, less common, but potentially actionable findings such as these mutations could be overlooked unless appropriate algorithms are in place. We present two cases of metastatic CRC with a mutation, both of which are ultramutated and MSS. The basic biochemical mechanisms leading to a unique phenotype in deficiency as well as challenges faced with interpreting the genomic profiling of tumors in this important subset of patients and the potential clinical implications will be discussed here. 2017;22:497-502 KEY POINTS: Clinicians should recognize that tumors with high tumor mutation burden and that are microsatellite stable may harbor a mutation, which is associated with an ultramutated phenotype.Work-up for deficiency should indeed become part of the routine molecular testing paradigm for patients with colorectal cancer.This subset of patients may benefit from clinical trials where the higher number of mutation-associated neoantigens and defect in DNA repair may be exploited therapeutically.
[Mh] Termos MeSH primário: Neoplasias Colorretais/genética
DNA Polimerase II/genética
Instabilidade de Microssatélites
Proteínas de Ligação a Poli-ADP-Ribose/genética
Prognóstico
[Mh] Termos MeSH secundário: Neoplasias Colorretais/patologia
DNA Polimerase II/deficiência
Reparo do DNA/genética
Genótipo
Mutação em Linhagem Germinativa/genética
Seres Humanos
Masculino
Meia-Idade
Metástase Neoplásica
Fenótipo
Proteínas de Ligação a Poli-ADP-Ribose/deficiência
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Poly-ADP-Ribose Binding Proteins); EC 2.7.7.- (DNA Polymerase II); EC 2.7.7.7 (POLE protein, human)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE
[do] DOI:10.1634/theoncologist.2017-0034


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[PMID]:29320758
[Au] Autor:Voutsadakis IA
[Ad] Endereço:Division of Medical Oncology, Department of Internal Medicine, Sault Area Hospital, Sault Ste Marie, Ontario, Canada; Division of Clinical Sciences, Northern Ontario School of Medicine, Sudbury, Ontario, Canada. Electronic address: ivoutsadakis@nosm.ca.
[Ti] Título:Polymerase epsilon mutations and concomitant ß2-microglobulin mutations in cancer.
[So] Source:Gene;647:31-38, 2018 Mar 20.
[Is] ISSN:1879-0038
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Mutations in the exonuclease domain of polymerase epsilon (POLE), an enzyme of DNA synthesis, are involved in a newly described syndrome of colorectal polyposis and cancer, and have been associated with a high mutation burden with or without microsatellite instability (MSI) phenotype. The exonuclease domain of POLE executes a proofreading function that decreases the mutation rate during DNA replication by an estimated of one to two orders. The high mutation burden resulting from its loss of function could create a load of neo-antigens that would put the neoplastic cells in severe disadvantage of an immune attack if properly presented to the immune system. This paper investigates the mutagenic effect of different POLE mutations in various cancers, in published genomic studies and the effect that these POLE mutations have in selecting for mutations of the ß2 microglobulin (B2M) gene involved in antigen presentation.
[Mh] Termos MeSH primário: DNA Polimerase II/genética
Globulinas/genética
Mutação/genética
Neoplasias/genética
Proteínas de Ligação a Poli-ADP-Ribose/genética
[Mh] Termos MeSH secundário: Replicação do DNA/genética
Exodesoxirribonucleases/genética
Seres Humanos
Instabilidade de Microssatélites
Mutagênese/genética
Taxa de Mutação
Fenótipo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Globulins); 0 (Poly-ADP-Ribose Binding Proteins); EC 2.7.7.- (DNA Polymerase II); EC 2.7.7.7 (POLE protein, human); EC 3.1.- (Exodeoxyribonucleases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180209
[Lr] Data última revisão:
180209
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180111
[St] Status:MEDLINE


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[PMID]:29033319
[Au] Autor:Gan H; Yu C; Devbhandari S; Sharma S; Han J; Chabes A; Remus D; Zhang Z
[Ad] Endereço:Institute for Cancer Genetics and Department of Pediatrics and Genetics and Development, Columbia University, New York, NY 10032.
[Ti] Título:Checkpoint Kinase Rad53 Couples Leading- and Lagging-Strand DNA Synthesis under Replication Stress.
[So] Source:Mol Cell;68(2):446-455.e3, 2017 Oct 19.
[Is] ISSN:1097-4164
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The checkpoint kinase Rad53 is activated during replication stress to prevent fork collapse, an essential but poorly understood process. Here we show that Rad53 couples leading- and lagging-strand synthesis under replication stress. In rad53-1 cells stressed by dNTP depletion, the replicative DNA helicase, MCM, and the leading-strand DNA polymerase, Pol ε, move beyond the site of DNA synthesis, likely unwinding template DNA. Remarkably, DNA synthesis progresses further along the lagging strand than the leading strand, resulting in the exposure of long stretches of single-stranded leading-strand template. The asymmetric DNA synthesis in rad53-1 cells is suppressed by elevated levels of dNTPs in vivo, and the activity of Pol ε is compromised more than lagging-strand polymerase Pol δ at low dNTP concentrations in vitro. Therefore, we propose that Rad53 prevents the generation of excessive ssDNA under replication stress by coordinating DNA unwinding with synthesis of both strands.
[Mh] Termos MeSH primário: Proteínas de Ciclo Celular/metabolismo
Quinase do Ponto de Checagem 2/metabolismo
DNA Polimerase III/metabolismo
DNA Polimerase II/metabolismo
Replicação do DNA/fisiologia
DNA Fúngico/biossíntese
Proteínas de Saccharomyces cerevisiae/metabolismo
Saccharomyces cerevisiae/metabolismo
[Mh] Termos MeSH secundário: Proteínas de Ciclo Celular/genética
Quinase do Ponto de Checagem 2/genética
DNA Polimerase II/genética
DNA Polimerase III/genética
DNA Fúngico/genética
Saccharomyces cerevisiae/genética
Proteínas de Saccharomyces cerevisiae/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cell Cycle Proteins); 0 (DNA, Fungal); 0 (Saccharomyces cerevisiae Proteins); EC 2.7.1.11 (Checkpoint Kinase 2); EC 2.7.12.1 (RAD53 protein, S cerevisiae); EC 2.7.7.- (DNA Polymerase II); EC 2.7.7.- (DNA Polymerase III)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171017
[St] Status:MEDLINE


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[PMID]:28911114
[Au] Autor:Liu T; Liu Z; Ye Q; Pan S; Wang X; Li Y; Peng W; Liang Y; She Q; Peng N
[Ad] Endereço:State Key Laboratory of Agricultural Microbiology, College of Life Science and Technology, Huazhong Agricultural University, Wuhan, 430070, P.R. China.
[Ti] Título:Coupling transcriptional activation of CRISPR-Cas system and DNA repair genes by Csa3a in Sulfolobus islandicus.
[So] Source:Nucleic Acids Res;45(15):8978-8992, 2017 Sep 06.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:CRISPR-Cas system provides the adaptive immunity against invading genetic elements in prokaryotes. Recently, we demonstrated that Csa3a regulator mediates spacer acquisition in Sulfolobus islandicus by activating the expression of Type I-A adaptation cas genes. However, links between the activation of spacer adaptation and CRISPR transcription/processing, and the requirement for DNA repair genes during spacer acquisition remained poorly understood. Here, we demonstrated that de novo spacer acquisition required Csa1, Cas1, Cas2 and Cas4 proteins of the Sulfolobus Type I-A system. Disruption of genes implicated in crRNA maturation or DNA interference led to a significant accumulation of acquired spacers, mainly derived from host genomic DNA. Transcriptome and proteome analyses showed that Csa3a activated expression of adaptation cas genes, CRISPR RNAs, and DNA repair genes, including herA helicase, nurA nuclease and DNA polymerase II genes. Importantly, Csa3a specifically bound the promoters of the above DNA repair genes, suggesting that they were directly activated by Csa3a for adaptation. The Csa3a regulator also specifically bound to the leader sequence to activate CRISPR transcription in vivo. Our data indicated that the Csa3a regulator couples transcriptional activation of the CRISPR-Cas system and DNA repair genes for spacer adaptation and efficient interference of invading genetic elements.
[Mh] Termos MeSH primário: Proteínas Arqueais/genética
Sistemas CRISPR-Cas
Reparo do DNA
DNA Arqueal/genética
Regulação da Expressão Gênica em Archaea
Sulfolobus/genética
Ativação Transcricional
[Mh] Termos MeSH secundário: Proteínas Arqueais/imunologia
Sequência de Bases
Proteínas Associadas a CRISPR/genética
Proteínas Associadas a CRISPR/imunologia
Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas
DNA Helicases/genética
DNA Helicases/imunologia
DNA Polimerase II/genética
DNA Polimerase II/imunologia
DNA Arqueal/imunologia
Endodesoxirribonucleases/genética
Endodesoxirribonucleases/imunologia
Chaperonas Moleculares/genética
Chaperonas Moleculares/imunologia
Regiões Promotoras Genéticas
Alinhamento de Sequência
Homologia de Sequência do Ácido Nucleico
Sulfolobus/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Archaeal Proteins); 0 (CRISPR-Associated Proteins); 0 (DNA, Archaeal); 0 (Molecular Chaperones); EC 2.7.7.- (DNA Polymerase II); EC 3.1.- (Endodeoxyribonucleases); EC 3.6.4.- (DNA Helicases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171012
[Lr] Data última revisão:
171012
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170916
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx612


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[PMID]:28846956
[Au] Autor:Nebot-Bral L; Brandao D; Verlingue L; Rouleau E; Caron O; Despras E; El-Dakdouki Y; Champiat S; Aoufouchi S; Leary A; Marabelle A; Malka D; Chaput N; Kannouche PL
[Ad] Endereço:UMR8200 - CNRS, Stabilité Génétique et Oncogenèse, France; Gustave Roussy Cancer Campus, F-94805, Villejuif, France; Université Paris Saclay, Paris Sud - Orsay, F-91400, France.
[Ti] Título:Hypermutated tumours in the era of immunotherapy: The paradigm of personalised medicine.
[So] Source:Eur J Cancer;84:290-303, 2017 Oct.
[Is] ISSN:1879-0852
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Immune checkpoint inhibitors have demonstrated unprecedented clinical activity in a wide range of cancers. Significant therapeutic responses have recently been observed in patients presenting mismatch repair-deficient (MMRD) tumours. MMRD cancers exhibit a remarkably high rate of mutations, which can result in the formation of neoantigens, hypothesised to enhance the antitumour immune response. In addition to MMRD tumours, cancers mutated in the exonuclease domain of the catalytic subunit of the DNA polymerase epsilon (POLE) also exhibit an ultramutated genome and are thus likely to benefit from immunotherapy. In this review, we provide an overview of recent data on hypermutated tumours, including MMRD and POLE-mutated cancers, with a focus on their distinctive clinicopathological and molecular characteristics as well as their immune environment. We also discuss the emergence of immune therapy to treat these hypermutated cancers, and we comment on the recent Food and Drug Administration approval of an immune checkpoint inhibitor, the programmed cell death 1 antibody (pembrolizumab, Keytruda), for the treatment of patients with metastatic MMRD cancers regardless of the tumour type. This breakthrough represents a turning point in the management of these hypermutated tumours and paves the way for broader strategies in immunoprecision medicine.
[Mh] Termos MeSH primário: Antígenos de Neoplasias/genética
Biomarcadores Tumorais/genética
Imunoterapia/métodos
Mutação
Neoplasias/genética
Neoplasias/terapia
Medicina de Precisão/métodos
[Mh] Termos MeSH secundário: Antígenos de Neoplasias/imunologia
Biomarcadores Tumorais/imunologia
Reparo de Erro de Pareamento de DNA
Análise Mutacional de DNA
DNA Polimerase II/genética
DNA Polimerase II/metabolismo
DNA Polimerase III/genética
DNA Polimerase III/metabolismo
Predisposição Genética para Doença
Seres Humanos
Instabilidade de Microssatélites
Terapia de Alvo Molecular
Neoplasias/imunologia
Neoplasias/patologia
Fenótipo
Proteínas de Ligação a Poli-ADP-Ribose
Valor Preditivo dos Testes
Evasão Tumoral
Microambiente Tumoral
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antigens, Neoplasm); 0 (Biomarkers, Tumor); 0 (Poly-ADP-Ribose Binding Proteins); EC 2.7.7.- (DNA Polymerase II); EC 2.7.7.- (DNA Polymerase III); EC 2.7.7.- (POLD1 protein, human); EC 2.7.7.7 (POLE protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170829
[St] Status:MEDLINE


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[PMID]:28805995
[Au] Autor:Andrianova MA; Chetan GK; Sibin MK; Mckee T; Merkler D; Narasinga RK; Ribaux P; Blouin JL; Makrythanasis P; Seplyarskiy VB; Antonarakis SE; Nikolaev SI
[Ad] Endereço:Institute of Information Transmission Problems, Moscow, Russia.
[Ti] Título:Germline PMS2 and somatic POLE exonuclease mutations cause hypermutability of the leading DNA strand in biallelic mismatch repair deficiency syndrome brain tumours.
[So] Source:J Pathol;243(3):331-341, 2017 Nov.
[Is] ISSN:1096-9896
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Biallelic mismatch repair deficiency (bMMRD) in tumours is frequently associated with somatic mutations in the exonuclease domains of DNA polymerases POLE or POLD1, and results in a characteristic mutational profile. In this article, we describe the genetic basis of ultramutated high-grade brain tumours in the context of bMMRD. We performed exome sequencing of two second-cousin patients from a large consanguineous family of Indian origin with early onset of high-grade glioblastoma and astrocytoma. We identified a germline homozygous nonsense variant, p.R802*, in the PMS2 gene. Additionally, by genome sequencing of these tumours, we found extremely high somatic mutation rates (237/Mb and 123/Mb), as well as somatic mutations in the proofreading domain of POLE polymerase (p.P436H and p.L424V), which replicates the leading DNA strand. Most interestingly, we found, in both cancers, that the vast majority of mutations were consistent with the signature of POLE exo , i.e. an abundance of C>A and C>T mutations, particularly in special contexts, on the leading strand. We showed that the fraction of mutations under positive selection among mutations in tumour suppressor genes is more than two-fold lower in ultramutated tumours than in other glioblastomas. Genetic analyses enabled the diagnosis of the two consanguineous childhood brain tumours as being due to a combination of PMS2 germline and POLE somatic variants, and confirmed them as bMMRD/POLE exo disorders. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
[Mh] Termos MeSH primário: Neoplasias Encefálicas/genética
Reparo de Erro de Pareamento de DNA/genética
DNA Polimerase II/genética
Predisposição Genética para Doença
Mutação em Linhagem Germinativa/genética
Endonuclease PMS2 de Reparo de Erro de Pareamento/genética
[Mh] Termos MeSH secundário: Neoplasias Encefálicas/patologia
DNA/genética
Feminino
Seres Humanos
Masculino
Proteínas de Ligação a Poli-ADP-Ribose
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Poly-ADP-Ribose Binding Proteins); 9007-49-2 (DNA); EC 2.7.7.- (DNA Polymerase II); EC 2.7.7.7 (POLE protein, human); EC 3.6.1.- (PMS2 protein, human); EC 3.6.1.3 (Mismatch Repair Endonuclease PMS2)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170815
[St] Status:MEDLINE
[do] DOI:10.1002/path.4957


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[PMID]:28784720
[Au] Autor:Yu C; Gan H; Zhang Z
[Ad] Endereço:Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA.
[Ti] Título:Both DNA Polymerases δ and ε Contact Active and Stalled Replication Forks Differently.
[So] Source:Mol Cell Biol;37(21), 2017 Nov 01.
[Is] ISSN:1098-5549
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Three DNA polymerases, polymerases α, δ, and ε (Pol α, Pol δ, and Pol ε), are responsible for eukaryotic genome duplication. When DNA replication stress is encountered, DNA synthesis stalls until the stress is ameliorated. However, it is not known whether there is a difference in the association of each polymerase with active and stalled replication forks. Here, we show that each DNA polymerase has a distinct pattern of association with active and stalled replication forks. Pol α is enriched at extending Okazaki fragments of active and stalled forks. In contrast, although Pol δ contacts the nascent lagging strands of active and stalled forks, it binds to only the matured (and not elongating) Okazaki fragments of stalled forks. Pol ε has greater contact with the nascent single-stranded DNA (ssDNA) of the leading strand on active forks than on stalled forks. We propose that the configuration of DNA polymerases at stalled forks facilitates the resumption of DNA synthesis after stress removal.
[Mh] Termos MeSH primário: DNA Polimerase III/metabolismo
DNA Polimerase II/metabolismo
DNA Fúngico/metabolismo
Saccharomyces cerevisiae/genética
[Mh] Termos MeSH secundário: DNA/metabolismo
Replicação do DNA
DNA de Cadeia Simples/metabolismo
Saccharomyces cerevisiae/enzimologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA, Fungal); 0 (DNA, Single-Stranded); 0 (Okazaki fragments); 9007-49-2 (DNA); EC 2.7.7.- (DNA Polymerase II); EC 2.7.7.- (DNA Polymerase III)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171110
[Lr] Data última revisão:
171110
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170809
[St] Status:MEDLINE


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[PMID]:28647100
[Au] Autor:Proctor L; Pradhan M; Leung S; Cheng A; Lee CH; Soslow RA; Gilks CB; Talhouk A; McAlpine JM; Danielsen HE; Hoang LN
[Ad] Endereço:Department of Gynecology and Obstetrics, University of British Columbia, Vancouver, British Columbia, Canada.
[Ti] Título:Assessment of DNA Ploidy in the ProMisE molecular subgroups of endometrial cancer.
[So] Source:Gynecol Oncol;146(3):596-602, 2017 Sep.
[Is] ISSN:1095-6859
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: We sought to determine whether DNA ploidy correlates with the four molecular subgroups of endometrial carcinoma (EC) as determined using ProMisE (Proactive Molecular Risk Classifier for Endometrial Cancer). METHODS: 90 cases of EC previously characterized by clinicopathological parameters, outcomes, and ProMisE molecular subgroup (POLE EDM, MMR-D, p53 wt or p53 abn) were assessed for DNA ploidy using image cytometry. Associations of ploidy with traditional clinicopathological parameters were also tested. RESULTS: Abnormal DNA ploidy status differed amongst the ProMisE groups (p<0.001) and was found in 80.9% (17/21) of p53 abn, 37.0% (10/27) of p53 wt, 28.6% (4/14) of POLE EDM and 14.3% (4/28) of MMR-D. Abnormal DNA content was significantly associated with lower BMI (p=0.034) and grade 3 tumors (p=0.001). In the entire cohort, abnormal DNA content was significantly associated with worse progression free survival (p=0.0094) but not disease specific survival (p=0.249) or overall survival (p=0.187). When examining ploidy within each of the ProMisE groups, abnormal DNA content correlated with worse overall survival (p=0.041) and progression free survival (p=0.011) in the MMR-D group. No statistically significant relationship was seen in the remaining 3 groups. CONCLUSION: Abnormal DNA ploidy status did correlate with the molecular subgroups of EC; abnormal DNA content was seen in the large majority of p53 abn cases. Abnormal ploidy however was also seen in smaller numbers in the p53 wt, POLE EDM and MMR-D groups; therefore abnormal DNA content was not a specific marker for any one molecular group. The addition of ploidy to the ProMisE molecular categories conferred additional prognostic value within the MMR-D group, which merits further study.
[Mh] Termos MeSH primário: Carcinoma/genética
Carcinoma/patologia
DNA de Neoplasias/genética
Neoplasias do Endométrio/genética
Neoplasias do Endométrio/patologia
Ploidias
[Mh] Termos MeSH secundário: Idoso
Aneuploidia
Carcinoma/química
Reparo de Erro de Pareamento de DNA/genética
DNA Polimerase II/genética
Diploide
Intervalo Livre de Doença
Neoplasias do Endométrio/química
Feminino
Seres Humanos
Meia-Idade
Mutação
Gradação de Tumores
Invasividade Neoplásica
Estadiamento de Neoplasias
Proteínas de Ligação a Poli-ADP-Ribose
Receptores de Estradiol/análise
Receptores de Progesterona/análise
Taxa de Sobrevida
Tetraploidia
Proteína Supressora de Tumor p53/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA, Neoplasm); 0 (Poly-ADP-Ribose Binding Proteins); 0 (Receptors, Estradiol); 0 (Receptors, Progesterone); 0 (Tumor Suppressor Protein p53); EC 2.7.7.- (DNA Polymerase II); EC 2.7.7.7 (POLE protein, human)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170626
[St] Status:MEDLINE


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[PMID]:28609784
[Au] Autor:Hagedorn C; Gogol-Döring A; Schreiber S; Epplen JT; Lipps HJ
[Ad] Endereço:University of Witten/Herdecke, ZBAF, Institute of Cell Biology, Stockumer Strasse 10, 58453 Witten, Germany.
[Ti] Título:Genome-wide profiling of S/MAR-based replicon contact sites.
[So] Source:Nucleic Acids Res;45(13):7841-7854, 2017 Jul 27.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Autonomously replicating vectors represent a simple and versatile model system for genetic modifications, but their localization in the nucleus and effect on endogenous gene expression is largely unknown. Using circular chromosome conformation capture we mapped genomic contact sites of S/MAR-based replicons in HeLa cells. The influence of cis-active sequences on genomic localization was assessed using replicons containing either an insulator sequence or an intron. While the original and the insulator-containing replicons displayed distinct contact sites, the intron-containing replicon showed a rather broad genomic contact pattern. Our results indicate a preference for certain chromatin structures and a rather non-dynamic behaviour during mitosis. Independent of inserted cis-active elements established vector molecules reside preferentially within actively transcribed regions, especially within promoter sequences and transcription start sites. However, transcriptome analyses revealed that established S/MAR-based replicons do not alter gene expression profiles of host genome. Knowledge of preferred contact sites of exogenous DNA, e.g. viral or non-viral episomes, contribute to our understanding of episome behaviour in the nucleus and can be used for vector improvement and guiding of DNA sequences to specific subnuclear sites.
[Mh] Termos MeSH primário: Replicon
[Mh] Termos MeSH secundário: Sítios de Ligação/genética
Cromatina/genética
Cromatina/metabolismo
DNA/genética
DNA/metabolismo
DNA Polimerase II/metabolismo
Replicação do DNA/genética
Perfilação da Expressão Gênica
Vetores Genéticos
Genoma Humano
Células HeLa
Seres Humanos
Modelos Genéticos
Plasmídeos/genética
Plasmídeos/metabolismo
Origem de Replicação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Chromatin); 9007-49-2 (DNA); EC 2.7.7.- (DNA Polymerase II)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170614
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx522


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[PMID]:28539555
[Au] Autor:Miyauchi T; Yaguchi T; Kawakami Y
[Ad] Endereço:Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine.
[Ti] Título:Inter-patient and Intra-tumor Heterogeneity in the Sensitivity to Tumor-targeted Immunity in Colorectal Cancer.
[So] Source:Nihon Rinsho Meneki Gakkai Kaishi;40(1):54-59, 2017.
[Is] ISSN:1349-7413
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:  Efficacy of immune checkpoint inhibitors such as PD-1 antibody for colorectal cancer remains to be proved except in microsatellite-instability-high (MSI-H) cases. While the objective response rate of MSI-H cases was 40%, that of microsatellite-stable (MSS) cases was 0%, showing that response rate to immune checkpoint inhibitors varies even among the microsatellite status. Some possible mechanisms that confer each patient variation in the response to immunotherapy should be considered. We focused on the combination of inter-patient heterogeneity and intra-tumor heterogeneity as a determining factor of immune reaction. An example of intra-tumor heterogeneity is the low expression of tumor antigen by CD271 cells in melanoma. It is not surprising that similar mechanism exists in CRC. Other related intra-tumor heterogeneity includes EMT and autophagy, both molecular mechanisms that are thought to promote immune-evading phenotype. Besides the microsatellite status, inter-patient heterogeneity in response to tumor immunity includes hypermutator phenotype, which is driven by POLE mutation, intrinsic cytokine production, and microbiota in the gut.
[Mh] Termos MeSH primário: Neoplasias Colorretais/imunologia
Neoplasias Colorretais/terapia
Instabilidade de Microssatélites
[Mh] Termos MeSH secundário: Anticorpos/uso terapêutico
Autofagia
Neoplasias Colorretais/genética
DNA Polimerase II/genética
Heterogeneidade Genética
Seres Humanos
Imunoterapia
Mutação
Proteínas do Tecido Nervoso/imunologia
Proteínas de Ligação a Poli-ADP-Ribose
Receptor de Morte Celular Programada 1/imunologia
Receptores de Fator de Crescimento Neural/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antibodies); 0 (NGFR protein, human); 0 (Nerve Tissue Proteins); 0 (PDCD1 protein, human); 0 (Poly-ADP-Ribose Binding Proteins); 0 (Programmed Cell Death 1 Receptor); 0 (Receptors, Nerve Growth Factor); EC 2.7.7.- (DNA Polymerase II); EC 2.7.7.7 (POLE protein, human)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170526
[St] Status:MEDLINE
[do] DOI:10.2177/jsci.40.54



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