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1.
Exp Suppl ; 111: 3-19, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588524

RESUMO

Genetics is the study of heredity. In this introductory chapter of the book Genetics of Endocrine Diseases and Syndromes, we present the basic terms of genetics and basic physiological and pathogenic molecular processes that are implicated in the wide array of genetically determined diseases. Mutations, chromosomes, polymorphisms, and epigenetic terms are also briefly discussed.


Assuntos
Cromossomos Humanos/genética , Doenças do Sistema Endócrino/genética , Hereditariedade , Polimorfismo Genético , Epigênese Genética , Humanos , Mutação
2.
Nat Cell Biol ; 21(6): 743-754, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31160708

RESUMO

Chromatin assembled with the histone H3 variant CENP-A is the heritable epigenetic determinant of human centromere identity. Using genome-wide mapping and reference models for 23 human centromeres, CENP-A binding sites are identified within the megabase-long, repetitive α-satellite DNAs at each centromere. CENP-A is shown in early G1 to be assembled into nucleosomes within each centromere and onto 11,390 transcriptionally active sites on the chromosome arms. DNA replication is demonstrated to remove ectopically loaded, non-centromeric CENP-A. In contrast, tethering of centromeric CENP-A to the sites of DNA replication through the constitutive centromere associated network (CCAN) is shown to enable precise reloading of centromere-bound CENP-A onto the same DNA sequences as in its initial prereplication loading. Thus, DNA replication acts as an error correction mechanism for maintaining centromere identity through its removal of non-centromeric CENP-A coupled with CCAN-mediated retention and precise reloading of centromeric CENP-A.


Assuntos
Proteína Centromérica A/genética , Centrômero/genética , Cromossomos Humanos/genética , Replicação do DNA/genética , Cromatina/genética , Proteínas Cromossômicas não Histona/genética , Fase G1/genética , Células HeLa , Histonas/genética , Humanos , Nucleossomos/genética
3.
Medicine (Baltimore) ; 98(23): e15953, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31169720

RESUMO

BACKGROUND: Studies showed the controversial results about the effect of common genetic polymorphisms on the atrial fibrillation (AF) recurrence. We performed the systematic review and meta-analysis to qualify the association between common genetic polymorphisms and AF recurrence. METHODS: Articles were systematically retrieved PubMed, Web of Science, EMBASE, Wanfang, and CNKI database and 9 studies including 3204 patients were enrolled in our meta-analysis. RESULTS: Results showed that the associations were significant under rs2200733 3 genetic models (TT vs CC: odds ratio [OR] [confidence interval [CI]] = 1.336 [1.061-1.683], P = .014; CT vs CC: OR [CI] = 0.759 [0.614-0.937], P = .01; TT vs CT + CC: OR [CI] = 2.308 [1.440-3.700], P = .001). The association was significant under rs10033464 genetic model (TT vs GG: OR [CI] = 1.517 [1.165-1.976], P = .002). CONCLUSIONS: Rs13376333 on chromosome 1q21 (in KCNN3), rs7193343 and rs2106261 on chromosome 16q22 (in ZFHX3) were not associated with AF recurrence in our meta-analysis. In total, our meta-analysis found that rs2200733 and rs10033464 on chromosome 4q25 (near PITX2) were associated with the risk of AF recurrence.


Assuntos
Fibrilação Atrial/genética , Cromossomos Humanos/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Idoso , Feminino , Proteínas de Homeodomínio/genética , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Recidiva , Canais de Potássio Ativados por Cálcio de Condutância Baixa/genética , Fatores de Transcrição/genética
4.
BMC Bioinformatics ; 20(Suppl 8): 283, 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31182012

RESUMO

BACKGROUND: Numerous essential algorithms and methods, including entropy-based quantitative methods, have been developed to analyze complex DNA sequences since the last decade. Exons and introns are the most notable components of DNA and their identification and prediction are always the focus of state-of-the-art research. RESULTS: In this study, we designed an integrated entropy-based analysis approach, which involves modified topological entropy calculation, genomic signal processing (GSP) method and singular value decomposition (SVD), to investigate exons and introns in DNA sequences. We optimized and implemented the topological entropy and the generalized topological entropy to calculate the complexity of DNA sequences, highlighting the characteristics of repetition sequences. By comparing digitalizing entropy values of exons and introns, we observed that they are significantly different. After we converted DNA data to numerical topological entropy value, we applied SVD method to effectively investigate exon and intron regions on a single gene sequence. Additionally, several genes across five species are used for exon predictions. CONCLUSIONS: Our approach not only helps to explore the complexity of DNA sequence and its functional elements, but also provides an entropy-based GSP method to analyze exon and intron regions. Our work is feasible across different species and extendable to analyze other components in both coding and noncoding region of DNA sequences.


Assuntos
Entropia , Éxons/genética , Íntrons/genética , Algoritmos , Sequência de Bases , Cromossomos Humanos/genética , DNA/genética , Genoma Humano , Humanos , Regiões Promotoras Genéticas/genética , Curva ROC , Análise de Sequência de DNA/métodos , Processamento de Sinais Assistido por Computador
5.
Anticancer Res ; 39(6): 2757-2765, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31177111

RESUMO

BACKGROUND/AIM: Clear cell renal cell carcinoma (ccRCC) shows variable chromosomal abnormalities. The aim of this study was to assess the prognostic role of ccRCC chromosomal abnormalities in a single-center cohort with an extended follow-up. MATERIALS AND METHODS: A systematic cytogenetic analysis was performed in 283 consecutive surgically-treated patients for renal masses between 1997 and 2002. Kaplan-Meier and multivariable Cox regression (MCR) models were used to calculate cancer specific survival (CSS). RESULTS: Among 174 ccRCC patients, the most common abnormality was deletion in chromosome 3 (54.6%). At a median follow-up of 119 months, 38 patients (21.8%) died from RCC. At MCR models, worse CSS was independently predicted by deletions in chromosomes 2, 19, 20 or 22 and insertions in chromosome 18. CONCLUSION: Specific ccRCC chromosomal abnormalities are independently associated with worse CSS. Cytogenetic evaluation may direct further genetic analysis for personalized prognostic stratification.


Assuntos
Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/cirurgia , Aberrações Cromossômicas , Cromossomos Humanos/genética , Neoplasias Renais/mortalidade , Neoplasias Renais/cirurgia , Idoso , Carcinoma de Células Renais/genética , Deleção Cromossômica , Citogenética , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/genética , Masculino , Pessoa de Meia-Idade , Mutagênese Insercional , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Resultado do Tratamento
6.
Biomed Res Int ; 2019: 9797104, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31061830

RESUMO

Translocations are the most common type of structural chromosomal abnormalities. Unbalanced translocations are usually found in children who present with congenital abnormalities, developmental delay, or intellectual disability. Balanced translocations are usually found in adults who frequently present with reproductive failure; either subfertility, or recurrent pregnancy loss. Herein, we report the spectrum and frequency of translocations in a Sri Lankan cohort. A database of patients undergoing cytogenetic testing was maintained prospectively from January 2007 to December 2016 and analyzed, retrospectively. A total of 15,864 individuals were tested. Among them, 277 (1.7%) had translocations. There were 142 (51.3%) unbalanced translocations and 135 (48.7%) balanced translocations. Majority (160; 57.8%) were Robertsonian translocations. There were 145 (52.3%) children and adolescents aged less than 18 years with translocations, and 142 (97.9%) were unbalanced translocations. Majority [138 (95.2%)] were referred due to congenital abnormalities, developmental delay, or intellectual disability, and 91 were children with translocation Down syndrome. All adults aged 18 years or above (132) had balanced translocations. Subfertility and recurrent pregnancy loss [84 (63.6%)] and offspring(s) with congenital abnormalities [48 (36.4%)] were the most common indications in this group. Majority (68.2%) in this group were females with reciprocal translocations (55.3%). Chromosomes 21, 14, and 13 were the most commonly involved with rob(14q21q) [72 (26%)], rob(21q21q) [30 (13.7%)], and rob(13q14q) [34 (12.3%)] accounting for 52% of the translocations. Chromosomes 1, 8, 11, and 18 were most commonly involved in reciprocal translocations. The observed high frequency of chromosomal translocations in our cohort highlights the importance of undertaking cytogenetic evaluation and providing appropriate genetic counseling for individuals with the phenotypes associated with these translocations.


Assuntos
Aborto Habitual/genética , Cromossomos Humanos/genética , Síndrome de Down/genética , Translocação Genética , Aborto Habitual/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , Síndrome de Down/epidemiologia , Feminino , Aconselhamento Genético , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sri Lanka/epidemiologia
7.
Radiat Res ; 191(6): 532-544, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31008688

RESUMO

Variation in cellular characteristics may determine tumor response and, consequently, patient survival in radiation therapy. However, patient-specific prediction of cellular radiation response is currently unavailable for treatment planning. Thus, the importance of developing a novel approach based on clinically accessible parameters prior to treatment (e.g., by biopsy) is high. The goal of this study was to predict in vitro cancer cell survival through the p53mutation status and the number of chromosomes (NoC). To predict cell survival, we modified a mechanistic radiation response model incorporating DNA repair and cell death, originally designed for normal human cells. Cell-specific parameters of 24 cell lines originating from two laboratories (OncoRay, Dresden, Germany and HIMAC, Chiba, Japan) were considered for modeling. In a first step, we obtained estimates of the only unknown model input parameter genome size (GS) by fitting cell survival simulations onto experimental data. We then analyzed measured and published input model parameters (NoC, p53-mutation status and cell-cycle distribution) to assess their impact on measured and simulated parameters (modeled GS, and measured α, ß, SF2 and γ-H2AX). The resulting data suggested a linear correlation between NoC and modeled GS (R2 > 0.93) allowing for estimating GS based on NoC. Applying the estimated GS resulted in predicted cell survival that matched measured data mostly within the experimental uncertainty. The measured radiobiological value ß increased quadratically with the cell's modeled GS irrespective of other cell-specific parameters. The measured α and SF2 split into two groups, depending on the cells' p53-mutation status, both linearly increasing and decreasing, respectively, with modeled GS. Model predictions of foci numbers were, on average, in agreement with published γ-H2AX measurement data. In conclusion, knowledge of clinically accessible parameters (p53-mutation status and NoC) may support patient stratification in radiotherapy based on cell-specific survival prediction testable in prospective clinical trials.


Assuntos
Modelos Estatísticos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos da radiação , Cromossomos Humanos/genética , Cromossomos Humanos/efeitos da radiação , Glioblastoma/patologia , Histonas/metabolismo , Humanos , Mutação , Proteína Supressora de Tumor p53/genética
8.
Klin Onkol ; 32(2): 101-108, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30995849

RESUMO

BACKGROUND: Chromosome rearrangements play an important role in cancer pathophysiology. Recently, chromothripsis has been proposed among the mechanisms leading to their formation. Chromothripsis leads to fragmentation of chromosomes and their reconstitution with tens to hundreds of rearrangements clustered in small genome regions. In contrast to the traditional concept of malignant transformation, abnormalities caused by chromothripsis are not accumulated gradually but arise during a single event. The resulting structural variants are extensive and often cause oncogene activation or tumor suppressor inactivation. Chromothripsis is associated with many tumor types, especially with brain and bone tumors. Besides that, it has been described also in congenital disorders. The exact mechanism of chromothripsis origin has not been clarified yet; however, several hypotheses have been prosed, among which DNA damage in micronucleus seems to be most likely. Similarly, an impact of chromothripsis on cellular processes has not been fully understood, yet its association with unfavorable prognosis has been observed. PURPOSE: The purpose of this article is to summarize the current knowledge about chromothripsis and to present gathered pieces of information in a structured way. We focused on describing the basic features of chromothripsis, potential mechanisms of its origin, its impact on cellular processes and providing an overview of diseases where chromothripsis has been noted, with particular attention to cancer. Finally, we suggest a potential use of current knowledge about chromothripsis in the optimization of personalized treatment. Supported by Ministry of Health of the Czech Republic, grant no. 15-31834A. All rights reserved. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 31. 12. 2018 Accepted: 19. 3. 2019.


Assuntos
Cromossomos Humanos/genética , Cromotripsia , Dano ao DNA , Neoplasias/genética , Neoplasias/patologia , Humanos
9.
BMC Genomics ; 20(Suppl 2): 186, 2019 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-30967119

RESUMO

BACKGROUND: Recent advances in genome analysis have established that chromatin has preferred 3D conformations, which bring distant loci into contact. Identifying these contacts is important for us to understand possible interactions between these loci. This has motivated the creation of the Hi-C technology, which detects long-range chromosomal interactions. Distance geometry-based algorithms, such as ChromSDE and ShRec3D, have been able to utilize Hi-C data to infer 3D chromosomal structures. However, these algorithms, being matrix-based, are space- and time-consuming on very large datasets. A human genome of 100 kilobase resolution would involve ∼30,000 loci, requiring gigabytes just in storing the matrices. RESULTS: We propose a succinct representation of the distance matrices which tremendously reduces the space requirement. We give a complete solution, called SuperRec, for the inference of chromosomal structures from Hi-C data, through iterative solving the large-scale weighted multidimensional scaling problem. CONCLUSIONS: SuperRec runs faster than earlier systems without compromising on result accuracy. The SuperRec package can be obtained from http://www.cs.cityu.edu.hk/~shuaicli/SuperRec .


Assuntos
Algoritmos , Cromatina/química , Cromossomos Humanos/química , Biologia Computacional/métodos , Genoma Humano , Cromatina/genética , Cromossomos Humanos/genética , Simulação por Computador , Humanos , Modelos Moleculares , Conformação de Ácido Nucleico
10.
Acta Haematol ; 141(4): 232-244, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30965338

RESUMO

Diagnosis and classification of acute myeloid leukaemia (AML) require cytogenetic and molecular genetic investigation. However, while these evaluations are pending, morphology supplemented by immunophenotyping can provide clues to the diagnosis of specific cytogenetic/genetic categories of AML. Most importantly, acute promyelocytic leukaemia can be diagnosed with a high degree of certainty. However, provisional identification of cases associated with t(8; 21), inv(16), t(1; 22), and NPM1 mutation may also be possible. In addition, transient abnormal myelopoiesis of Down's syndrome can generally be diagnosed morphologically.


Assuntos
Inversão Cromossômica , Cromossomos Humanos/genética , Leucemia Promielocítica Aguda , Mielopoese/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Translocação Genética , Síndrome de Down/genética , Humanos , Leucemia Promielocítica Aguda/classificação , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/terapia , Organização Mundial da Saúde
11.
Nat Commun ; 10(1): 1636, 2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30967549

RESUMO

DNA fluorescence in situ hybridization (DNA FISH) is a powerful method to study chromosomal organization in single cells. At present, there is a lack of free resources of DNA FISH probes and probe design tools which can be readily applied. Here, we describe iFISH, an open-source repository currently comprising 380 DNA FISH probes targeting multiple loci on the human autosomes and chromosome X, as well as a genome-wide database of optimally designed oligonucleotides and a freely accessible web interface ( http://ifish4u.org ) that can be used to design DNA FISH probes. We individually validate 153 probes and take advantage of our probe repository to quantify the extent of intermingling between multiple heterologous chromosome pairs, showing a much higher extent of intermingling in human embryonic stem cells compared to fibroblasts. In conclusion, iFISH is a versatile and expandable resource, which can greatly facilitate the use of DNA FISH in research and diagnostics.


Assuntos
Sondas de DNA/genética , Bases de Dados de Ácidos Nucleicos , Genoma Humano/genética , Hibridização in Situ Fluorescente/métodos , Células A549 , Mapeamento Cromossômico/métodos , Cromossomos Humanos/genética , Fibroblastos , Células-Tronco Embrionárias Humanas , Humanos , Oligonucleotídeos/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos , Projetos de Pesquisa
12.
Nat Commun ; 10(1): 1845, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015419

RESUMO

To better understand human health and disease, researchers create a wide variety of mouse models that carry human DNA. With recent advances in genome engineering, the targeted replacement of mouse genomic regions with orthologous human sequences has become increasingly viable, ranging from finely tuned humanisation of individual nucleotides and amino acids to the incorporation of many megabases of human DNA. Here, we examine emerging technologies for targeted genomic humanisation, we review the spectrum of existing genomically humanised mouse models and the insights such models have provided, and consider the lessons learned for designing such models in the future.


Assuntos
Edição de Genes/métodos , Genoma Humano/genética , Camundongos/genética , Modelos Animais , Animais , Cromossomos Humanos/genética , Edição de Genes/tendências , Técnicas de Transferência de Genes/tendências , Humanos , Camundongos Transgênicos , Projetos de Pesquisa
13.
Leg Med (Tokyo) ; 37: 95-102, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30831559

RESUMO

The unknown origin of DNA samples derived from crime scenes generates a considerable amount of uncertainty, as do unexpected short tandem repeat (STR) results caused by sample mix-ups, contamination, medical interventions, and transgender individuals (broad meaning). Genetic abnormalities such as somatic/germline mutations, mosaicism or chimerism, sex reversal cases, aneuploidies, and chromosomal structural rearrangements are also possible causes of such results. The evidence offered by the present study suggested that additional DYS385 alleles, as seen in mixed stain samples and in the potentially single-source DNA profile of a female, originated from the female DNA source only. For the case reported here, we propose an interchromosomal insertion hypothesis, in which a 768-kb segment including the P4 palindrome of the azoospermia factor (AZFb) region was deleted from the Y chromosome and inserted into the X chromosome or an autosome during male meiosis. Y-SNP data points from the AccuID platform and in-house PCR assays narrowed down the expected length of the target region. Bioinformatics analysis followed by whole genome amplification and whole genome sequencing showed that a 529-kb segment including the P4 palindrome (HSFY/DYS385)/DYS460 region from the female sample mapped to the Y reference sequence (GRCh37). To our knowledge, the interchromosomal insertional translocation event was identified as an unknown type of genomic rearrangement in the forensic genetic field.


Assuntos
Azoospermia/genética , Cromossomos Humanos Y/genética , Cromossomos Humanos/genética , Genética Forense/métodos , Técnicas de Genotipagem/métodos , Sequências Repetidas Invertidas/genética , Repetições de Microssatélites/genética , Análise para Determinação do Sexo/métodos , Translocação Genética/genética , Alelos , Cromossomos Humanos X/genética , Feminino , Loci Gênicos/genética , Humanos , Masculino , Meiose/genética , Sequenciamento Completo do Genoma
14.
Int J Hematol ; 109(5): 593-602, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30830578

RESUMO

Chromosomal microdeletions frequently cause loss of prognostically relevant tumor suppressor genes in hematologic malignancies; however, detection of minute deletions by conventional methods for chromosomal analysis, such as G-banding and fluorescence in situ hybridization (FISH), is difficult due to their low resolution. Here, we describe a new diagnostic modality that enables detection of chromosomal microdeletions, using CDKN2A gene deletion in B cell lymphomas (BCLs) as an example. In this method, which we refer to as amplified-FISH (AM-FISH), a 31-kb fluorescein isothiocyanate (FITC)-conjugated DNA probe encoding only CDKN2A was first hybridized with the chromosome, and then labeled with Alexa Fluor 488-conjugated anti-FITC secondary antibody to increase sensitivity. CDKN2A signals were equally identifiable by AM-FISH and conventional FISH in normal mononuclear blood cells. In contrast, when two BCL cell lines lacking CDKN2A were analyzed, CDKN2A signals were not detected by AM-FISH, whereas conventional FISH yielded false signals. Furthermore, AM-FISH detected CDKN2A deletions in two BCL patients with 9p21 microdeletions, which were not detected by conventional FISH. These results suggest that AM-FISH is a highly sensitive, specific, and simple method for diagnosis of chromosomal microdeletions.


Assuntos
Deleção Cromossômica , Cromossomos Humanos/genética , Cromossomos Humanos/metabolismo , Hibridização in Situ Fluorescente/métodos , Linfoma de Células B/genética , Linfoma de Células B/metabolismo , Linhagem Celular Tumoral , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Humanos , Linfoma de Células B/patologia
15.
BMC Med Genet ; 20(1): 27, 2019 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-30704416

RESUMO

BACKGROUND: Myopia is one of most common eye diseases in the world and affects 1 in 4 Americans. It is a complex disease caused by both environmental and genetics effects; the genetics effects are still not well understood. In this study, we performed genetic linkage analyses on Ashkenazi Jewish families with a strong familial history of myopia to elucidate any potential causal genes. METHODS: Sixty-four extended Ashkenazi Jewish families were previously collected from New Jersey. Genotypes from the Illumina ExomePlus array were merged with prior microsatellite linkage data from these families. Additional custom markers were added for candidate regions reported in literature for myopia or refractive error. Myopia was defined as mean spherical equivalent (MSE) of -1D or worse and parametric two-point linkage analyses (using TwoPointLods) and multi-point linkage analyses (using SimWalk2) were performed as well as collapsed haplotype pattern (CHP) analysis in SEQLinkage and association analyses performed with FBAT and rv-TDT. RESULTS: Strongest evidence of linkage was on 1p36(two-point LOD = 4.47) a region previously linked to refractive error (MYP14) but not myopia. Another genome-wide significant locus was found on 8q24.22 with a maximum two-point LOD score of 3.75. CHP analysis also detected the signal on 1p36, localized to the LINC00339 gene with a maximum HLOD of 3.47, as well as genome-wide significant signals on 7q36.1 and 11p15, which overlaps with the MYP7 locus. CONCLUSIONS: We identified 2 novel linkage peaks for myopia on chromosomes 7 and 8 in these Ashkenazi Jewish families and replicated 2 more loci on chromosomes 1 and 11, one previously reported in refractive error but not myopia in these families and the other locus previously reported in the literature. Strong candidate genes have been identified within these linkage peaks in our families. Targeted sequencing in these regions will be necessary to definitively identify causal variants under these linkage peaks.


Assuntos
Cromossomos Humanos/genética , Técnicas de Genotipagem/métodos , Judeus/genética , Miopia/genética , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 7/genética , Cromossomos Humanos Par 8/genética , Exoma , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Escore Lod , Masculino , Miopia/etnologia , Linhagem , RNA Longo não Codificante/genética
16.
Ann Hematol ; 98(5): 1135-1147, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30758645

RESUMO

Core-binding factor acute myeloid leukemia (CBF-AML) data in Asian countries has been rarely reported. We analyzed 392 patients with CBF-AML [281 with t(8;21), 111 with inv.(16)/t(16;16)] among data from 3041 patients with AML from the Korean AML Registry. Interestingly, del(9q) was less frequently detected in Korean than in German patients with t(8;21) (7.5% vs. 17%), and del(7q) was more frequently detected in Korean patients with inv(16). Overall survival (OS) was similar between patients in the first complete remission (CR) who received allogeneic (alloSCT) and autologous stem cell transplantation (ASCT) for CBF-AML. OS of t(8;21) patients was poor when undergoing alloSCT in second/third CR, while OS of inv(16) patients in second/third CR was similar to that in first CR. Patients with > 3-log reduction of RUNX1/RUNX1T1 qPCR had improved 3-year event-free survival (EFS) than those without (73.2% vs. 50.3%). Patients with t(8;21) AML with D816 mutation of the c-Kit gene showed inferior EFS and OS. These poor outcomes might be overcome by alloSCT. Multivariate analysis for OS in patients with t(8;21) revealed older age, > 1 course of induction chemotherapy to achieve CR, loss of sex chromosome, del(7q), and second/third CR or not in CR before SCT as independent prognostic variables. Especially, del(7q) is the most powerful prediction factor of poor outcomes, especially in patients with t(8;21) (hazard ratio, 27.23; P < 0.001). Further study is needed to clarify the clinical effect of cytogenetics and gene mutation in patients with CBF-AML, between Asian and Western countries.


Assuntos
Cromossomos Humanos , Fatores de Ligação ao Core , Leucemia Mieloide Aguda , Sistema de Registros , Translocação Genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos/genética , Cromossomos Humanos/metabolismo , Fatores de Ligação ao Core/genética , Fatores de Ligação ao Core/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias , República da Coreia/epidemiologia , Taxa de Sobrevida
17.
Int J Mol Sci ; 20(4)2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30769866

RESUMO

BACKGROUND: The concept of "chromosomics" was introduced by Prof. Uwe Claussen in 2005. Herein, the growing insights into human chromosome structure finally lead to a "chromosomic view" of the three-dimensional constitution and plasticity of genes in interphase nuclei are discussed. This review is dedicated to the memory of Prof. Uwe Claussen (30 April 1945⁻20 July 2008). RECENT FINDINGS: Chromosomics is the study of chromosomes, their three-dimensional positioning in the interphase nucleus, the consequences from plasticity of chromosomal subregions and gene interactions, the influence of chromatin-modification-mediated events on cells, and even individuals, evolution, and disease. Progress achieved in recent years is summarized, including the detection of chromosome-chromosome-interactions which, if damaged, lead to malfunction and disease. However, chromosomics in the Human Genetics field is not progressing presently, as research interest has shifted from single cell to high throughput, genomic approaches. CONCLUSION: Chromosomics and its impact were predicted correctly in 2005 by Prof. Claussen. Although some progress was achieved, present reconsiderations of the role of the chromosome and the single cell in Human Genetic research are urgently necessary.


Assuntos
Cromossomos Humanos/genética , Citogenética/tendências , Genoma Humano/genética , Núcleo Celular/genética , Genômica/tendências , Humanos
18.
Stroke ; 50(2): 298-304, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30661490

RESUMO

Background and Purpose- We sought to explore the effect of genetic imbalance on functional outcome after ischemic stroke (IS). Methods- Copy number variation was identified in high-density single-nucleotide polymorphism microarray data of IS patients from the CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) and SiGN (Stroke Genetics Network)/GISCOME (Genetics of Ischaemic Stroke Functional Outcome) networks. Genetic imbalance, defined as total number of protein-coding genes affected by copy number variations in an individual, was compared between patients with favorable (modified Rankin Scale score of 0-2) and unfavorable (modified Rankin Scale score of ≥3) outcome after 3 months. Subgroup analyses were confined to patients with imbalance affecting ohnologs-a class of dose-sensitive genes, or to those with imbalance not affecting ohnologs. The association of imbalance with outcome was analyzed by logistic regression analysis, adjusted for age, sex, stroke subtype, stroke severity, and ancestry. Results- The study sample comprised 816 CADISP patients (age 44.2±10.3 years) and 2498 SiGN/GISCOME patients (age 67.7±14.2 years). Outcome was unfavorable in 122 CADISP and 889 SiGN/GISCOME patients. Multivariate logistic regression analysis revealed that increased genetic imbalance was associated with less favorable outcome in both samples (CADISP: P=0.0007; odds ratio=0.89; 95% CI, 0.82-0.95 and SiGN/GISCOME: P=0.0036; odds ratio=0.94; 95% CI, 0.91-0.98). The association was independent of age, sex, stroke severity on admission, stroke subtype, and ancestry. On subgroup analysis, imbalance affecting ohnologs was associated with outcome (CADISP: odds ratio=0.88; 95% CI, 0.80-0.95 and SiGN/GISCOME: odds ratio=0.93; 95% CI, 0.89-0.98) whereas imbalance without ohnologs lacked such an association. Conclusions- Increased genetic imbalance was associated with poorer functional outcome after IS in both study populations. Subgroup analysis revealed that this association was driven by presence of ohnologs in the respective copy number variations, suggesting a causal role of the deleterious effects of genetic imbalance.


Assuntos
Isquemia Encefálica/genética , Dosagem de Genes , Adulto , Idoso , Isquemia Encefálica/reabilitação , Cromossomos Humanos/genética , Seguimentos , Duplicação Gênica , Genótipo , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Recuperação de Função Fisiológica , Índice de Gravidade de Doença
19.
Nat Commun ; 10(1): 392, 2019 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-30674876

RESUMO

Focal oncogene amplification and rearrangements drive tumor growth and evolution in multiple cancer types. We present AmpliconArchitect (AA), a tool to reconstruct the fine structure of focally amplified regions using whole genome sequencing (WGS) and validate it extensively on multiple simulated and real datasets, across a wide range of coverage and copy numbers. Analysis of AA-reconstructed amplicons in a pan-cancer dataset reveals many novel properties of copy number amplifications in cancer. These findings support a model in which focal amplifications arise due to the formation and replication of extrachromosomal DNA. Applying AA to 68 viral-mediated cancer samples, we identify a large fraction of amplicons with specific structural signatures suggestive of hybrid, human-viral extrachromosomal DNA. AA reconstruction, integrated with metaphase fluorescence in situ hybridization (FISH) and PacBio sequencing on the cell-line UPCI:SCC090 confirm the extrachromosomal origin and fine structure of a Forkhead box E1 (FOXE1)-containing hybrid amplicon.


Assuntos
Amplificação de Genes , Neoplasias/genética , Algoritmos , Linhagem Celular , Linhagem Celular Tumoral , Duplicação Cromossômica , Cromossomos Humanos/genética , Computadores Moleculares , Fatores de Transcrição Forkhead/genética , Genes Virais , Humanos , Hibridização in Situ Fluorescente
20.
J Korean Med Sci ; 34(4): e27, 2019 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-30686949

RESUMO

Background: The standard morphological evaluation has been widely used for embryo selection, but it has limitations. This study aimed to investigate the correlation between morphologic grading and euploidy rate of in vitro fertilization (IVF) preimplantation genetic screening (PGS) and compare the pregnancy rates in young and old ages. Methods: This is a retrospective study using the medical records of patients who underwent IVF procedures with PGS between January 2016 and February 2017 in a single center. The embryo grades were categorized into 4 groups: excellent, good, fair, and poor. Basic characteristics, euploidy rates, clinical pregnancy (CP) rates and ongoing pregnancy rates were analyzed. Results: The excellent group had significantly higher rate of euploid embryos than fair group (47.82% vs. 29.33%; P = 0.023) and poor group (47.82% vs. 29.60%; P = 0.005). When the four groups were recategorized into two groups (excellent and good vs. fair and poor), they also showed significant difference in euploidy rates (44.52% vs. 29.53%; P = 0.002). When the patients were divided into two groups by age 35, the CP rates for those under and over 35 years old were 44.74% and 47.83%, respectively, which showed no significant difference. Conclusion: The significant differences among the euploidy rates of different morphologic embryo grades demonstrated the positive correlations between the morphologic grading of the embryo and the euploidy rate of PGS. Additionally, there was no significant difference between the younger and older patients' CP rates. These findings emphasize the fact that old age patients might benefit from PGS whatever the indication of PGS is.


Assuntos
Blastocisto/citologia , Fertilização In Vitro/métodos , Testes Genéticos , Diagnóstico Pré-Implantação , Adulto , Blastocisto/patologia , Cromossomos Humanos/genética , Transferência Embrionária , Embrião de Mamíferos/citologia , Feminino , Humanos , Modelos Logísticos , Masculino , Idade Materna , Gravidez , Taxa de Gravidez , Estudos Retrospectivos
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