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1.
Nat Commun ; 11(1): 603, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32001676

RESUMO

Immunotherapy targeting T cells is increasingly utilized to treat solid tumors including non-small cell lung cancer (NSCLC). This requires a better understanding of the T cells in the lungs of patients with NSCLC. Here, we report T cell repertoire analysis in a cohort of 236 early-stage NSCLC patients. T cell repertoire attributes are associated with clinicopathologic features, mutational and immune landscape. A considerable proportion of the most prevalent T cells in tumors are also prevalent in the uninvolved tumor-adjacent lungs and appear specific to shared background mutations or viral infections. Patients with higher T cell repertoire homology between the tumor and uninvolved tumor-adjacent lung, suggesting a less tumor-focused T cell response, exhibit inferior survival. These findings indicate that a concise understanding of antigens and T cells in NSCLC is needed to improve therapeutic efficacy and reduce toxicity with immunotherapy, particularly adoptive T cell therapy.

2.
Oncogene ; 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31831835

RESUMO

The original version of this Article omitted the following from the Acknowledgements: Professor Stebbing sits on SABs for Celltrion, Singapore Biotech, Vor Biopharma, TLC Biopharmaceuticals and Benevolent AI, has consulted with Lansdowne partners, Vitruvian and Social Impact Capital and Chairs the Board of Directors for BB Biotech Healthcare Trust and Xerion Healthcare. This has now been corrected in both the PDF and HTML versions of the Article.

3.
Oncogene ; 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31754213

RESUMO

EGFR-mutant non-small-cell lung cancer (NSCLC) patients inevitably develop drug resistance when treated with EGFR tyrosine kinase inhibitors (TKIs). Systematic genetic analysis is important to understand drug-resistant mechanisms; however, the clinical significance of co-occurring genetic alterations at baseline, co-acquired mutations at progressive disease (PD), and the clonal evolution remain underinvestigated. We performed targeted sequencing of pre-treatment and PD tumor samples from 54 EGFR-mutant NSCLC patients. Ten additional patients were sequenced using whole-exome sequencing to infer the clonal evolution patterns. We observed a domain-dependent effect of PIK3CA mutation at baseline on patient progression-free survival (PFS). In addition, at baseline, 9q34.3/19p13.3 (NOTCH1/STK11/GNA11) showed a co-deletion pattern, which was associated with a significantly worse PFS (p = 0.00079). T790M-postive patients with other concurrent acquired oncogenic mutations had a significantly shorter PFS (p = 0.005). Besides acquired T790M mutation, chromosomal instability (CIN) related genes, including AURKA and TP53 alterations, were the most frequently acquired events. CIN significantly increased during TKI treatment in T790M-negative patients and is a candidate resistance mechanism to the first-generation TKIs. Clonal evolution analyses suggest that the composition and relationship among resistant subclones, particularly relationship with T790M subclone, affect patients' outcomes. Overall, our findings of novel co-occurring alterations and clonal evolution patterns can be served as predictive biomarkers to stratify patients and help to better understand the drug-resistant mechanism to TKIs.

4.
Mol Genet Genomics ; 293(5): 1217-1229, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29882166

RESUMO

Recurrent oncogenic fusion genes play a critical role in the development of various cancers and diseases and provide, in some cases, excellent therapeutic targets. To date, analysis tools that can identify and compare recurrent fusion genes across multiple samples have not been available to researchers. To address this deficiency, we developed Co-occurrence Fusion (Co-fuse), a new and easy to use software tool that enables biologists to merge RNA-seq information, allowing them to identify recurrent fusion genes, without the need for exhaustive data processing. Notably, Co-fuse is based on pattern mining and statistical analysis which enables the identification of hidden patterns of recurrent fusion genes. In this report, we show that Co-fuse can be used to identify 2 distinct groups within a set of 49 leukemic cell lines based on their recurrent fusion genes: a multiple myeloma (MM) samples-enriched cluster and an acute myeloid leukemia (AML) samples-enriched cluster. Our experimental results further demonstrate that Co-fuse can identify known driver fusion genes (e.g., IGH-MYC, IGH-WHSC1) in MM, when compared to AML samples, indicating the potential of Co-fuse to aid the discovery of yet unknown driver fusion genes through cohort comparisons. Additionally, using a 272 primary glioma sample RNA-seq dataset, Co-fuse was able to validate recurrent fusion genes, further demonstrating the power of this analysis tool to identify recurrent fusion genes. Taken together, Co-fuse is a powerful new analysis tool that can be readily applied to large RNA-seq datasets, and may lead to the discovery of new disease subgroups and potentially new driver genes, for which, targeted therapies could be developed. The Co-fuse R source code is publicly available at https://github.com/sakrapee/co-fuse .


Assuntos
Genômica , Leucemia Mieloide Aguda/genética , Proteínas de Fusão Oncogênica/genética , Software , Biologia Computacional , Bases de Dados Genéticas , Humanos , Leucemia Mieloide Aguda/patologia , Proteínas de Fusão Oncogênica/isolamento & purificação , Análise de Sequência de RNA
7.
Cancer Discov ; 7(10): 1088-1097, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28733428

RESUMO

Genomic intratumor heterogeneity (ITH) may be associated with postsurgical relapse of localized lung adenocarcinomas. Recently, mutations, through generation of neoantigens, were shown to alter tumor immunogenicity through T-cell responses. Here, we performed sequencing of the T-cell receptor (TCR) in 45 tumor regions from 11 localized lung adenocarcinomas and observed substantial intratumor differences in T-cell density and clonality with the majority of T-cell clones restricted to individual tumor regions. TCR ITH positively correlated with predicted neoantigen ITH, suggesting that spatial differences in the T-cell repertoire may be driven by distinct neoantigens in different tumor regions. Finally, a higher degree of TCR ITH was associated with an increased risk of postsurgical relapse and shorter disease-free survival, suggesting a potential clinical significance of T-cell repertoire heterogeneity.Significance: The present study provides insights into the ITH of the T-cell repertoire in localized lung adenocarcinomas and its potential biological and clinical impact. The results suggest that T-cell repertoire ITH may be tightly associated to genomic ITH and disease relapse. Cancer Discov; 7(10); 1088-97. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 1047.


Assuntos
Adenocarcinoma/cirurgia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Neoplasias Pulmonares/cirurgia , Recidiva Local de Neoplasia/genética , Receptores de Antígenos de Linfócitos T/genética , Sequenciamento Completo do Exoma/métodos , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Intervalo Livre de Doença , Regulação Neoplásica da Expressão Gênica , Heterogeneidade Genética , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Mutação , Recidiva Local de Neoplasia/imunologia
8.
Oncotarget ; 8(13): 21994-22002, 2017 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-28423542

RESUMO

Cancers are composed of cells with distinct molecular and phenotypic features within a given tumor, a phenomenon termed intratumor heterogeneity (ITH). Previously, we have demonstrated genomic ITH in localized lung adenocarcinomas; however, the nature of methylation ITH in lung cancers has not been well investigated. In this study, we generated methylation profiles of 48 spatially separated tumor regions from 11 localized lung adenocarcinomas and their matched normal lung tissues using Illumina Infinium Human Methylation 450K BeadChip array. We observed methylation ITH within the same tumors, but to a much less extent compared to inter-individual heterogeneity. On average, 25% of all differentially methylated probes compared to matched normal lung tissues were shared by all regions from the same tumors. This is in contrast to somatic mutations, of which approximately 77% were shared events amongst all regions of individual tumors, suggesting that while the majority of somatic mutations were early clonal events, the tumor-specific DNA methylation might be associated with later branched evolution of these 11 tumors. Furthermore, our data showed that a higher extent of DNA methylation ITH was associated with larger tumor size (average Euclidean distance of 35.64 (> 3cm, median size) versus 27.24 (<= 3cm), p = 0.014), advanced age (average Euclidean distance of 34.95 (above 65) verse 28.06 (below 65), p = 0.046) and increased risk of postsurgical recurrence (average Euclidean distance of 35.65 (relapsed patients) versus 29.03 (patients without relapsed), p = 0.039).


Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Metilação de DNA , Heterogeneidade Genética , Neoplasias Pulmonares/genética , Mutação/genética , Recidiva Local de Neoplasia/genética , Adenocarcinoma/patologia , Idoso , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia , Masculino , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico
9.
F1000Res ; 5: 671, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27583131

RESUMO

Helicobacter pylori is a gastric pathogen that causes several gastroduodenal disorders such as peptic ulcer disease and gastric cancer.  Eradication efforts of H. pylori are often hampered by antimicrobial resistance in many countries, including Vietnam.  Here, the study aimed to investigate the occurrence of antimicrobial resistance among H. pylori clinical isolates across 13 hospitals in Vietnam.  The study further evaluated the clarithromycin resistance patterns of H. pylori strains.  In order to address the study interests, antimicrobial susceptibility testing, epsilometer test and PCR-based sequencing were performed on a total of 193 strains isolated from patients, including 136 children (3-15 years of age) and 57 adults (19-69 years of age).  Antimicrobial susceptibility testing showed that the overall resistance to amoxicillin, clarithromycin, levofloxacin, metronidazole, and tetracycline was 10.4%, 85.5%, 24.4%, 37.8%, and 23.8% respectively.  The distribution of minimum inhibitory concentrations (MICs) of clarithromycin-resistant strains was 85.5% with MIC >0.5 µg/mL.  The majority of the clarithromycin resistant isolates (135 of 165 subjects) have MICs ranging from 2 µg/mL to 16 µg/mL.  Furthermore, sequencing detection of mutations in 23S rRNA gene revealed that strains resistant and susceptible to clarithromycin contained both A2143G and T2182C mutations.  Of all isolates, eight clarithromycin-resistant isolates (MIC >0.5 µg/mL) had no mutations in the 23S rRNA gene.  Collectively, these results demonstrated that a proportion of clarithromycin-resistant H. pylori strains, which are not related to the 23S rRNA gene mutations, could be potentially related to other mechanisms such as the presence of an efflux pump or polymorphisms in the CYP2C19 gene.  Therefore, the present study suggests that providing susceptibility testing prior to treatment or alternative screening strategies for antimicrobial resistance is important for future clinical practice.  Further studies on clinical guidelines and treatment efficacy are pivotal for successful eradication of H. pylori infection.

10.
Nature ; 531(7592): 47-52, 2016 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-26909576

RESUMO

Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-ß, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.


Assuntos
Genes Neoplásicos/genética , Genoma Humano/genética , Genômica , Mutação/genética , Neoplasias Pancreáticas/classificação , Neoplasias Pancreáticas/genética , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Carcinoma Ductal Pancreático/classificação , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Metilação de DNA , Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Fator 3-beta Nuclear de Hepatócito/genética , Fator 3-gama Nuclear de Hepatócito/genética , Histona Desmetilases/genética , Proteínas de Homeodomínio/genética , Humanos , Camundongos , Proteínas Nucleares/genética , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Prognóstico , Receptores Citoplasmáticos e Nucleares/genética , Análise de Sobrevida , Transativadores/genética , Fatores de Transcrição/genética , Transcrição Genética , Transcriptoma , Proteína Supressora de Tumor p53/genética , Proteínas Supressoras de Tumor/genética , Proteínas de Peixe-Zebra
12.
Nature ; 521(7553): 489-94, 2015 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-26017449

RESUMO

Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Genoma Humano/genética , Neoplasias Ovarianas/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Estudos de Coortes , Ciclina E/genética , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/genética , Metilação de DNA , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Feminino , Genes BRCA1 , Genes BRCA2 , Genes da Neurofibromatose 1 , Mutação em Linhagem Germinativa/genética , Humanos , Mutagênese/genética , Proteínas Oncogênicas/genética , Neoplasias Ovarianas/tratamento farmacológico , PTEN Fosfo-Hidrolase/genética , Regiões Promotoras Genéticas/genética , Proteína do Retinoblastoma/genética
13.
Nature ; 518(7540): 495-501, 2015 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-25719666

RESUMO

Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.


Assuntos
Análise Mutacional de DNA , Genoma Humano/genética , Genômica , Mutação/genética , Neoplasias Pancreáticas/genética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Animais , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Reparo do DNA/genética , Feminino , Genes BRCA1 , Genes BRCA2 , Marcadores Genéticos/genética , Instabilidade Genômica/genética , Genótipo , Humanos , Camundongos , Neoplasias Pancreáticas/classificação , Neoplasias Pancreáticas/tratamento farmacológico , Platina/farmacologia , Mutação Puntual/genética , Inibidores de Poli(ADP-Ribose) Polimerases , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Nat Commun ; 5: 5224, 2014 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-25351503

RESUMO

Oesophageal adenocarcinoma (EAC) incidence is rapidly increasing in Western countries. A better understanding of EAC underpins efforts to improve early detection and treatment outcomes. While large EAC exome sequencing efforts to date have found recurrent loss-of-function mutations, oncogenic driving events have been underrepresented. Here we use a combination of whole-genome sequencing (WGS) and single-nucleotide polymorphism-array profiling to show that genomic catastrophes are frequent in EAC, with almost a third (32%, n=40/123) undergoing chromothriptic events. WGS of 22 EAC cases show that catastrophes may lead to oncogene amplification through chromothripsis-derived double-minute chromosome formation (MYC and MDM2) or breakage-fusion-bridge (KRAS, MDM2 and RFC3). Telomere shortening is more prominent in EACs bearing localized complex rearrangements. Mutational signature analysis also confirms that extreme genomic instability in EAC can be driven by somatic BRCA2 mutations. These findings suggest that genomic catastrophes have a significant role in the malignant transformation of EAC.


Assuntos
Adenocarcinoma/genética , Adenocarcinoma/patologia , Carcinogênese/genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Rearranjo Gênico/genética , Genoma Humano/genética , Carcinogênese/patologia , Quebra Cromossômica , Cromossomos Humanos/genética , Humanos , Mutação/genética
15.
Biotechniques ; 57(1): 31-8, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25005691

RESUMO

Somatic rearrangements, which are commonly found in human cancer genomes, contribute to the progression and maintenance of cancers. Conventionally, the verification of somatic rearrangements comprises many manual steps and Sanger sequencing. This is labor intensive when verifying a large number of rearrangements in a large cohort. To increase the verification throughput, we devised a high-throughput workflow that utilizes benchtop next-generation sequencing and in-house bioinformatics tools to link the laboratory processes. In the proposed workflow, primers are automatically designed. PCR and an optional gel electrophoresis step to confirm the somatic nature of the rearrangements are performed. PCR products of somatic events are pooled for Ion Torrent PGM and/or Illumina MiSeq sequencing, the resulting sequence reads are assembled into consensus contigs by a consensus assembler, and an automated BLAT is used to resolve the breakpoints to base level. We compared sequences and breakpoints of verified somatic rearrangements between the conventional and high-throughput workflow. The results showed that next-generation sequencing methods are comparable to conventional Sanger sequencing. The identified breakpoints obtained from next-generation sequencing methods were highly accurate and reproducible. Furthermore, the proposed workflow allows hundreds of events to be processed in a shorter time frame compared with the conventional workflow.


Assuntos
Pontos de Quebra do Cromossomo , Cromossomos Humanos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequência de Bases , Carcinoma Ductal Pancreático/genética , Aberrações Cromossômicas , Primers do DNA , Humanos , Dados de Sequência Molecular , Neoplasias/genética , Neoplasias Pancreáticas/genética , Reação em Cadeia da Polimerase/métodos , Fluxo de Trabalho
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