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2.
PLoS One ; 15(7): e0235613, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32634176

RESUMO

Germline variants inactivating the mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 cause Lynch syndrome that implies an increased cancer risk, where colon and endometrial cancer are the most frequent. Identification of these pathogenic variants is important to identify endometrial cancer patients with inherited increased risk of new cancers, in order to offer them lifesaving surveillance. However, several other genes are also part of the MMR pathway. It is therefore relevant to search for variants in additional genes that may be associated with cancer risk by including all known genes involved in the MMR pathway. Next-generation sequencing was used to screen 22 genes involved in the MMR pathway in constitutional DNA extracted from full blood from 199 unselected endometrial cancer patients. Bioinformatic pipelines were developed for identification and functional annotation of variants, using several different software tools and custom programs. This facilitated identification of 22 exonic, 4 UTR and 9 intronic variants that could be classified according to pathogenicity. This study has identified several germline variants in genes of the MMR pathway that potentially may be associated with an increased risk for cancer, in particular endometrial cancer, and therefore are relevant for further investigation. We have also developed bioinformatics strategies to analyse targeted sequencing data, including low quality data and genomic regions outside of the protein coding exons of the relevant genes.


Assuntos
Reparo de Erro de Pareamento de DNA , Neoplasias do Endométrio/patologia , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Variações do Número de Cópias de DNA , DNA de Neoplasias/sangue , DNA de Neoplasias/química , DNA de Neoplasias/metabolismo , Neoplasias do Endométrio/genética , Éxons , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Íntrons , Fatores de Risco , Regiões não Traduzidas/genética
3.
Nat Commun ; 11(1): 3166, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32576827

RESUMO

Mutational processes acting on cancer genomes can be traced by investigating mutational signatures. Because high sequencing costs limit current studies to small numbers of good-quality samples, we propose a robust, cost- and time-effective method, called mutREAD, to detect mutational signatures from small quantities of DNA, including degraded samples. We show that mutREAD recapitulates mutational signatures identified by whole genome sequencing, and will ultimately allow the study of mutational signatures in larger cohorts and, by compatibility with formalin-fixed paraffin-embedded samples, in clinical settings.


Assuntos
Análise Mutacional de DNA/métodos , DNA de Neoplasias/isolamento & purificação , Testes Genéticos/métodos , Mutação , Neoplasias/genética , Biologia Computacional , Primers do DNA , Genes Neoplásicos/genética , Genoma Humano , Humanos , Análise de Sequência de DNA/métodos , Sequenciamento Completo do Genoma
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 Commun ; 11(1): 3232, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32591530

RESUMO

CRISPR-Cas9 has emerged as a powerful technology that relies on Cas9/sgRNA ribonucleoprotein complexes (RNPs) to target and edit DNA. However, many therapeutic targets cannot currently be accessed due to the lack of carriers that can deliver RNPs systemically. Here, we report a generalizable methodology that allows engineering of modified lipid nanoparticles to efficiently deliver RNPs into cells and edit tissues including muscle, brain, liver, and lungs. Intravenous injection facilitated tissue-specific, multiplexed editing of six genes in mouse lungs. High carrier potency was leveraged to create organ-specific cancer models in livers and lungs of mice though facile knockout of multiple genes. The developed carriers were also able to deliver RNPs to restore dystrophin expression in DMD mice and significantly decrease serum PCSK9 level in C57BL/6 mice. Application of this generalizable strategy will facilitate broad nanoparticle development for a variety of disease targets amenable to protein delivery and precise gene correction approaches.


Assuntos
Proteína 9 Associada à CRISPR/metabolismo , Sistemas CRISPR-Cas/genética , Edição de Genes , Nanopartículas/química , Especificidade de Órgãos/genética , Ribonucleoproteínas/metabolismo , Animais , Cátions , DNA de Neoplasias/isolamento & purificação , Distrofina/genética , Células HeLa , Humanos , Lipídeos/química , Camundongos Endogâmicos C57BL
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
9.
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
10.
Anticancer Res ; 40(6): 3435-3444, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487642

RESUMO

BACKGROUND/AIM: Although it has been suggested that circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) might be used in a complementary manner in lung cancer diagnosis, limited confirmatory data are available. In this prospective study, we evaluated the diagnostic performance of each assay separately and in combination. PATIENTS AND METHODS: From March 2018 to January 2019, patients with suspected primary lung cancer, who underwent routine lung cancer work-up and peripheral blood sampling, were prospectively enrolled in the study. Epithelial cell adhesion molecule and cytokeratin served as markers of CTCs. In terms of ctDNA analysis, single-nucleotide variants were evaluated via next-generation sequencing. RESULTS: We analyzed 111 patients, including 99 with primary lung cancer and 12 with benign pulmonary disease. The median number of CTCs in 10 ml of blood was 3. The most frequently detected single nucleotide variants of ctDNA were TP53, CDKN2A, and EGFR. The diagnostic sensitivity of conventional tumor marker (combination of carcinoembryonic antigen/CYFRA 21-1/neuron-specific enolase) was 66.7%, while those of the ctDNA and CTC assays were 72.7% and 65.7%, respectively. The sensitivity of the CTC/ctDNA combination (95.0%) was significantly greater than those of the CTC (p<0.001), ctDNA (p<0.001), or conventional tumor marker (p<0.001) alone. Subgroup analysis revealed that the sensitivity of the combination assay was greater than those of the CTC or ctDNA assays alone, regardless of tumor stage or histopathology type. CONCLUSION: The CTC/ctDNA combination assay enhanced the sensitivity of primary lung cancer diagnosis. The combination assay strategy may be clinically useful and could enhance the early detection of lung cancer (ClinicalTrials.gov number: NCT03479099).


Assuntos
Biomarcadores Tumorais , DNA Tumoral Circulante , DNA de Neoplasias , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/etiologia , Células Neoplásicas Circulantes/patologia , Idoso , Idoso de 80 Anos ou mais , DNA de Neoplasias/sangue , Suscetibilidade a Doenças , Feminino , Humanos , Biópsia Líquida , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Polimorfismo de Nucleotídeo Único
11.
J Hematol Oncol ; 13(1): 43, 2020 05 04.
Artigo em Inglês | MEDLINE | ID: covidwho-165275

RESUMO

The novel coronavirus (2019-nCoV) is an emerging causative agent that was first described in late December 2019 and causes a severe respiratory infection in humans. Notably, many of affected patients of COVID-19 were people with malignancies. Moreover, cancer has been identified as an individual risk factor for COVID-19. In addition, the expression of angiotensin converting enzyme 2 (ACE2), the receptor of COVID-19, were aberrantly expressed in many tumors. However, a systematic analysis of ACE2 aberration remained to be elucidated in human cancers. Here, we analyzed genetic alteration, RNA expression, and DNA methylation of ACE2 across over 30 tumors. Notably, overexpression of ACE2 have been observed in including colon adenocarcinoma (COAD), kidney renal papillary cell carcinoma (KIRP), pancreatic adenocarcinoma (PAAD), rectum adenocarcinoma (READ), stomach adenocarcinoma (STAD), and lung adenocarcinoma (LUAD). In addition, hypo DNA methylation of ACE2 has also been identified in most of these ACE2 highly expressed tumors. Conclusively, our study for the first time curated both genetic and epigenetic variations of ACE2 in human malignancies. Notably, because our study is a bioinformatics assay, further functional and clinical validation is warranted.


Assuntos
Betacoronavirus , Infecções por Coronavirus , Neoplasias/enzimologia , Pandemias , Peptidil Dipeptidase A , Pneumonia Viral , Receptores Virais , Infecções por Coronavirus/enzimologia , Infecções por Coronavirus/etiologia , Infecções por Coronavirus/virologia , Metilação de DNA , DNA de Neoplasias/metabolismo , Humanos , Neoplasias/complicações , Peptidil Dipeptidase A/biossíntese , Peptidil Dipeptidase A/genética , Pneumonia Viral/enzimologia , Pneumonia Viral/etiologia , Pneumonia Viral/virologia , RNA/biossíntese , Receptores Virais/biossíntese , Receptores Virais/genética
12.
Nat Commun ; 11(1): 2350, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32393766

RESUMO

BET inhibitors are promising therapeutic agents for the treatment of triple-negative breast cancer (TNBC), but the rapid emergence of resistance necessitates investigation of combination therapies and their effects on tumor evolution. Here, we show that palbociclib, a CDK4/6 inhibitor, and paclitaxel, a microtubule inhibitor, synergize with the BET inhibitor JQ1 in TNBC lines. High-complexity DNA barcoding and mathematical modeling indicate a high rate of de novo acquired resistance to these drugs relative to pre-existing resistance. We demonstrate that the combination of JQ1 and palbociclib induces cell division errors, which can increase the chance of developing aneuploidy. Characterizing acquired resistance to combination treatment at a single cell level shows heterogeneous mechanisms including activation of G1-S and senescence pathways. Our results establish a rationale for further investigation of combined BET and CDK4/6 inhibition in TNBC and suggest novel mechanisms of action for these drugs and new vulnerabilities in cells after emergence of resistance.


Assuntos
Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos , Proteínas/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Azepinas/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Clonais , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , DNA de Neoplasias/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Camundongos , Modelos Biológicos , Mutação/genética , Paclitaxel/farmacologia , Piperazinas/farmacologia , Ploidias , Proteínas/metabolismo , Piridinas/farmacologia , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo , Resultado do Tratamento , Triazóis/farmacologia , Neoplasias de Mama Triplo Negativas/genética , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
14.
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
15.
Anticancer Res ; 40(5): 2675-2685, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366412

RESUMO

BACKGROUND/AIM: To evaluate the anti-cancer mechanism of N-Farnesyl-norcantharimide (NC15). MATERIALS AND METHODS: The viability of NC15-treated human leukemic Jurkat T (JKT) cells was assessed using the Kit-8 cell counting method. Flow cytometry analysis, human apoptosis antibody array assay, and whole genome sequencing were adopted to investigate the mechanism underlying the anti-cancer activity of NC15 in JKT cells. RESULTS: The growth inhibition rates of NC15 in JKT cells were about 80% and 95% after treatment with 8 µmol/l NC15 for 24 and 48 h, respectively. The percentages of NC15-treated JKT cells in the sub-G1 phase at 24 and 48 h were 22.0% and 34.3%, respectively, in contrast to the 1.5% in the control. Next-generation sequencing showed that many tumor suppressor genes (TSG) were up-regulated, while many genes associated with steroid biosynthesis, metabolic pathways, and fatty acid metabolism were down-regulated. CONCLUSION: NC15 can reduce the cell viability and increase the percentage of JKT cells in the sub-G1 phase by up-regulating TSG and related genes, and down-regulating the genes for steroid biosynthesis, metabolic pathways and fatty acid metabolism, instead of through apoptosis.


Assuntos
Cantaridina/análogos & derivados , Regulação para Baixo/efeitos dos fármacos , Ácidos Graxos/metabolismo , Genes Supressores de Tumor , Redes e Vias Metabólicas/genética , Esteroides/biossíntese , Linfócitos T/citologia , Regulação para Cima/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Apoptose/genética , Vias Biossintéticas/efeitos dos fármacos , Vias Biossintéticas/genética , Cantaridina/química , Cantaridina/farmacologia , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Proliferação de Células/efeitos dos fármacos , DNA de Neoplasias/metabolismo , Regulação para Baixo/genética , Humanos , Células Jurkat , Redes e Vias Metabólicas/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Regulação para Cima/genética
16.
J Hematol Oncol ; 13(1): 43, 2020 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-32366279

RESUMO

The novel coronavirus (2019-nCoV) is an emerging causative agent that was first described in late December 2019 and causes a severe respiratory infection in humans. Notably, many of affected patients of COVID-19 were people with malignancies. Moreover, cancer has been identified as an individual risk factor for COVID-19. In addition, the expression of angiotensin converting enzyme 2 (ACE2), the receptor of COVID-19, were aberrantly expressed in many tumors. However, a systematic analysis of ACE2 aberration remained to be elucidated in human cancers. Here, we analyzed genetic alteration, RNA expression, and DNA methylation of ACE2 across over 30 tumors. Notably, overexpression of ACE2 have been observed in including colon adenocarcinoma (COAD), kidney renal papillary cell carcinoma (KIRP), pancreatic adenocarcinoma (PAAD), rectum adenocarcinoma (READ), stomach adenocarcinoma (STAD), and lung adenocarcinoma (LUAD). In addition, hypo DNA methylation of ACE2 has also been identified in most of these ACE2 highly expressed tumors. Conclusively, our study for the first time curated both genetic and epigenetic variations of ACE2 in human malignancies. Notably, because our study is a bioinformatics assay, further functional and clinical validation is warranted.


Assuntos
Betacoronavirus , Infecções por Coronavirus , Neoplasias/enzimologia , Pandemias , Peptidil Dipeptidase A , Pneumonia Viral , Receptores Virais , Infecções por Coronavirus/enzimologia , Infecções por Coronavirus/etiologia , Infecções por Coronavirus/virologia , Metilação de DNA , DNA de Neoplasias/metabolismo , Humanos , Neoplasias/complicações , Peptidil Dipeptidase A/biossíntese , Peptidil Dipeptidase A/genética , Pneumonia Viral/enzimologia , Pneumonia Viral/etiologia , Pneumonia Viral/virologia , RNA/biossíntese , Receptores Virais/biossíntese , Receptores Virais/genética
17.
J Cancer Res Clin Oncol ; 146(7): 1625-1645, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32338295

RESUMO

Hepatocellular carcinoma (HCC) and pancreatic cancer (PC) belong to the most lethal malignancies worldwide. Despite advances in surgical techniques and perioperative multidisciplinary management, the prognosis of both carcinoma entities remains poor mainly because of rapid tumor progression and early dissemination with diagnosis in advanced tumor stages with poor sensitivity to current therapy regimens. Both highly heterogeneous visceral carcinomas exhibit unique somatic alterations, but share common driver genes and mutations as well. Recently, circulating tumor DNA (ctDNA) could be identified as a liquid biopsy tool with huge potential as non-invasive biomarker in early diagnosis and prognosis. CtDNA released from necrotic or apoptotic cells of primary tumors, metastasis, and circulating tumor cells can reveal genetic and epigenetic alterations with tumor-specific and individual mutation and methylation profiles. In this article, we focus on clinical impact of ctDNA as potential biomarker in patients with HCC and PC.


Assuntos
Biomarcadores Tumorais , Carcinoma Hepatocelular/genética , DNA Tumoral Circulante , DNA de Neoplasias , Neoplasias Hepáticas/genética , Neoplasias Pancreáticas/genética , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/diagnóstico , Metilação de DNA , Variação Genética , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Biópsia Líquida , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/diagnóstico , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/diagnóstico , Prognóstico
19.
PLoS One ; 15(4): e0232365, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32330187

RESUMO

Circulating tumor DNA (ctDNA), which carries tumor-specific mutations, is an emerging candidate biomarker for malignancies and for monitoring disease status in various human tumors. Recently, BRAF V595E mutation has been reported in 80% of dogs with urothelial carcinoma. This study investigates the BRAF V595E allele concentration in circulating cell-free DNA (cfDNA) and assesses the clinical significance of BRAF-mutated ctDNA levels in canines with urothelial carcinoma. A total of 15 dogs with urothelial carcinoma were included. cfDNA concentration was measured using a real-time polymerase chain reaction (PCR) of the LINE-1 gene. To measure the concentration of the mutated BRAF gene in cfDNA, allele-specific real-time PCR with a locked nucleic acid probe was performed. BRAF mutations were detected in 11 (73%) of the 15 tested tumor samples. BRAF-mutated ctDNA concentrations were significantly higher in dogs with the BRAF mutation (14.05 ± 13.51 ng/ml) than in wild-type dogs (0.21 ± 0.41 ng/ml) (p = 0.031). The amount of BRAF-mutated ctDNA in plasma increased with disease progression and responded to treatment. Our results show that BRAF-mutated ctDNA can be detected using allele-specific real-time PCR in plasma samples of canines with urothelial carcinoma with the BRAF V595E mutation. This ctDNA analysis may be a potentially useful tool for monitoring the progression of urothelial carcinoma and its response to treatment.


Assuntos
Carcinoma de Células de Transição/veterinária , Ácidos Nucleicos Livres/sangue , Doenças do Cão/genética , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Urológicas/veterinária , Alelos , Animais , Biomarcadores Tumorais/sangue , Carcinoma de Células de Transição/sangue , Carcinoma de Células de Transição/genética , DNA de Neoplasias/sangue , Doenças do Cão/sangue , Cães , Feminino , Masculino , Proteínas Proto-Oncogênicas B-raf/sangue , Neoplasias Urológicas/sangue , Neoplasias Urológicas/genética
20.
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
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