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1.
Strahlenther Onkol ; 2020 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-32211941

RESUMO

PURPOSE: The relation between functional imaging and intrapatient genetic heterogeneity remains poorly understood. The aim of our study was to investigate spatial sampling and functional imaging by FDG-PET/MRI to describe intrapatient tumour heterogeneity. METHODS: Six patients with oropharyngeal cancer were included in this pilot study. Two tumour samples per patient were taken and sequenced by next-generation sequencing covering 327 genes relevant in head and neck cancer. Corresponding regions were delineated on pretherapeutic FDG-PET/MRI images to extract apparent diffusion coefficients and standardized uptake values. RESULTS: Samples were collected within the primary tumour (n = 3), within the primary tumour and the involved lymph node (n = 2) as well as within two independent primary tumours (n = 1). Genetic heterogeneity of the primary tumours was limited and most driver gene mutations were found ubiquitously. Slightly increasing heterogeneity was found between primary tumours and lymph node metastases. One private predicted driver mutation within a primary tumour and one in a lymph node were found. However, the two independent primary tumours did not show any shared mutations in spite of a clinically suspected field cancerosis. No conclusive correlation between genetic heterogeneity and heterogeneity of PET/MRI-derived parameters was observed. CONCLUSION: Our limited data suggest that single sampling might be sufficient in some patients with oropharyngeal cancer. However, few driver mutations might be missed and, if feasible, spatial sampling should be considered. In two independent primary tumours, both lesions should be sequenced. Our data with a limited number of patients do not support the concept that multiparametric PET/MRI features are useful to guide biopsies for genetic tumour characterization.

2.
Genome Med ; 11(1): 28, 2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-31039795

RESUMO

BACKGROUND: Although mutated HLA ligands are considered ideal cancer-specific immunotherapy targets, evidence for their presentation is lacking in hepatocellular carcinomas (HCCs). Employing a unique multi-omics approach comprising a neoepitope identification pipeline, we assessed exome-derived mutations naturally presented as HLA class I ligands in HCCs. METHODS: In-depth multi-omics analyses included whole exome and transcriptome sequencing to define individual patient-specific search spaces of neoepitope candidates. Evidence for the natural presentation of mutated HLA ligands was investigated through an in silico pipeline integrating proteome and HLA ligandome profiling data. RESULTS: The approach was successfully validated in a state-of-the-art dataset from malignant melanoma, and despite multi-omics evidence for somatic mutations, mutated naturally presented HLA ligands remained elusive in HCCs. An analysis of extensive cancer datasets confirmed fundamental differences of tumor mutational burden in HCC and malignant melanoma, challenging the notion that exome-derived mutations contribute relevantly to the expectable neoepitope pool in malignancies with only few mutations. CONCLUSIONS: This study suggests that exome-derived mutated HLA ligands appear to be rarely presented in HCCs, inter alia resulting from a low mutational burden as compared to other malignancies such as malignant melanoma. Our results therefore demand widening the target scope for personalized immunotherapy beyond this limited range of mutated neoepitopes, particularly for malignancies with similar or lower mutational burden.


Assuntos
Antígenos de Neoplasias/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Transcriptoma , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/metabolismo , Carcinoma Hepatocelular/imunologia , Exoma , Feminino , Genômica/métodos , Humanos , Neoplasias Hepáticas/imunologia , Masculino , Pessoa de Meia-Idade , Taxa de Mutação
3.
Strahlenther Onkol ; 195(9): 771-779, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31123786

RESUMO

PURPOSE: Genetic tumour profiles and radiomic features can be used to complement clinical information in head and neck squamous cell carcinoma (HNSCC) patients. Radiogenomics imply the potential to investigate complementarity or interrelations of radiomic and genomic features, and prognostic factors might be determined. The aim of our study was to explore radiogenomics in HNSCC. METHODS: For 20 HNSCC patients treated with primary radiochemotherapy, next-generation sequencing (NGS) of tumour and corresponding normal tissue was performed. In total, 327 genes were investigated by panel sequencing. Radiomic features were extracted from computed tomography data. A hypothesis-driven approach was used for radiogenomic correlations of selected image-based heterogeneity features and well-known driver gene mutations in HNSCC. RESULTS: The most frequently mutated driver genes in our cohort were TP53 (involved in cell cycle control), FAT1 (Wnt signalling, cell-cell contacts, migration) and KMT2D (chromatin modification). Radiomic features of heterogeneity did not correlate significantly with somatic mutations in TP53 or KMT2D. However, somatic mutations in FAT1 and smaller primary tumour volumes were associated with reduced radiomic intra-tumour heterogeneity. CONCLUSION: The landscape of somatic variants in our cohort is well in line with previous reports. An association of somatic mutations in FAT1 with reduced radiomic tumour heterogeneity could potentially elucidate the previously described favourable outcomes of these patients. Larger studies are needed to validate this exploratory data in the future.


Assuntos
Caderinas/genética , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Heterogeneidade Genética , Proteínas de Neoplasias/genética , Neoplasias Otorrinolaringológicas/genética , Neoplasias Otorrinolaringológicas/radioterapia , Proteína Supressora de Tumor p53/genética , Correlação de Dados , Humanos , Tolerância a Radiação
4.
Radiother Oncol ; 129(3): 575-581, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30097252

RESUMO

BACKGROUND AND PURPOSE: Radiochemotherapy is a standard treatment option for patients with head and neck cancer (HNSCC). During radiation, local toxicities are common and need to be differentiated from infections. As levels of circulating cell-free DNA (cfDNA) are known to be elevated during infections, cfDNA might complement clinical parameters. The aim of the study was to investigate the dynamics of cfDNA during radiochemotherapy. MATERIAL AND METHODS: In total, 78 blood samples of 20 patients with HNSCC were analysed in this prospective biomarker study. Blood samples were taken before and during treatment. CfDNA levels were quantified fluorometrically and results were compared to laboratory and clinical parameters. RESULTS: Elevated cfDNA levels were associated with the pre-treatment volumes of lymph node metastases (p = 0.0002), gastrostomy tube placement (20.23 ng/ml vs. 9.04 ng/ml (median), p = 0.025), the application of antibiotics (16.47 ng/ml vs. 9.04 ng/ml, p = 0.006) and manifest infections (16.81 ng/ml vs. 9.04 ng/ml, p = 0.010). Furthermore, a significant difference between moderate inflammation (radiation-induced toxicity RTOG grade 2-3) and manifest infections could be observed (8.97 ng/ml vs. 16.81 ng/ml, p = 0.014), allowing for a more pronounced differentiation than by CRP levels (p = 0.119). There might be an association between the application of G-CSF and elevated cfDNA levels. CONCLUSION: CfDNA levels are correlated with infections during radiochemotherapy and could represent an informative complemental biomarker to drive therapeutic decision-making. Estimated levels of circulating cell-free tumour DNA (ctDNA) in plasma should be interpreted cautiously when monitoring tumour outcome by next-generation-sequencing, as confounders like infections or drug application might influence the fraction of ctDNA in total cfDNA.


Assuntos
Ácidos Nucleicos Livres/sangue , Quimiorradioterapia , Neoplasias de Cabeça e Pescoço/terapia , Inflamação/diagnóstico , Adulto , Biomarcadores , Proteína C-Reativa/análise , Feminino , Humanos , Inflamação/sangue , Masculino , Estudos Prospectivos
5.
BMC Med Genet ; 19(1): 144, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30111295

RESUMO

BACKGROUND: The PTEN-hamartoma-tumor-syndrome (PHTS) is caused by germline mutations in Phosphatase and Tensin homolog (PTEN) and predisposes to the development of several typical malignancies. Whereas PTEN mutations have been implicated in the occurrence of malignant mesotheliomas, the genetic landscape of verrucous carcinomas (VC) is largely uncharted. Both VC and malignant peritoneal mesotheliomas (MPM) are exceedingly rare and a potential link between these malignancies and PHTS has never been reported. CASE PRESENTATION: We here describe the clinical course of a PHTS patient who, in addition to a typical thyroid carcinoma at the age of 36 years, developed a highly-differentiated oral VC and an epithelioid MPM six years later. The patient with a history of occupational asbestos exposure underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for MPM. The clinical diagnosis of PHTS was consequently corroborated by a germline PTEN deletion. Sequencing of tumor tissue revealed a second hit in PTEN in the thyroid carcinoma and VC, confirmed by a PTEN loss and activation of the PI3K/AKT pathway in immunohistochemistry. Furthermore, additional somatic mutations in the thyroid carcinoma as well as in the VC were detected, whereas the genetics of MPM remained unrevealing. DISCUSSION AND CONCLUSIONS: We here report the very unusual clinical course of a patient with rare tumors that have a germline mutation first hit in PTEN in common. Since this patient was exposed to asbestos and current evidence suggests molecular mechanisms that might render PHTS patients particularly susceptible to mesothelioma, we strongly recommend PHTS patients to avoid even minimal exposure.


Assuntos
Carcinoma Verrucoso/genética , Mutação em Linhagem Germinativa/genética , Neoplasias Pulmonares/genética , Mesotelioma/genética , Neoplasias Bucais/genética , PTEN Fosfo-Hidrolase/genética , Humanos , Doenças Raras
6.
Bioinformatics ; 33(11): 1721-1722, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28130233

RESUMO

Summary: Quality control (QC) is an important part of all NGS data analysis stages. Many available tools calculate QC metrics from different analysis steps of single sample experiments (raw reads, mapped reads and variant lists). Multi-sample experiments, as sequencing of tumor-normal pairs, require additional QC metrics to ensure validity of results. These multi-sample QC metrics still lack standardization. We therefore suggest a new workflow for QC of DNA sequencing of tumor-normal pairs. With this workflow well-known single-sample QC metrics and additional metrics specific for tumor-normal pairs can be calculated. The segmentation into different tools offers a high flexibility and allows reuse for other purposes. All tools produce qcML, a generic XML format for QC of -omics experiments. qcML uses quality metrics defined in an ontology, which was adapted for NGS. Availability and Implementation: All QC tools are implemented in C ++ and run both under Linux and Windows. Plotting requires python 2.7 and matplotlib. The software is available under the 'GNU General Public License version 2' as part of the ngs-bits project: https://github.com/imgag/ngs-bits. Contact: christopher.schroeder@med.uni-tuebingen.de. Supplementary information: Supplementary data are available at Bioinformatics online.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias/genética , Controle de Qualidade , Análise de Sequência de DNA/métodos , Software , Fluxo de Trabalho , Sequenciamento de Nucleotídeos em Larga Escala/normas , Humanos , Análise de Sequência de DNA/normas
8.
J Hepatol ; 65(4): 849-855, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27397612

RESUMO

BACKGROUND & AIMS: We report a novel experimental immunotherapeutic approach in a patient with metastatic intrahepatic cholangiocarcinoma. In the 5year course of the disease, the initial tumor mass, two local recurrences and a lung metastasis were surgically removed. Lacking alternative treatment options, aiming at the induction of anti-tumor T cells responses, we initiated a personalized multi-peptide vaccination, based on in-depth analysis of tumor antigens (immunopeptidome) and sequencing. METHODS: Tumors were characterized by immunohistochemistry, next-generation sequencing and mass spectrometry of HLA ligands. RESULTS: Although several tumor-specific neo-epitopes were predicted in silico, none could be validated by mass spectrometry. Instead, a personalized multi-peptide vaccine containing non-mutated tumor-associated epitopes was designed and applied. Immunomonitoring showed vaccine-induced T cell responses to three out of seven peptides administered. The pulmonary metastasis resected after start of vaccination showed strong immune cell infiltration and perforin positivity, in contrast to the previous lesions. The patient remains clinically healthy, without any radiologically detectable tumors since March 2013 and the vaccination is continued. CONCLUSIONS: This remarkable clinical course encourages formal clinical studies on adjuvant personalized peptide vaccination in cholangiocarcinoma. LAY SUMMARY: Metastatic cholangiocarcinomas, cancers that originate from the liver bile ducts, have very limited treatment options and a fatal prognosis. We describe a novel therapeutic approach in such a patient using a personalized multi-peptide vaccine. This vaccine, developed based on the characterization of the patient's tumor, evoked detectable anti-tumor immune responses, associating with long-term tumor-free survival.


Assuntos
Colangiocarcinoma , Neoplasias dos Ductos Biliares , Vacinas Anticâncer , Humanos , Recidiva Local de Neoplasia , Vacinas de Subunidades
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