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1.
Nat Commun ; 11(1): 5070, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33033260

RESUMO

The evolutionary progression from primary to metastatic prostate cancer is largely uncharted, and the implications for liquid biopsy are unexplored. We infer detailed reconstructions of tumor phylogenies in ten prostate cancer patients with fatal disease, and investigate them in conjunction with histopathology and tumor DNA extracted from blood and cerebrospinal fluid. Substantial evolution occurs within the prostate, resulting in branching into multiple spatially intermixed lineages. One dominant lineage emerges that initiates and drives systemic metastasis, where polyclonal seeding between sites is common. Routes to metastasis differ between patients, and likely genetic drivers of metastasis distinguish the metastatic lineage from the lineage that remains confined to the prostate within each patient. Body fluids capture features of the dominant lineage, and subclonal expansions that occur in the metastatic phase are non-uniformly represented. Cerebrospinal fluid analysis reveals lineages not detected in blood-borne DNA, suggesting possible clinical utility.


Assuntos
Linhagem da Célula , Biópsia Líquida , Neoplasias da Próstata/patologia , Líquidos Corporais/metabolismo , Cromossomos Humanos Par 8/genética , Células Clonais , Variações do Número de Cópias de DNA/genética , DNA de Neoplasias/genética , Loci Gênicos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Filogenia
2.
Nat Commun ; 11(1): 4469, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32901013

RESUMO

Dissecting tumor heterogeneity is a key to understanding the complex mechanisms underlying drug resistance in cancers. The rich literature of pioneering studies on tumor heterogeneity analysis spurred a recent community-wide benchmark study that compares diverse modeling algorithms. Here we present FastClone, a top-performing algorithm in accuracy in this benchmark. FastClone improves over existing methods by allowing the deconvolution of subclones that have independent copy number variation events within the same chromosome regions. We characterize the behavior of FastClone in identifying subclones using stage III colon cancer primary tumor samples as well as simulated data. It achieves approximately 100-fold acceleration in computation for both simulated and patient data. The efficacy of FastClone will allow its application to large-scale data and clinical data, and facilitate personalized medicine in cancers.


Assuntos
Algoritmos , Variações do Número de Cópias de DNA , Neoplasias/genética , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Biologia Computacional/métodos , Simulação por Computador , DNA de Neoplasias/genética , Resistencia a Medicamentos Antineoplásicos/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Modelos Genéticos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Filogenia , Medicina de Precisão , Análise de Sequência de DNA
3.
Biochim Biophys Acta Rev Cancer ; 1874(1): 188392, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32735964

RESUMO

Although the eukaryotic genome is mainly comprised of linear chromosomal DNA, genes can also be found outside of chromosomes. The unconventional presence of extrachromosomal genes is usually found to be circular, and these structures are named extrachromosomal circular DNA (eccDNA), which are often observed in cancer cells. Various types of eccDNA including small polydispersed DNA (spcDNA), telomeric cirlces, microDNA, etc. have been discovered. Among these eccDNA, extrachromosomal DNA (ecDNA), which encompasses the full spectrum of large, gene-containing extrachromosomal particles, has regained great research interest due to recent technological advances such as next-generation sequencing and super-resolution microscopy. In this review, we summarize the different types of eccDNA and discuss the role of eccDNA, especially ecDNA in tumor heterogeneity and progression. Additionally, we discuss some possible future investigative directions related to ecDNA biogenesis and its clinical application.


Assuntos
DNA Circular/classificação , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Heterogeneidade Genética , Neoplasias/genética , DNA Circular/genética , DNA Circular/metabolismo , DNA de Neoplasias/química , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Amplificação de Genes , Humanos , Micronúcleos com Defeito Cromossômico , Neoplasias/patologia , Neoplasias/terapia , Biogênese de Organelas
4.
Medicine (Baltimore) ; 99(21): e20299, 2020 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-32481313

RESUMO

BACKGROUND: The role of xeroderma pigmentosum complementation group D (XPD) gene polymorphisms in breast and ovarian cancer development has long been controversial and existing data were inconsistent. Here, we conducted a comprehensive systemic review and meta-analysis to better clarify the association. METHODS: Relevant case-control studies published in electronic data base from October 1999 to September 2019 were assessed. The statistical analyses of the pooled odds ratios (ORs) and the corresponding 95% confidence intervals (95%CIs) were calculated by using Revman 5.2 software (Cochrane Collaboration, Copenhagen). RESULTS: 31 articles including 38 case-control studies and 2 XPD polymorphisms (rs1799793 and rs238406) were analyzed. The results showed statistical significance in heterozygous mutants among Asian population for rs1799793 (GA vs GG + AA: OR = 1.38, 95%CI = 1.21-1.56), and Caucasian population for rs238406 (CA vs AA + CC: OR = 0.63, 95%CI = 0.49-0.80), while the rest comparisons including overall groups and subgroups stratified by cancer types and ethnicity failed to indicate any association with breast and ovarian cancer risk. CONCLUSIONS: The current meta-analysis suggested no concrete correlation of XPD rs1799793(G/A) and rs238406(C/A) polymorphisms with breast cancer or ovarian cancer susceptibility. However, it indicated that heterozygous genotypes might share different pathophysiologic mechanism from not only homozygous wildtypes but also homozygous mutants. More case-control studies with well-adjusted data and diverse populations are essential for validation of our conclusion.


Assuntos
Neoplasias da Mama/genética , DNA de Neoplasias/genética , Neoplasias Ovarianas/genética , Polimorfismo de Nucleotídeo Único , Proteína Grupo D do Xeroderma Pigmentoso/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Feminino , Humanos , Neoplasias Ovarianas/metabolismo , Proteína Grupo D do Xeroderma Pigmentoso/metabolismo
5.
Nat Med ; 26(7): 1114-1124, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32483360

RESUMO

In many areas of oncology, we lack sensitive tools to track low-burden disease. Although cell-free DNA (cfDNA) shows promise in detecting cancer mutations, we found that the combination of low tumor fraction (TF) and limited number of DNA fragments restricts low-disease-burden monitoring through the prevailing deep targeted sequencing paradigm. We reasoned that breadth may supplant depth of sequencing to overcome the barrier of cfDNA abundance. Whole-genome sequencing (WGS) of cfDNA allowed ultra-sensitive detection, capitalizing on the cumulative signal of thousands of somatic mutations observed in solid malignancies, with TF detection sensitivity as low as 10-5. The WGS approach enabled dynamic tumor burden tracking and postoperative residual disease detection, associated with adverse outcome. Thus, we present an orthogonal framework for cfDNA cancer monitoring via genome-wide mutational integration, enabling ultra-sensitive detection, overcoming the limitation of cfDNA abundance and empowering treatment optimization in low-disease-burden oncology care.


Assuntos
Biomarcadores Tumorais/genética , DNA Tumoral Circulante/sangue , DNA de Neoplasias/genética , Neoplasias/sangue , Biomarcadores Tumorais/sangue , Ácidos Nucleicos Livres/sangue , Variações do Número de Cópias de DNA/genética , DNA de Neoplasias/sangue , Intervalo Livre de Doença , Feminino , Genoma Humano/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Estimativa de Kaplan-Meier , Masculino , Mutação/genética , Neoplasias/genética , Neoplasias/patologia , Carga Tumoral/genética , Sequenciamento Completo do Genoma
6.
PLoS One ; 15(6): e0233445, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32497048

RESUMO

OBJECTIVE: The present study aims to explore the role of smoking factors in the risk of lung cancer and screen the feature risk pathways of smoking-induced lung cancer. METHODS: The expression profiles of the patient data from GEO database were standardized, and differentially expressed genes (DEGs) were analyzed by limma algorithm. Samples and genes were analyzed by Unsupervised hierarchical clustering method, while GO and KEGG enrichment analyses were performed on DEGs. The data of the protein-protein interaction (PPI) network were downloaded from the BioGrid and HPRD databases, and the DEGs were mapped into the PPI network to identify the interaction relationship. The enriched significant pathways were used to calculate the anomaly score and RFE method was used to optimize the feature sets. The model was trained using the support vector machine (SVM) and the predicted results were plotted into ROC curves. The AUC value was calculated to evaluate the predictive performance of the SVM model. RESULTS: A total of 1923 DEGs were obtained, of which 826 were down-regulated and 1097 were up-regulated. Unsupervised hierarchical clustering analysis showed that the diagnosis accuracy of lung cancer smokers was 74%, and that of non-lung cancer smokers was 75%. Five optimal feature pathway sets were obtained by screening, the clinical diagnostic ability of which was detected by SVM model with the accuracy improved to 84%. The diagnostic accuracy was 90% after combining clinical information. CONCLUSION: We verified that five signaling pathways combined with clinical information could be used as a feature risk pathway for identifying lung cancer smokers and non-lung cancer smokers and increased the diagnostic accuracy.


Assuntos
Perfilação da Expressão Gênica , Neoplasias Pulmonares/etiologia , Fumar/efeitos adversos , Máquina de Vetores de Suporte , Área Sob a Curva , Análise por Conglomerados , DNA de Neoplasias/análise , DNA de Neoplasias/genética , Bases de Dados Genéticas , Ontologia Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , Mapeamento de Interação de Proteínas , Curva ROC , Fatores de Risco , Transdução de Sinais
7.
Medicine (Baltimore) ; 99(26): e20431, 2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32590728

RESUMO

BACKGROUND: Lung Cancer is one of the most common cancers with high degree of malignancy, is a devastating disease with a poor prognosis worldwide. prognostic prediction for patients with non small-cell lung cancer (NSCLC) is still challenge. MATERIAL AND METHODS: The cohort consisted of 64 consecutive patients with NSCLC identified from June1, 2014, to June 30, 2018. Liquid biopsy samples were collected. Genomic mutation DNA was calculated by including all substitutions and indels over the entire somatic, coding, sequencing length. statistical evaluations were carried out using SPSS software. RESULTS: Quantity of total ctDNA was successfully determined in all 64 patients from whom baseline circulating DNA was available. ctDNA concentration ranged from 4000 to 3,562,000 genome equivalents per milliliter. Treatments induced a significant decrease in cancer specific markers in most patients with response to treatments, while the methylated DNA demonstrated favorable prediction efficiency regardless of the response status. Patients with ctDNA mutation and methylated DNA decreasing have favorable overall survival (P < .05). combination of genetic and methylated DNA decreasing had high reliability in predicting overall survival of patients with NSCLC. CONCLUSIONS: We have detected both tumor mutations and methylated DNA in plasma of patients with NSCLC. Combined genetic and methylated DNA decreasing after treatment was an independent risk factor for prognosis of patients with NSCLC. Meanwhile, it had favorable predict value and had potential to be defined as a novel biomarker for patients with NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Metilação de DNA , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Mutação , Carcinoma Pulmonar de Células não Pequenas/terapia , Ácidos Nucleicos Livres/sangue , China , DNA Tumoral Circulante , Estudos de Coortes , DNA de Neoplasias/genética , Feminino , Humanos , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico
8.
PLoS One ; 15(6): e0233900, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32520976

RESUMO

OBJECTIVES: To identify differences in the mutational profile of endometrial tumours between British White (BW) and South Asian (BSA) women. METHODS: We analysed primary tumours from matched cohorts of British White (BW) and British South Asian (BSA) women resident in Leicestershire diagnosed with EC. Next Generation Sequencing was performed to investigate mutational differences in a panel of 10 genes previously identified as being commonly mutated in EC. The presence of somatic Mismatch Repair (MMR) gene deficiencies was determined by immunohistochemistry. RESULTS: In total, 57 tumours (27 BSA and 30 BW) were sequenced. There was no significant difference in the overall mutation frequency of the 10 genes analysed; however, numerous differences were observed between the groups. There was a positive association between PIK3CA and PTEN mutations in the BSA group, with 78% of PIK3CA-mutant tumours harbouring a PTEN mutation, whereas only 11% of PIK3CA wild-type (wt) tumours were PTEN mutant positive (p = 0.0012). In BW women, 90% of ARID1A mutant tumours had co-existent PI3K pathway mutations versus 50% of wild-type (wt) ARID1A patients (p = 0.0485). This trend was not significant in the BSA group (p = 0.66). The age at diagnosis was significantly higher in the BW group with a somatic MMR gene deficiency compared to those with no deficiency (72.8 years versus 59.6 years, p = 0.007), whereas this difference was not seen in the BSA group (64 years versus 60 years, p = 0.37). CONCLUSION: We have identified differences in the mutational profile of primary EC tumours from BW and BSA women. Further research is needed to confirm these findings and to explore their potential implications for early detection, treatment response and prognosis.


Assuntos
Carcinoma Endometrioide/genética , Enzimas Reparadoras do DNA/genética , DNA de Neoplasias/genética , Neoplasias do Endométrio/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático , Estudos de Coortes , Análise Mutacional de DNA/métodos , Grupo com Ancestrais do Continente Europeu , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Pessoa de Meia-Idade , Mutação , Reino Unido
9.
PLoS One ; 15(5): e0233461, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32442190

RESUMO

Cancer development has been ascribed with diverse genetic variations which are identified in both mitochondrial and nuclear genomes. Mitochondrial DNA (mtDNA) alterations have been detected in several tumours which include lung, colorectal, renal, pancreatic and breast cancer. Several studies have explored the breast tumour-specific mtDNA alteration mainly in Western population. This study aims to identify mtDNA alterations of 20 breast cancer patients in Malaysia by next generation sequencing analysis. Twenty matched tumours with corresponding normal breast tissues were obtained from female breast cancer patients who underwent mastectomy. Total DNA was extracted from all samples and the entire mtDNA (16.6kb) was amplified using long range PCR amplification. The amplified PCR products were sequenced using mtDNA next-generation sequencing (NGS) on an Illumina Miseq platform. Sequencing involves the entire mtDNA (16.6kb) from all pairs of samples with high-coverage (~ 9,544 reads per base). MtDNA variants were called and annotated using mtDNA-Server, a web server. A total of 18 of 20 patients had at least one somatic mtDNA mutation in their tumour samples. Overall, 65 somatic mutations were identified, with 30 novel mutations. The majority (59%) of the somatic mutations were in the coding region, whereas only 11% of the mutations occurred in the D-loop. Notably, somatic mutations in protein-coding regions were non-synonymous (49%) in which 15.4% of them are potentially deleterious. A total of 753 germline mutations were identified and four of which were novel mutations. Compared to somatic alterations, less than 1% of germline missense mutations are harmful. The findings of this study may enhance the current knowledge of mtDNA alterations in breast cancer. To date, the catalogue of mutations identified in this study is the first evidence of mtDNA alterations in Malaysian female breast cancer patients.


Assuntos
Neoplasias da Mama/genética , DNA Mitocondrial/genética , DNA de Neoplasias/genética , Mutação , Adulto , Idoso , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Análise Mutacional de DNA , Feminino , Genoma Mitocondrial , Mutação em Linhagem Germinativa , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Malásia , Pessoa de Meia-Idade , Fosforilação Oxidativa , Análise de Sequência de DNA
10.
Virchows Arch ; 477(4): 527-534, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32296928

RESUMO

The distinction between well-differentiated intrahepatic cholangiocarcinoma (iCCA) from its morphological mimics such as bile duct adenoma (BDA) and hamartoma (BDH) can be challenging, particularly in small biopsies. Although a few cases of BDA and BDH have been reported to undergo malignant transformation into iCCA, their neoplastic versus benign nature remains debated. DNA flow cytometry was performed on 47 formalin-fixed paraffin-embedded samples of iCCA, 14 BDA, and 18 BDH. Aneuploidy was detected in 22 iCCA (47%) but in none of the 32 BDA and BDH samples. Among the 34 iCCA patients who underwent complete resection and were followed up to tumor recurrence, tumor-related death, or at least for 1 year, the overall recurrence or death rates (regardless of flow cytometric results) were 18, 56, and 71% within 1, 3, and 5 years, respectively. The 1-, 3-, and 5-year recurrence or death rates in 18 iCCA patients with aneuploidy were 28, 66, and 66%, respectively, whereas 16 iCCA patients in the setting of normal DNA content had 1-, 3-, and 5-year rates of 6, 44, and 72%, respectively. Although aneuploid tumors were associated with worse outcomes during the first 3 years, this difference was not statistically significant (hazard ratio = 1.4, p = 0.473) in the present sample size. In conclusion, the frequency of aneuploidy was significantly higher in iCCA (47%) than in its benign morphological mimics (0%), suggesting that it may potentially serve as a diagnostic marker of malignancy in challenging situations. Our findings also suggest that most BDAs and BDHs, if not all, are benign entities and may not represent precursor lesions to iCCAs that often harbor aneuploidy. Although a larger cohort will be necessary to further determine the prognostic significance of aneuploidy in iCCA patients after resection, the patients with aneuploid tumors may have a higher risk for tumor progression, especially during the first 3 years.


Assuntos
Adenoma/genética , Aneuploidia , Neoplasias dos Ductos Biliares/genética , Colangiocarcinoma/genética , DNA de Neoplasias/genética , Citometria de Fluxo , Hamartoma/genética , Adenoma/mortalidade , Adenoma/patologia , Adenoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/cirurgia , Colangiocarcinoma/mortalidade , Colangiocarcinoma/patologia , Colangiocarcinoma/cirurgia , Bases de Dados Factuais , Diagnóstico Diferencial , Progressão da Doença , Feminino , Hamartoma/mortalidade , Hamartoma/patologia , Hamartoma/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Fatores de Risco , Fatores de Tempo
11.
Georgian Med News ; (299): 147-150, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32242863

RESUMO

Gastric cancer represents the fifth most common malignancy and third most common cause of cancer deaths worldwide. There are two major types of gastric carcinoma: enteric type and diffuse type. Diffuse type gastric cancer is frequently associated with the mutations in E-cadherin coding gene CDH1. In cases of CDH1 mutations complete gastrectomy is indicated. CDH1 mutations are reflected with CDH1 protein loss by immunohistochemistry. The relationship between CDH1 mutations and other markers of tumour aggressiveness, such as tumour proliferation index and the presence of p53 mutations and Her2 amplification is not well studied. Therefore, the aim of our study was to analyse the correlation between CDH1 loss and the expression of Ki67 proliferation marker, mutant oncoprotein p53 and Her2. Standard immunohistochemistry was used to detect the following antigens: CDH1 (MCH-38, Invitrogen), Ki67 (EP5, Bio SB), p53 (DO-7, Leica) and Her2 (EP3, Bio SB). The study results showed that CDH1 mutations, reflected with CDH1 protein loss by immunohistochemistry are detected in 40% of diffuse gastric carcinomas, whilst it is not detected in enteric type gastric carcinomas. Diffuse gastric carcinomas with CDH1 mutations are characterised with more aggressive phenotype, particularly with the presence of higher Ki67 labelling index, p53 mutations and the presence of Her2 positivity. In cases of histological diagnosis of diffuse gastric carcinoma CDH1 testing is recommended.


Assuntos
Antígenos CD/genética , Caderinas/genética , Genes erbB-2/genética , Antígeno Ki-67/genética , Neoplasias Gástricas/genética , Proteína Supressora de Tumor p53/genética , Análise Mutacional de DNA , DNA de Neoplasias/genética , Gastrectomia , Marcadores Genéticos , Predisposição Genética para Doença , Testes Genéticos/métodos , Humanos , Mutação , Reação em Cadeia da Polimerase , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia
12.
Cancer Cell ; 37(4): 485-495, 2020 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-32289272

RESUMO

Predictive biomarkers aid selection of personalized therapy targeted to molecular alterations within an individual's tumor. Patients' responses to targeted therapies are commonly followed by treatment resistance. Here, we survey liquid biopsies as alternatives to tumor biopsies to assess predictive and therapy response biomarkers. We examine the potential of liquid biopsies to meet the challenges of minimal residual disease monitoring after curative intent treatment for earlier detection of disease recurrence. We focus on blood, the most commonly collected minimally invasive clinical sample, and on the two most widely studied assays, circulating tumor DNA and circulating tumor cells.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , DNA de Neoplasias/análise , Resistencia a Medicamentos Antineoplásicos/genética , Biópsia Líquida/métodos , Neoplasias/patologia , Células Neoplásicas Circulantes/patologia , DNA de Neoplasias/genética , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Medicina de Precisão
13.
Med Sci Monit ; 26: e921040, 2020 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-32200389

RESUMO

Circulating tumor DNA (ctDNA) describes the fragmented DNA released from tumor cells into the blood. The ctDNA may have the same genetic changes as the primary tumor. Currently, ctDNA has become a popular biomarker for diagnosis, treatment, real-time clinical response monitoring, and prognosis, for solid tumors. Detection of ctDNA is minimally invasive, and repeat sampling can easily be performed. However, due to its low quality and short DNA fragment length, ctDNA detection still faces challenges and requires highly sensitive analytical techniques. Recently, liquid biopsies for the analysis of circulating tumor cells (CTCs) and circulating tumor-derived exosomes have been studied, and nanotechnology techniques have rapidly developed. Compared to traditional analytical methods, these nanotechnology-based platforms have the advantages of sensitivity, multiplex detection, simplicity, miniaturization, and automation, which support their potential use in clinical practice. This review aims to discuss the recent nanotechnological strategies for ctDNA analysis and the design of reliable techniques for ctDNA detection and to identify the potential clinical applications.


Assuntos
DNA Tumoral Circulante/sangue , DNA de Neoplasias/genética , Nanotecnologia/métodos , Neoplasias/genética , Células Neoplásicas Circulantes/metabolismo , Biomarcadores Tumorais/sangue , DNA Tumoral Circulante/genética , DNA de Neoplasias/sangue , Detecção Precoce de Câncer/métodos , Humanos , Biópsia Líquida , Neoplasias/sangue , Neoplasias/diagnóstico
14.
Mutat Res ; 819-820: 111694, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32120135

RESUMO

Precise execution of the cell division cycle is vital for all organisms. The Cyclin dependent kinases (CDKs) are the main cell cycle drivers, however, their activities must be precisely fine-tuned to ensure orderly cell cycle progression. A major regulatory axis is guarded by WEE1 kinase, which directly phosphorylates and inhibits CDK1 and CDK2. The role of WEE1 in the G2/M cell-cycle phase has been thoroughly investigated, and it is a focal point of multiple clinical trials targeting a variety of cancers in combination with DNA-damaging chemotherapeutic agents. However, the emerging role of WEE1 in S phase has so far largely been neglected. Here, we review how WEE1 regulates cell-cycle progression highlighting the importance of this kinase for proper S phase. We discuss how its function is modulated throughout different cell-cycle stages and provide an overview of how WEE1 levels are regulated. Furthermore, we outline recent clinical trials targeting WEE1 and elaborate on the mechanisms behind the anticancer efficacy of WEE1 inhibition. Finally, we consider novel biomarkers that may benefit WEE1-inhibition approaches in the clinic.


Assuntos
Proteína Quinase CDC2/genética , Proteínas de Ciclo Celular/genética , Quinase 2 Dependente de Ciclina/genética , Replicação do DNA , DNA de Neoplasias/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , Proteínas Tirosina Quinases/genética , Antineoplásicos/uso terapêutico , Proteína Quinase CDC2/metabolismo , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Ensaios Clínicos como Assunto , Quinase 2 Dependente de Ciclina/metabolismo , Dano ao DNA , Reparo do DNA/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , DNA de Neoplasias/metabolismo , Humanos , Mitose/efeitos dos fármacos , Terapia de Alvo Molecular/métodos , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Neoplasias/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Fase S/efeitos dos fármacos , Fase S/genética , Transdução de Sinais
15.
Proc Jpn Acad Ser B Phys Biol Sci ; 96(3): 107-121, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32161209

RESUMO

During the past decade, substantial progress has been made in the field of the genetics of myelodysplastic syndromes (MDS). These comprise a group of chronic myeloid neoplasms with abnormal cell morphology and progression to acute myeloid leukemia (AML), where revolutionary sequencing technologies have played a major role. Through extensive sequencing of a large number of MDS genomes, a comprehensive registry of driver mutations involved in the pathogenesis of MDS has been revealed, along with their impacts on clinical phenotype and prognosis. The most frequently affected molecules are involved in DNA methylations, chromatin modification, RNA splicing, transcription, signal transduction, cohesin regulation, and DNA repair. These mutations show strong positive and negative correlations with each other, suggesting the presence of functional interactions between mutations, which dictate disease progression. Because these mutations are associated with disease phenotype, drug response, and clinical outcomes, it is essential to be familiar with MDS genetics not only for better understanding of MDS pathogenesis but also for management of patients.


Assuntos
DNA de Neoplasias/genética , Síndromes Mielodisplásicas/classificação , Síndromes Mielodisplásicas/genética , Proteínas de Ciclo Celular/genética , Proteínas Cromossômicas não Histona/genética , Metilação de DNA , Reparo do DNA , DNA de Neoplasias/metabolismo , Progressão da Doença , Regulação Leucêmica da Expressão Gênica , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide de Fase Crônica/genética , Mutação , Fenótipo , Prognóstico , Processamento de RNA , Análise de Sequência de DNA , Transdução de Sinais
16.
J Cancer Res Clin Oncol ; 146(5): 1115-1124, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32144534

RESUMO

PURPOSE: Aberrant DNA methylation could regulate the expression of tumor suppressor gene DLEC1 and oncogene PBX3 and was related to the occurrence and prognosis of gastric cancer (GC). In this study, the associations between DLEC1 and PBX3 promoter methylation in peripheral blood leukocytes (PBLs) and the risk and prognosis of GC were investigated. METHODS: The methylation status of DLEC1 and PBX3 promoter in PBLs of 368 GC cases and 382 controls was detected by the methylation-sensitive high-resolution melting (MS-HRM) method. Logistic and Cox regression were adopted to analyze the associations of DLEC1 and PBX3 methylation with GC risk and prognosis, respectively. Confounding biases were controlled by propensity score (PS). RESULTS: Compared with negative methylation (Nm), DLEC1-positive methylation (Pm) was associated with increased GC risk in PS (OR 2.083, 95% CI 1.220-3.558, P = 0.007), but PBX3 Pm was not associated with GC risk. In the elderly group (≥ 60 years), DLEC1 Pm was associated with increased GC risk (OR 2.951, 95% CI 1.426-6.104, P = 0.004). The combined effects between DLEC1 methylation and consumption of dairy products, fried food intake and Helicobacter pylori (H. pylori) infection on GC risk were discovered (ORc 3.461, 95% CI 1.847-6.486, P < 0.001, ORc 3.246, 95% CI 1.708-6.170, P < 0.001 and ORc 2.964, 95% CI 1.690-5.197, P < 0.001, respectively). Furthermore, DLEC1 and PBX3 methylation were not associated with GC prognosis. CONCLUSION: DLEC1 methylation in PBLs and the combined effects of gene-environment can influence GC risk.


Assuntos
Proteínas de Homeodomínio/genética , Leucócitos/metabolismo , Proteínas Proto-Oncogênicas/genética , Neoplasias Gástricas/genética , Proteínas Supressoras de Tumor/genética , Estudos de Casos e Controles , Metilação de DNA , DNA de Neoplasias/sangue , DNA de Neoplasias/genética , Feminino , Interação Gene-Ambiente , Predisposição Genética para Doença , Infecções por Helicobacter/genética , Helicobacter pylori/isolamento & purificação , Humanos , Leucócitos/patologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Neoplasias Gástricas/sangue , Neoplasias Gástricas/patologia
18.
Mutat Res ; 819-820: 111690, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32120136

RESUMO

The serine/threonine kinase AKT, also known as protein kinase B (PKB), is the major substrate to phosphoinositide 3-kinase (PI3K) and consists of three paralogs: AKT1 (PKBα), AKT2 (PKBß) and AKT3 (PKBγ). The PI3K/AKT pathway is normally activated by binding of ligands to membrane-bound receptor tyrosine kinases (RTKs) as well as downstream to G-protein coupled receptors and integrin-linked kinase. Through multiple downstream substrates, activated AKT controls a wide variety of cellular functions including cell proliferation, survival, metabolism, and angiogenesis in both normal and malignant cells. In human cancers, the PI3K/AKT pathway is most frequently hyperactivated due to mutations and/or overexpression of upstream components. Aberrant expression of RTKs, gain of function mutations in PIK3CA, RAS, PDPK1, and AKT itself, as well as loss of function mutation in AKT phosphatases are genetic lesions that confer hyperactivation of AKT. Activated AKT stimulates DNA repair, e.g. double strand break repair after radiotherapy. Likewise, AKT attenuates chemotherapy-induced apoptosis. These observations suggest that a crucial link exists between AKT and DNA damage. Thus, AKT could be a major predictive marker of conventional cancer therapy, molecularly targeted therapy, and immunotherapy for solid tumors. In this review, we summarize the current understanding by which activated AKT mediates resistance to cancer treatment modalities, i.e. radiotherapy, chemotherapy, and RTK targeted therapy. Next, the effect of AKT on response of tumor cells to RTK targeted strategies will be discussed. Finally, we will provide a brief summary on the clinical trials of AKT inhibitors in combination with radiochemotherapy, RTK targeted therapy, and immunotherapy.


Assuntos
DNA de Neoplasias/genética , Regulação Neoplásica da Expressão Gênica , Terapia de Alvo Molecular/métodos , Neoplasias/terapia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Quinases Dependentes de 3-Fosfoinositídeo/genética , Proteínas Quinases Dependentes de 3-Fosfoinositídeo/metabolismo , Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto , Dano ao DNA , Reparo do DNA/efeitos dos fármacos , DNA de Neoplasias/metabolismo , Raios gama/uso terapêutico , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/genética , Isoenzimas/metabolismo , Neoplasias/enzimologia , Neoplasias/genética , Neoplasias/patologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Resultado do Tratamento , Proteínas ras/genética , Proteínas ras/metabolismo
19.
Sci Adv ; 6(10): eaaz0575, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32181355

RESUMO

Although photodynamic therapy (PDT) has been clinically applied tumor hypoxia still greatly restricts the performance of this oxygen-dependent oncological treatment. The delivery of oxygen donors to tumor may produce excessive reactive oxygen species (ROS) and damage the peripheral tissues. Herein, we developed a strategy to solve the hypoxia issue by enhancing the lethality of ROS. Before PDT, the ROS-defensing system of the cancer cells was obstructed by an inhibitor to MTH1, which is a key for the remediation of ROS-caused DNA damage. As a result, both nuclei and mitochondrial DNA damages were increased, remarkably promoting cellular apoptosis. The therapeutic results demonstrated that the performance of PDT can be improved by the MTH1 inhibitor, leading to efficient cancer cell killing effect in the hypoxic tumor. This strategy makes better use of the limited oxygen, holding the promise to achieve satisfactory therapeutic effect by PDT without generating redundant cytotoxic ROS.


Assuntos
Antineoplásicos/farmacologia , Enzimas Reparadoras do DNA/genética , DNA de Neoplasias/genética , Inibidores Enzimáticos/farmacologia , Melanoma Experimental/tratamento farmacológico , Monoéster Fosfórico Hidrolases/genética , Pirimidinas/farmacologia , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/genética , Enzimas Reparadoras do DNA/antagonistas & inibidores , Enzimas Reparadoras do DNA/metabolismo , DNA de Neoplasias/antagonistas & inibidores , DNA de Neoplasias/metabolismo , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/síntese química , Composição de Medicamentos/métodos , Inibidores Enzimáticos/química , Feminino , Expressão Gênica , Células HCT116 , Células HeLa , Humanos , Luz , Células MCF-7 , Melanoma Experimental/enzimologia , Melanoma Experimental/patologia , Camundongos Nus , Nanopartículas/administração & dosagem , Nanopartículas/química , Monoéster Fosfórico Hidrolases/antagonistas & inibidores , Monoéster Fosfórico Hidrolases/metabolismo , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacocinética , Porfirinas/química , Porfirinas/farmacocinética , Pirimidinas/química , Espécies Reativas de Oxigênio/metabolismo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Life Sci ; 248: 117467, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32105706

RESUMO

BACKGROUND: NQO1 protein acts as a cellular protective system, on account of its role as a quinone reductase and redox regulator. Nonetheless, new NQO1 roles are emerging-including its regulation of the cellular proliferation of many tumor cells-and this enzyme has been found to relate to the incidence of various diseases, including chronic myeloid leukemia. However, the mechanisms through which NQO1 influences leukemia progression remain unclear. MARTIAL AND METHODS: The current study looks to name NQO1 as a novel molecular target that modulates DNA synthesis and chronic myeloid leukemia growth. RESULTS AND CONCLUSION: Our results indicate that the frequency of the T allele of NQO1 polymorphism in chronic myeloid leukemia patients is higher than that among healthy East Asian individuals (0.492 vs. 0.419) and much higher than the average level of the general population (0.492 vs. 0.289) (1000 Genomes). Functionally, NQO1 knockdown increases the protein expression of the TOP2A and MCM complex, and consequently promotes DNA synthesis and K562 cell growth. NQO1 knockdown also promotes tumorigenesis in a xenograft model. NQO1 overexpression, on the other hand, was found to have the opposite effects. SIGNIFICANCE: Our results show that NQO1 downregulation promotes K562 cellular proliferation via the elevation of DNA synthesis.


Assuntos
DNA de Neoplasias/genética , Regulação Leucêmica da Expressão Gênica , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucócitos/metabolismo , NAD(P)H Desidrogenase (Quinona)/genética , Adulto , Alelos , Animais , Grupo com Ancestrais do Continente Asiático , Linhagem Celular Tumoral , Proliferação de Células , DNA Topoisomerases Tipo II/genética , DNA Topoisomerases Tipo II/metabolismo , DNA de Neoplasias/biossíntese , Feminino , Xenoenxertos , Humanos , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/etnologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucócitos/patologia , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , NAD(P)H Desidrogenase (Quinona)/antagonistas & inibidores , NAD(P)H Desidrogenase (Quinona)/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/genética , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Polimorfismo Genético , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais
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