Дисертації з теми "Tumour sequencing"
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Burns, Alice Sin Ying Wai. "The role of the p53 tumour suppressor pathway in central primitive neuroectodermal tumours." Thesis, University of Newcastle Upon Tyne, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.300357.
Повний текст джерелаDuarte, Antonio. "Regulation of gene expression by the Wilms' tumour suppressor, WT1." Thesis, University of Oxford, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.389178.
Повний текст джерелаMurtaza, Muhammed. "Identification and monitoring of somatic mutations in solid cancers by sequencing circulating tumour DNA." Thesis, University of Cambridge, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708647.
Повний текст джерелаRoss, Edith. "Inferring tumour evolution from single-cell and multi-sample data." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/274604.
Повний текст джерелаFewings, Eleanor Rose. "The use of whole exome sequencing data to identify candidate genes involved in cancer and benign tumour predisposition." Thesis, University of Cambridge, 2019. https://www.repository.cam.ac.uk/handle/1810/285963.
Повний текст джерелаAsante, Du-Bois. "Development and evaluation of methodologies for analysis of CTC and ctDNA in patients with ovarian carcinoma." Thesis, Edith Cowan University, Research Online, Perth, Western Australia, 2022. https://ro.ecu.edu.au/theses/2570.
Повний текст джерелаNaven, Marc. "Development of a pipeline and protocols for next generation sequencing of blood and formalin-fixed, paraffin-embedded tumour DNA samples." Thesis, Cardiff University, 2015. http://orca.cf.ac.uk/91435/.
Повний текст джерелаBucher, Katharina M. I. "The tumour suppressor gene p53 in the horse : identification, cloning and sequencing : its possible role in the pathogenesis of equine sarcoid /." [S.l.] : [s.n.], 1995. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.
Повний текст джерелаChoudhry, Hani. "Genome-wide analysis of the hypoxic breast cancer transcriptome using next generation sequencing." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:9a66b553-a66c-4164-a854-5881be65ca45.
Повний текст джерелаStrakova, Andrea. "Genome diversity and evolution in canine transmissible venereal tumour." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/276037.
Повний текст джерелаBrown, David Norman. "Application of phylogenetic inference methods to quantify intra-tumour heterogeneity and evolution of breast cancers." Doctoral thesis, Universite Libre de Bruxelles, 2017. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/260251.
Повний текст джерелаDoctorat en Sciences biomédicales et pharmaceutiques (Médecine)
info:eu-repo/semantics/nonPublished
Marass, Francesco. "Latent feature models and non-invasive clonal reconstruction." Thesis, University of Cambridge, 2017. https://www.repository.cam.ac.uk/handle/1810/267784.
Повний текст джерелаLeventoux, Nicolas. "Etude des foyers d’hétérogénéité tumorale dans les gliomes diffus de bas grade de l’adulte mutés IDH1." Thesis, Montpellier, 2018. http://www.theses.fr/2018MONTT037.
Повний текст джерелаGliomas are the main primary brain tumours affecting around 4000 new patients in France each year. Half of gliomas are detected in the advanced stage of glioblastoma (grade IV) while 15% of tumours are diagnosed in stage II (diffuse low-grade gliomas-DLGG). These tumors affect young patients and bear characteristic mutations, including a mutation for the enzyme IDH1 commonly found in secondary glioblastomas. These low-grade tumours are treated by surgery, ideally in awake condition but due to their diffuse nature, the residual part will progress inexorably to stage III or IV with overall survival between 5 and 15 years after diagnosis. Tumor progression is highly variable and unpredictable from one patient to another. Foci of tumor progression have been identified in 20% of patients with DLGG. These foci show a higher cell density and an increased Ki67. My thesis work consisted in studying the cellular and molecular changes associated with tumor progression. From the RNA profile of the foci and adjacent territories, I was able to highlight through high-throughput techniques significant decrease in gene expression in the foci, particularly of AGXT2L1/ETNPPL, carboxypeptidase E, EDNRB, SFRP2. I hypothesized that SFRP2 and ETNPLL could oppose cell proliferation and that their decrease would pave the way for tumor transformation. An inverse correlation between the amount of ETNPPL and the survival of patients with hepatocarcinoma has been published. By limiting the amount of phospholipid precursors in the cell, ETNPPL could act as a brake against proliferation and indeed, its decrease in glioma transformation foci could remove this inhibition. My PhD work will have been innovative in the comparative approach of the different tumors’ compartments for each patient studied and will have revealed ETNPPL as correlated to gliomagenesis and as potential therapeutic target
Behjati, Sam. "Massively parallel sequencing of benign and malignant human tumours." Thesis, University of Cambridge, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708693.
Повний текст джерелаFishler, Kristen B. S. "“It’s the Wild, Wild West Out There” Experiences of a Multidisciplinary Genomic Breast Cancer Tumor Board Implementing Tumor Sequencing in Clinical Care." University of Cincinnati / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1525169475571341.
Повний текст джерелаAnamaria, Crisan. "Mutation discovery in regions of segmental cancer genome amplifications from next generation sequencing of tumours." Thesis, University of British Columbia, 2010. http://hdl.handle.net/2429/29454.
Повний текст джерелаFinetti, Martina Anna. "Next-generation sequencing identifies mechanisms of tumourigenesis caused by loss of SMARCB1 in Malignant Rhabdoid Tumours." Thesis, University of Newcastle upon Tyne, 2015. http://hdl.handle.net/10443/3891.
Повний текст джерелаChicard, Mathieu. "Utilisation de l’ADN circulant pour l’étude de l'hétérogénéité tumorale et l'évolution clonale en oncologie pédiatrique Whole Exome Sequencing of Cell-Free DNA Reveals Temporo-Spatial Heterogeneity and Identifies Treatment-Resistant Clones in Neuroblastoma." Thesis, université Paris-Saclay, 2020. https://tel.archives-ouvertes.fr/tel-03154451.
Повний текст джерелаPediatric cancers represent a therapeutic challenge, and an understanding of the mechanisms of escape from treatment is necessary in order to be able to develop new therapeutic approaches. Circulating DNA can be released by a tumor in bodily fluids and enable to detect and follow genetic alterations in tumors by successive minimally invasive samples such as a blood test. In this work, a “whole exome” sequencing technique for circulating DNA was developed to allow the study of genetic tumor alterations in plasma in children with cancer. These analyzes highlight the frequent spatial and temporal genetic heterogeneity of pediatric cancers. In addition, an important role of clonal evolution in the progression of the disease was thus highlighted. Approaches using the particular characteristics of circulating DNA have also made it possible to infer the expression profile, based on the imprint of the transcription start sites, or the epigenetic profile of the tumor. In addition to an aid in the classification of tumors, these features may help to observe a change in cellular identity under treatment. Circulating DNA is therefore an important tool for better understanding mechanisms of escape from treatment of a tumor based on spatial and temporal heterogeneity and cellular plasticity
Batra, Rajbir Nath. "Decoding the regulatory role and epiclonal dynamics of DNA methylation in 1482 breast tumours." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/274923.
Повний текст джерелаSivertsson, Åsa. "Detection and analysis of genetic alterations in normal skin and skin tumours." Doctoral thesis, KTH, Biotechnology, 2002. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-3432.
Повний текст джерелаThe investigation of genetic alterations in cancer-relatedgenes is useful for research, prognostic and therapeuticpurposes. However, the genetic heterogeneity that often occursduring tumour progression can make correct analysischallenging. The objective of this work has been to develop,evaluate and apply techniques that are sufficiently sensitiveand specific to detect and analyse genetic alterations in skintumours as well as in normal skin.
Initially, a method based on laser-assisted microdissectionin combination with conventional dideoxy sequencing wasdeveloped and evaluated for the analysis of the p53 tumoursuppressor gene in small tissue samples. This method was shownto facilitate the analysis of single somatic cells fromhistologic tissue sections. In two subsequent studies themethod was used to analyse single cells to investigate theeffects of ultraviolet (UV) light on normal skin. Single p53immunoreactive and nonimmunoreactive cells from differentlayers of sunexposed skin, as well as skin protected fromexposure, were analysed for mutations in the p53 gene. Theresults revealed the structure of a clandestine p53 clone andprovided new insight into the possible events involved innormal differentiation by suggesting a role for allele dropout.The mutational effect of physiological doses of ultravioletlight A (UVA) on normal skin was then investigated by analysingthe p53 gene status in single immunoreactive cells at differenttime-points. Strong indications were found that UVA (even atlow doses) is indeed a mutagen and that its role should not bedisregarded in skin carcinogenesis.
After slight modifications, the p53 mutation analysisstrategy was thenused to complement an x-chromosomeinactivation assay for investigation of basal cell cancer (BCC)clonality. The conclusion was that although the majority ofBCCs are of monoclonal origin, an occasional tumour withapparently polyclonal origin exists. Finally, apyrosequencing-based mutation detection method was developedand evaluated for detection of hot-spot mutations in the N-rasgene of malignant melanoma. More than 80 melanoma metastasissamples were analysed by the standard approach of single strandconformation polymorphism analysis (SSCP)/DNA sequencing and bythis pyrosequencing strategy. Pyrosequencing was found to be agood alternative to SSCP/DNA sequencing and showed equivalentreproducibility and sensitivity in addition to being a simpleand rapid technique.
Keywords:single cell, DNA sequencing, p53, mutation,UV, BCC, pyrosequencing, malignant melanoma, N-ras
Fermey, Pierre. "Identification de nouvelles bases moléculaires des cancers précoces par séquençage à haut débit." Thesis, Normandie, 2017. http://www.theses.fr/2017NORMR110/document.
Повний текст джерелаOne of the greatest advances in oncology and genetics over the past 20 years has been the identification of hereditary forms of cancer and of the cancer genes. Nevertheless, in a majority of patients suspected to present an inherited form of cancer, analyses of the genes known to be involved in the Mendelian predispositions to cancer often remain negative. Today, thanks to the emergence of high-throughput sequencing (NGS), it is now possible to sequence all exons of an individual (exome) or several hundred genes in a short period of time and for a reasonable cost. In this context, we have applied several strategiesbased on these new tools in order to identify new molecular basis of early-onset cancers. First, we applied an intra-familial exome analysis strategy to an atypical family with chondrosarcomas of the chest, for which no molecular basis could be identified. Using this strategy, we were able to identify a truncating alteration of the EXT2 gene NM_000401.3; c.237G> A; p.Trp79 *). The documented loss of function alterations of this gene are implicated in a disease called multiple osteochondromas (OM), associated with benign lesions. Interestingly, these patients showed no clinical signs of OM indicating a potential phenotypic extension of EXT2 mutations. Plus, this work allowed us to change the clinical management of this family. We then used a strategy of subtractive exomic analysis of trio sick child/healthy parents in order to identify de novo mutations in a young patient who developed a medulloblastoma of the cerebellum at 8 years-old followed by a meningioma at 22 years-old. The analysis of the trio revealed the existence of a de novo mutation affecting a highly conserved amino acid of the HID-1 protein. HID-1 is specifically expressed in neuronal and secretory cells, and seems to function around the Golgi apparatus to regulate the sorting of newly formed vesicles. Our hypothesis is that a defect of the HID-1 protein linked to a mutation of the HID-1 gene, could alter the secretory pathway therefore contributing to the development of the tumor. This work, which is still ongoing, demonstrates both the strength of the trio strategy for the rapid identification of de novo mutations and illustrates all the difficulty of interpreting variants detected in genes not yet involved in cancer. Then, thanks to the recruitment of the Laboratory of Molecular Genetics of the CHU of Rouen, we have collected a cohort of 10 patients who developed an adrenocortical carcinoma (ACC) at a very early age and for which no molecular basis could be identified. Despite subtractive and inter-familial exomic analyses, we were unable to highlight new molecular bases for these cases of pediatric ACC. Finally, under the assumption that rare or private mutations in a limited number of genes involved in cancer could contribute to inherited forms of cancer, we undertook a project to sequence 201 genes involved in cancer in patients who developed tumors at a pediatric age. The first results of this project confirmed the robustness of this technique and suggested a phenotypic extension of the DICER1 mutation spectrum as well as an oligogenic contribution of DNA repair genes in pediatric tumors. Soon, these results will be compiled in a database and will benefit from a statistical analysis with the objective to identify enrichment of rare variants in specific genes or biological pathways in these patients compared to control individuals
Goldstein, Ellen Sara. "Estimating the Incidence of Germline Mutations in Patients with Bone and Soft Tissue Sarcoma using Clinical Tumor Sequencing." The Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1592844958063832.
Повний текст джерелаOliveira, Juliana Gonçalves de [UNESP]. "Detecção de mutação no gene supressor de tumor p53 e associação e cepas patogênicas do Helicobacter pylori em câncer gástrico." Universidade Estadual Paulista (UNESP), 2008. http://hdl.handle.net/11449/87824.
Повний текст джерелаFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
O câncer gástrico é o quarto tipo mais comum e o segundo em mortalidade. Apesar da diminuição do número de casos nos últimos tempos ainda é um grande problema mundial. E mais, sua associação com o Helicobacter pylori (HP) está cada vez mais preocupante, devido à alta prevalência de cepas patogênicas dessa bactéria. Além disso, mutações em genes que agem no ciclo celular podem levar ao câncer. O gene que codifica a proteína p53 é responsável pelo reparo de lesões no DNA durante o ciclo celular funcionando como um regulador transcricional. Quando o reparo não é viável a proteína p53 induz a entrada da célula danificada em apoptose. Mutações mais freqüentes ocorrem nos exons 5, 6, 7 8 e 9. No atual trabalho investigou-se a possível associação da mutação no gene p53, correlação com presença da cepa patogênica CagA+ e estadiamento do tumor. Foram estudadas 55 amostras de câncer gástrico extraídas por biópsia durante gastrectomia. PCR foi utilizada para os exons 5 ao 9, análise de mutação por sequenciamento automático e dados clínicos foram coletados incluindo infecção por Helicobacter pylori/CagA+. Trinta e dois casos apresentaram mutações em p53 sendo que 6 deles apresentaram mutação em mais de um exon. 53% apresentaram-se infectados por HP CagA+. 87% dos pacientes estavam em estadiamento avançado do tumor (II, III e IV) e 80% eram do tipo intestinal. Quanto a correlação de p53 e cagA+ a casuística é relativamente pequena, e assim a correlação de p53 e cagA não foi vista. Os resultados confirmam a relevância das mutações em p53 e da presença da cepa patogênica CagA nos casos de câncer gástrico, contudo estudos devem ser realizados com um maior número amostral. Neste caso, o uso da p53 mutada pode ser utilizada em diagnóstico indicando, assim um melhor tratamento, desde que há casos em que sua alteração impõe resistência...
The gastric cancer is the fourth most common type and the second in mortality. Despite the decrease in the number of cases in recent times is still a major problem worldwide. Moreover, its association with Helicobacter pylori (HP) is increasingly worrying, because of the high prevalence of pathogenic strains of this bacterium. Furthermore, mutations in genes that act in the cell cycle can lead to cancer. The gene encoding the p53 protein is responsible for repair of lesions in DNA during cell cycle working as a transcriptional regulator. When the repair is not viable in the p53 protein induces the entry of the cell into apoptosis damaged. Change frequently occur in exons 5, 6, 7 8 and 9. In the current work investigated is the possible association of the mutation in the p53 gene, correlation with the presence of pathogenic strain CagA + and staging of the tumor. We studied 55 samples of gastric cancer extracted by biopsy taken during gastrectomy. PCR was used to the exons 5 to 9, analysis of mutation by sequencing automatic and clinical data were collected including infection by Helicobacter pylori / CagA +. Thirty-two patients had mutations in p53 is that 6 of them had more than one mutation in exon. 53% showed up infected HP CagA +. 87% of the patients were in advanced staging of the tumor (II, III and IV) and 80% were of the intestinal type. As the correlation of p53 and cagA + the casuistic is relatively small, and thus the relationship of p53 and cagA was not seen. The results confirm the relevance of mutations in p53 in the presence of pathogenic strain CagA in cases of gastric cancer, but studies must be conducted with greater sample. In this case, the use of p53 mutant can be used in diagnosis indicating thus a better treatment, since there are cases where its amendment requires resistance to certain types of treatment, regardless of the presence of H pylori... (Complete abstract click electronic access below)
Le, Loarer François. "Dérégulation du complexe BAF dans les sarcomes épithélioïdes et leur variants génétiques." Thesis, Lyon 1, 2015. http://www.theses.fr/2015LYO10127.
Повний текст джерелаEpithelioid sarcomas (ES) display loss of SMARCB1 nuclear expression in 85% of cases. SMARCB1 is encoded by a tumor suppressor gene located in 22q11 which was first linked to cancer in malignant rhabdoid tumors. While investigating a series of 40 epithelioid sarcomas with BAC-FISH (Bacterial Artificial Chromosome-Fluorescence In Situ Hybridization), we demonstrated that SMARCB1 loss in ES occurred through genomic deletions in 85% of cases. We were also able to highlight the first case of ES associated with a heterozygous SMARCB1 deletion in the germ line, which feature was previously thought to be restricted to malignant rhadboid tumors (MRT). We subsequently investigated a series of 16 SMARCB1-retained ES to identify its underlying culprit gene with a focus on the candidate tumor suppressor gene SMARCA4. SMARCA4 encodes one of the ATPase subunit of BAF complexes. Interestingly, SMARCB1 is also a core submit of these complexes which regulate chromatin remodeling. We were able to identify a set of 6 cases displaying SMARCA4 inactivation with this discovery cohort. The review of medical records highlighted these cases had similar presentation : all tumors presented with large compressive and aggressive mediastinopulmonary masses. We further recruited 13 cases based on these characteristics including 5 prospective cases. The characterization of their transcriptomes by RNA-sequencing (n=13/19) confirmed their remarkable homogeneity, all our samples clustering together with MRT. However our variant diverge from malignant rhabdoid tumors as it lacks SMARCA4 alteration in the germline (n=0/11) and displays complex polyploidy genetic profiles. We therefore called this new tumor variant “SMARCA4-deficient thoracic sarcoma” (SMARCA4-DTS). The transcriptomic vicinity of SMARCA4-DTS and MRT let foresee they share common therapeutic vulnerabilities
Rodríguez, Sodupe Pau 1993. "Liquid biopsy for early tumor relapse detection : Development of hypersensitive genomic sequencing methodologies for the detection of ultra-rare genetic variants in the blood plasma of pediatric cancer patients." Doctoral thesis, TDX (Tesis Doctorals en Xarxa), 2022. http://hdl.handle.net/10803/673741.
Повний текст джерелаL’anàlisi d'ADN tumoral circulant (ADNtc) al plasma sanguini, sovint conegut com a biòpsia líquida, ha despertat recentment gran interès en la recerca del càncer. Aquesta estratègia mínimament invasiva es basa en que l’ADNtc representa, almenys parcialment, l'estat en temps real del genoma del tumor i té un gran potencial per a la detecció precoç del càncer. Tanmateix, la fracció d'ADNct en l'ADN lliure circulant (ADNlc) total és sovint molt baixa i es requereixen mètodes ultra-sensibles i específics per a la seva detecció. Aquesta tesi se centra en el desenvolupament i la implementació de mètodes ultra-sensibles basats en tecnologies de seqüenciació massiva (NGS) que permetin la identificació de variants rares en plasma de forma específica. En resum, aquest treball presenta una estratègia integral i rendible pel seguiment de mutacions tumorals en el plasma de pacients pediàtrics de manera personalitzada. La nostra estrategia pretén oferir una eina que permeti anticiparse en la detecció i tractament de recidives tumorals.
Akhavanfard, Sara. "NEXT-GENERATION SEQUENCING APPROACHES TO CHARACTERIZE GENOMIC PREDISPOSITION OF SOLID TUMORS IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS (C-AYA)." Case Western Reserve University School of Graduate Studies / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=case1575571085728229.
Повний текст джерелаOliveira, Juliana Gonçalves de. "Detecção de mutação no gene supressor de tumor p53 e associação e cepas patogênicas do Helicobacter pylori em câncer gástrico /." Botucatu : [s.n.], 2008. http://hdl.handle.net/11449/87824.
Повний текст джерелаBanca: Elaine Sbroggio de Oliveira Rodini
Banca: Daniel Araki Ribeiro
Resumo: O câncer gástrico é o quarto tipo mais comum e o segundo em mortalidade. Apesar da diminuição do número de casos nos últimos tempos ainda é um grande problema mundial. E mais, sua associação com o Helicobacter pylori (HP) está cada vez mais preocupante, devido à alta prevalência de cepas patogênicas dessa bactéria. Além disso, mutações em genes que agem no ciclo celular podem levar ao câncer. O gene que codifica a proteína p53 é responsável pelo reparo de lesões no DNA durante o ciclo celular funcionando como um regulador transcricional. Quando o reparo não é viável a proteína p53 induz a entrada da célula danificada em apoptose. Mutações mais freqüentes ocorrem nos exons 5, 6, 7 8 e 9. No atual trabalho investigou-se a possível associação da mutação no gene p53, correlação com presença da cepa patogênica CagA+ e estadiamento do tumor. Foram estudadas 55 amostras de câncer gástrico extraídas por biópsia durante gastrectomia. PCR foi utilizada para os exons 5 ao 9, análise de mutação por sequenciamento automático e dados clínicos foram coletados incluindo infecção por Helicobacter pylori/CagA+. Trinta e dois casos apresentaram mutações em p53 sendo que 6 deles apresentaram mutação em mais de um exon. 53% apresentaram-se infectados por HP CagA+. 87% dos pacientes estavam em estadiamento avançado do tumor (II, III e IV) e 80% eram do tipo intestinal. Quanto a correlação de p53 e cagA+ a casuística é relativamente pequena, e assim a correlação de p53 e cagA não foi vista. Os resultados confirmam a relevância das mutações em p53 e da presença da cepa patogênica CagA nos casos de câncer gástrico, contudo estudos devem ser realizados com um maior número amostral. Neste caso, o uso da p53 mutada pode ser utilizada em diagnóstico indicando, assim um melhor tratamento, desde que há casos em que sua alteração impõe resistência... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: The gastric cancer is the fourth most common type and the second in mortality. Despite the decrease in the number of cases in recent times is still a major problem worldwide. Moreover, its association with Helicobacter pylori (HP) is increasingly worrying, because of the high prevalence of pathogenic strains of this bacterium. Furthermore, mutations in genes that act in the cell cycle can lead to cancer. The gene encoding the p53 protein is responsible for repair of lesions in DNA during cell cycle working as a transcriptional regulator. When the repair is not viable in the p53 protein induces the entry of the cell into apoptosis damaged. Change frequently occur in exons 5, 6, 7 8 and 9. In the current work investigated is the possible association of the mutation in the p53 gene, correlation with the presence of pathogenic strain CagA + and staging of the tumor. We studied 55 samples of gastric cancer extracted by biopsy taken during gastrectomy. PCR was used to the exons 5 to 9, analysis of mutation by sequencing automatic and clinical data were collected including infection by Helicobacter pylori / CagA +. Thirty-two patients had mutations in p53 is that 6 of them had more than one mutation in exon. 53% showed up infected HP CagA +. 87% of the patients were in advanced staging of the tumor (II, III and IV) and 80% were of the intestinal type. As the correlation of p53 and cagA + the casuistic is relatively small, and thus the relationship of p53 and cagA was not seen. The results confirm the relevance of mutations in p53 in the presence of pathogenic strain CagA in cases of gastric cancer, but studies must be conducted with greater sample. In this case, the use of p53 mutant can be used in diagnosis indicating thus a better treatment, since there are cases where its amendment requires resistance to certain types of treatment, regardless of the presence of H pylori... (Complete abstract click electronic access below)
Mestre
Tirier, Stephan Marius [Verfasser], and Roland [Akademischer Betreuer] Eils. "Dissecting tumor cell heterogeneity in 3D cell culture systems by combining imaging and next generation sequencing technologies / Stephan Marius Tirier ; Betreuer: Roland Eils." Heidelberg : Universitätsbibliothek Heidelberg, 2018. http://d-nb.info/1198484292/34.
Повний текст джерелаRubio, Pérez Carlota 1990. "Understanding the genomic makeup of tumors to guide personalized medicine." Doctoral thesis, Universitat Pompeu Fabra, 2017. http://hdl.handle.net/10803/664287.
Повний текст джерелаEl càncer és una malaltia del genoma. L'estudi de les alteracions genòmiques dels tumors s’utilitza com a guia en varies estratègies de medicina de precisió, algunes d'elles aprovades i d'altres en assajos clínics. D'altra banda, l’estudi de la immunitat tumoral està esdevenint una peça clau per l’èxit d’altres estratègies terapèutiques, anomenades immunoteràpies. Al llarg d'aquesta tesi, mitjançant l'estudi de les dades “òmiques” tumorals, he contribuït de varies maneres cap a l'avenç de la medicina de precisió pel càncer. Primer, he identificat el panorama de les teràpies anticanceroses guiades per alteracions genòmiques. Segon, he desenvolupat OncoPaD, una eina pel disseny cost-efectiu i racional de panells de seqüenciació per càncer. A més, he contribuït al desenvolupament del Cancer Genome Interpreter, una eina que ajuda a la interpretació biològica i terapèutica de les variants presents a tumors novament seqüenciats. Per últim, he identificat diversos mecanismes mitjançant els quals els tumors són capaços d'evadir l’atac del sistema immunològic.
Tomasini, Pascale. "Établissement d'un profil génomique spécifique des métastases cérébrales des adénocarcinomes bronchiques." Thesis, Aix-Marseille, 2019. http://www.theses.fr/2019AIXM0692.
Повний текст джерелаLung cancer is the leading cause of cancer-related deaths, partly because it is the first cause of brain metastases (BM). A better knowledge of non-small cell lung cancer (NSCLC) molecular biology and the development of targeted therapies have improved patients’ outcomes. However, the intracranial efficacy of these new treatments is inconstant. The objective of this work was a better knowledge of BM biology in lung adenocarcinoma and a better knowledge of genomic heterogeneity between BM and PT to guide patients’ treatment strategy.We showed that intracranial efficacy of immunotherapy was inconstant and that BM incidence and recurrence after local treatment was associated with mutation profile. We then compared whole exome sequencing of paired frozen samples from PT and BM of patients with NSCLC and identified 13 genes with recurrent mutations in BM never mutated in PT samples. We then analyzed a prospective cohort of patients with CBNPC and resected BM. In these BM, the number of mutations was high, including 2 genes among the 13 genes identified. Moreover, CSF ctDNA was representative of BM mutation status.This work highlights the importance of tumor heterogeneity between BM, PT and ctDNA. Whereas it is difficult to establish a specific signature of BM because of the poor number of samples available and the difficulty to have paired PT/BM samples for each patient, CSF ctDNA study may be a way to assess BM biology. We plan to study brain microenvironment and use new approaches such as mathematical modeling for a better understanding of BM biology
Abecassis, Judith. "Statistical methods for deciphering intra-tumor hereterogeneity : challenges and opportunities for cancer clinical management." Thesis, Université Paris sciences et lettres, 2020. http://www.theses.fr/2020UPSLM065.
Повний текст джерелаAccessing the repertoire of cancer somatic alterations has been instrumental in our current understanding of carcinogenesis. However, efforts in genomic characterization of cancers are not sufficient to predict a patient's outcome or response to therapy, which is key to inform their clinical management. This failure is partly attributed to the evolutionary aspect of cancers. Indeed, as any biological population able to acquire heritable transformations, tumor cells are shaped by natural selection and genetic drift, resulting in a mosaic structure, where several subclones with distinct genomes and properties coexist. This has important implications for cancer treatment as those subpopulations can be sensitive or resistant to different therapies, and new resistant phenotypes can keep emerging as the diseases progresses further. An important number of mathematical or statistical methods have been developed to detect and quantify the intra-tumor heterogeneity (ITH), but no systematic evaluation of their performances and potential for clinical application has been performed. Our first contribution consists in a survey of existing approaches to decipher ITH, that allows to navigate the different underlying ideas easily. We have also proposed a framework to assess the robustness of those approaches, and their potential for use in patient stratification. This survey has allowed us to identify an unexploited type of data in the process of ITH reconstruction, and our second contribution fills remedies to this shortfall. Indeed, besides observed prevalences of somatic mutations within a tumor sample that allow us to distinguish several clones, the nucleotidic context of those mutations reveals the unknown causative mutational processes. We illustrate on both simulated and real data the opportunity to jointly model those two aspects of tumor evolution. In conclusion, we highlight the need to reinforce data integration from several sources or samples to harness the potential of tumor evolution for cancer clinical management
Giner-Calabuig, Mar. "Novel Germline and somatic processes in mismatch repair deficient tumors." Doctoral thesis, Universidad de Alicante, 2020. http://hdl.handle.net/10045/113914.
Повний текст джерелаTatsuoka, Hisato. "Single-cell Transcriptome Analysis Dissects the Replicating Process of Pancreatic Beta Cells in Partial Pancreatectomy Model." Doctoral thesis, Kyoto University, 2021. http://hdl.handle.net/2433/263543.
Повний текст джерелаZhu, Yan. "Microfluidic Technology for Low-Input Epigenomic Analysis." Diss., Virginia Tech, 2018. http://hdl.handle.net/10919/83402.
Повний текст джерелаPh. D.
Hubert, Jean-Noël. "Génomique des populations appliquée : détection de signatures de sélection au sein de populations expérimentales." Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS141/document.
Повний текст джерелаPopulation genomics makes it possible to detect traces of selection in the genome. Studies in this field have mainly focused on long time scale (~ 10³ generations). In comparison, short-term experimental studies (~ 10 generations) have attracted much less interest. Such experiments are, however, likely to inform us about the genetic basis of complex characters. We propose a likelihood method based on a Wright-Fisher model to detect selection from genetic temporal samples collected over ten generations. We show through simulation that our method can disentangle signals due to the combination of genetic drift and selection to those due to drift alone. We also show through simulation that it is possible to estimate the selection coefficient applied to a tested locus. In addition, we illustrate the interest of our method for the detection of candidate markers for selection through two genome scans performed on real data, in the Tasmanian devil (Sarcophilus harrisii) and in the rainbow trout (Oncorhynchus mykiss). These practical applications highlight candidate genomic regions for complex phenotypes in different contexts. Collectively, our results show the possibility of detecting genes submitted to strong directional selection from genetic time-series, even if selection is applied on a short time period and if the examined populations are small
Zapata, Ortiz Luis 1985. "On the evolution of cancer genomes : Signatures of selection reveal cancer genes across multiple tumor types." Doctoral thesis, Universitat Pompeu Fabra, 2016. http://hdl.handle.net/10803/456685.
Повний текст джерелаEl tumor esta compuesto de células que crecen indiscriminadamente, bajo la lupa de selección natural. En esta tesis hemos intentado reconstruir los principios básicos de la evolución del cáncer, como estos describen la adquisición de mutaciones que inician la malignidad tumoral. El primer trabajo es un anaálisis genómico de un paciente con leucemia. El Segundo explora la heterogeneidad intratumoral para identificar genes drivers del cáncer. Y el último trabajo se enfoca en desenmascarar las señales de selección negativa. Nuestros resultados de estos tres trabajos constituyen una fuente de nuevos genes que pueden ser explorados como dianas terapéuticas del cáncer.
Daher, Tamás [Verfasser]. "Comparative TP53 targeted next generation sequencing analysis as a diagnostic tool for determining lung tumor origin in patients with head and neck squamous cell carcinoma and synchronous / metachronous squamous cell lung carcinoma / Tamás Daher." Gießen : Universitätsbibliothek, 2018. http://d-nb.info/1170582079/34.
Повний текст джерелаShinde, Jayendra. "Mutational signatures reveal the dynamic interplay of risk factors and cellular process during liver tumorigenesis." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCC324/document.
Повний текст джерелаCancer is a disease of the genome. A normal cell goes rogue and is transformed into a cancerous cell due to acquired somatic mutations in its genome. The catalogue of these somatic mutations observed in the cancer genome is the outcome of multiple mutational processes that have been operative over the lifetime of a patient. These mutational processes that have occurred throughout the development of cancer may be infidelity of the DNA replication machinery, impaired DNA repair system, enzymatic modifications of DNA, or exposures to exogenous or endogenous mutagens. Each mutational process leaves a characteristic pattern – a “mutational signature” on the cancer genome. Various genomic features related to genome architecture, including DNA replication and transcription, modulate these mutational processes. During my PhD, I analyzed whole exome and whole genome sequencing data from liver tumors to understand the mutational processes remodeling these tumor genomes, their interaction with risk factors, cellular processes, and driver genes, and their evolution along the tumor histories. For that aim, I used existing statistical methods and I developed innovative computational tools to:- extract mutational and structural variant signatures from next-generation sequencing data- identify risk factors or genetic alterations underlying each process- predict the mutational process at the origin of each somatic mutation- explore correlations between mutation rates and cellular processes like replication and transcription- reconstruct the clonal history of a tumor and the timing of mutational processes and copy-number changes These innovative analytical strategies allowed me to identify 10 mutational signatures: 5 ubiquitous signatures operative in every liver cancer but modulated by risk factors (gender, alcohol, tobacco), and 5 sporadic signatures operative in <5% of HCC and associated with specific known (aflatoxin B1, aristolochic acid) or unknown mutational processes. I also identified 6 structural variant signatures, including striking duplicator or deletor phenotypes in rare tumors. Each mutational process showed a different relationship with replication and transcription. Signatures of bulky DNA adducts (polycyclic aromatic hydrocarbons, aflatoxin B1, aristolochic acid) strongly decreased in highly expressed genes due to transcription-coupled repair, whereas the alcohol-related signature 16 displayed a unique feature of transcription-coupled damage. A striking positive correlation between indel rate and gene expression was observed, leading to recurrent mutations in very highly expressed tissue-specific genes. Finally, reconstructing the clonal history of HCC revealed the evolution of mutational processes along tumor development and identified synchronous chromosome duplications as late events probably leading to fast tumor growth and clinical detection of the tumor. Together, these findings shed new light on the mechanisms generating DNA alterations along the natural history of liver cancers
Courtier, Frédéric. "Caractérisation moléculaire des néoplasies myéloprolifératives et de leur transformation en leucémie aigüe myéloïde." Thesis, Aix-Marseille, 2019. http://www.theses.fr/2019AIXM0651.
Повний текст джерелаClassical Philadelphia-negative Myeloproliferative Neoplasms (MPN) include essential thrombocythemia, polycythemia vera and primary myelofibrosis and are slow evolving and good prognostic blood cancers due to the alteration of one of three driver genes JAK2, CALR or MPL. However, other genetic abnormalities may occur and lead to an aggravation, of which the worst stage is transformation to Acute Myeloid Leukemia (AML).To better understand the mechanisms responsible for this transformation, I used DNA sequencing to identify mutations and abnormalities responsible for each stage of the disease.Chronic phase of an MPN results from a small number of additional mutations outside the drivers, and a large number of mutations is associated with a higher risk of evolution of the disease. Mutations in the functions of chromatin modifiers and RNA splicing are associated with myelofibrosis. These mutations in chromatin modifiers (mutations in ASXL1, EZH2) and RNA splicing (mutations in SRSF2, U2AF1, SF3B1) seem to predispose to transformation to AML, which requires the occurrence of other abnormalities affecting other functions, such as DNA methylation (mutations in IDH1/2, TET2, DNMT3A), transcription factors (mutations in RUNX1, CUX1,...), or TP53 mutations. These mutations associated with MF or acute phases could be found during chronic phase before the diagnosis of evolution, which could identify them as predictive markers.Knowledge of the mechanisms of transformation and the identification of associated markers may improve the care of patients with poor prognosis and help offer them specific treatment in the context of personalized medicine
Delhomme, Tiffany. "Using the systematic nature of errors in NGS data to efficiently detect mutations : computational methods and application to early cancer detection." Thesis, Lyon, 2019. http://www.theses.fr/2019LYSE1098/document.
Повний текст джерелаComprehensive characterization of DNA variations can help to progress in multiple cancer genomics fields. Next Generation Sequencing (NGS) is currently the most efficient technique to determine a DNA sequence, due to low experiment cost and time compared to the traditional Sanger sequencing. Nevertheless, detection of mutations from NGS data is still a difficult problem, in particular for somatic mutations present in very low abundance like when trying to identify tumor subclonal mutations, tumor-derived mutations in cell free DNA, or somatic mutations from histological normal tissue. The main difficulty is to precisely distinguish between true mutations from sequencing artifacts as they reach similar levels. In this thesis we have studied the systematic nature of errors in NGS data to propose efficient methodologies in order to accurately identify mutations potentially in low proportion. In a first chapter, we describe needlestack, a new variant caller based on the modelling of systematic errors across multiple samples to extract candidate mutations. In a second chapter, we propose two post-calling variant filtering methods based on new summary statistics and on machine learning, with the aim of boosting the precision of mutation detection through the identification of non-systematic errors. Finally, in a last chapter we apply these approaches to develop cancer early detection biomarkers using circulating tumor DNA
Dupain, jourda Célia. "Découverte de nouveaux transcrits de fusion dans des tumeurs pédiatriques en rechute et caractérisation fonctionnelle d’un nouvel oncogène LMO3-BORCS5." Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS310/document.
Повний текст джерелаPediatric cancers represent the first cause of death by disease in children as 20% of patients harbor resistances and die from recurrence of the malignancy. Nowadays treatment are at their limits of efficacy but also toxicity. Improving the knowledge on the biology of the relapsed/resistant tumors and identifying new molecular targets are needed for these rare, extremely diverse and misunderstood pathologies. Fusion oncogenes are known to be major drivers of oncogenesis, responsible for ~20% of cancers. Due to their particular biology, we hypothesized that pediatric tumors would be more likely to harbor fusions and that their exploration, especially at relapse where very limited data are available, could help to understand the particularity of these malignancies and consequently to provide new therapeutic targets. Our first aim was to detect new fusion transcripts in a cohort of 48 pediatric patients at relapse included in the precision medicine trial MOSCATO-01, previously conducted in Gustave Roussy. From the RNA-seq data, we described the landscape of fusions in these tumors and classified the most confident candidates according to their biological function and druggability predictions. A new fusion named LMO3-BORCS5 found in biopsies of a patient with Ewing's sarcoma, at diagnosis and at relapse as well as in various cell lines particularly caught our attention. Functional studies showed that LMO3-BORCS5 has a high impact on tumorigenesis and treatment sensitivity and that BORCS5 would act, in vivo, as a tumor suppressor gene. Our results strengthened the critical role of fusion transcripts in tumor initiation, progression and resistance and reinforces the idea that a private fusion oncogene should not be ignored. Indeed, the future of cancer care lays in precision medicine, with fusion transcripts being one of the most remarkable tool for treatment decision
Mallaret, Martial. "Identification de nouveaux gènes d'ataxies cérébelleuses récessives et intérêt du séquençage haut débit dans le diagnostic des ataxies d'origine génétique." Thesis, Strasbourg, 2015. http://www.theses.fr/2015STRAJ090/document.
Повний текст джерелаHereditary cerebellar ataxias are a group of neurodegenerative or neurodevelopemental diseases responsible of major disability. We found thanks to exome sequencing mutations in the WWOX gene in two consaguineous families presenting with cerebellar ataxia, epilepsy and mental retardation. This gene was until recently only recognized to be a tumor suppressor.With a 57 ataxia genes targeted capture strategy, next generation sequencing in 155 patients found 20,6% of positive diagnosis, including several new mutations in ANO10 and SYNE1. Multi center studies allow to extend clinical knowledge with severes phenotypes especially in ARCA1.We validate a clinico-biological algorithm for recesssive ataxias diagnosis published by Anheim in the in New England Journal of Medicine, 2012 in a blinded manner
Thery, Jean-Christophe. "Détection et contribution de variants rares constitutionnels dans les formes précoces de cancer du sein : Apports du Séquençage de Nouvelle Génération. Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome Germline mutations of inhibins in early-onset ovarian epithelial tumors." Thesis, Normandie, 2019. http://www.theses.fr/2019NORMR111.
Повний текст джерелаDespite previous identifications of deleterious variants on BRCA1, BRCA2, PALB2,RAD51C and RAD51D supporting the hereditary breast and ovarian cancer syndrom, and thecontribution of TP53 mutations in very early-onset breast carcinomas, a large fraction of patientssuggestive of Medelian disease remains without molecular diagnosis. In the past years,sequencing of the Human genome and next-generation sequencing offered major advances, inparticular in the field of genome variability and de novo variants.We applied these new tools and concepts in the context of very early-onset breastcarcinomas, in order to identify new molecular germline determinants. First, we dealt withsoustractive exomes, in parents - child trios, and succeed in the identification of a deleterious denovo variant in the INHBA gene, in the context of very early-onset of ovarian cancer. However, wehave failed with this approach in a second trio with an index affected by early-onset breastcarcinoma. We also tried a comparative exome sequencing approach in a remarkable pedigreewith multiple probands affected by early-onset breast carcinomas, without identification of ashared deleterious variant. Secondly, we used a home-made 201 genes panel assuming thatgenes somatically affected in cancers might be altered in inherited conditions. We analyzed acohort of very early-onset breast carcinomas, and identified a mosaic TP53 variation. Moreover,we identified some interesting candidate variants and observed a non-significant trend of rarevariants enrichment in the DNA repair pathway. Finally, we designed a specific TP53 gene capturein order to detect mosaic variants in pediatric cancers and very early-onset breast carcinomas.We confirmed the clinically significant prevalence of these alterations, which support TP53analysis in these conditions even in sporadic presentations
Lode, Laurence. "Etude moléculaire de l'évolution clonalede TP53 des Syndromes Myélodysplasiques avec del(5q) : conséquences sur la résistance au traitement et la progression du cancer." Thesis, Montpellier, 2017. http://www.theses.fr/2017MONTT071/document.
Повний текст джерелаP53 protein is named «guardian of the genome » because it must be altered to let cancer grow.TP53 is the most mutated gene in agressive cancers.Numerous systemic therapies are successful for treatment of disseminated cancers. However, clinical response is often transient, and cancer undergo relapse or progression due to emergence of resistant populations. These latter often harbour TP53 mutations. We studied TP53 in chronic lymphoid leukemia (CLL) and lower-risk myelodysplastic syndroms with del(5q), MDS del(5q). We conducted a retrospective longitudinal study in 40 patients suffering from MDS del(5q). We obtained targeted NGS data showing that TP53 mutational status at diagnosis could not predict tumor progression, by contrast with previously published data (Jädersten et al., JCO 2011). We show that TP53 clonal evolution is the key feature of tumor progression in MDS del(5q). We observed numerous mutated sub-clones emerging between diagnosis and follow-up. In our study, this emergence always followed onset of lenalidomide treatment. Lenalidomide was recently approved as a new therapy specifically improving anemia in patients with MDS del(5q). It allows most patients to become red-blood-cells-transfusion independent. Lenalidomide often eradicates the major tumor clone harbouring the isolated genetic abnormality deletion (5q) and allows clinical remission. Unfortunately, this remission is short (median, 2 years) and is followed, in 1 case out of 2, by a secondary acute leukemic transformation with a very poor prognosis.We studied the issue of a possible link between lenalidomide therapy and TP53 clonal evolution by annotating TP53 sequencing results with acute biological, clinical and therapeutic features in the 24 patients with sequential samples analyzed. In our study, patients with tumor progression (10 TP53 clonal evolution and 1 RUNX1 clonal evolution) were given a higher cumulative dose of lenalidomide compared to patients with stable disease (p = 0.036). Similarly to « adaptive therapy theory »(Gatenby 2009), we observed that eradication of the tumor wasn’t useful for improvement of quality of life. Absence of eradication might even allow to maintain a clonal equilibrium and a clonal competition between the distinct tumor sub-clones, resistant to lenalidomide or not, and therefore maintain stable disease.This theory of adaptive therapy questions the classical protocols of treatments against cancer, in which the maximal tolerated dose is preferred to the minimal effective dose. The latter might however slow down cancer progression or cancer relapse, with decreased side effects in patients, and decreased health costs.To date, few clinical trials (if any) questions such protocols of adaptive therapy. However, in vivo experiments (xenografts) and in silico statistical models allowed to study evolutionary dynamics of tumor sub-populations with and without therapy.The models predict that host survival can be maximized if “treatment-for-cure strategy” is replaced by “treatment-for-stability.” Specifically, the models predict that an optimal treatment strategy will modulate therapy to maintain a stable population of chemosensitive cells that can, in turn, suppress the growth of resistant populations under normal tumor conditions, Dr Gatenby said
Faugeroux, Vincent. "Caractérisation moléculaire et fonctionnelle de cellules tumorales circulantes dans le cancer de la prostate et le cancer bronchique non à petites cellules." Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS481/document.
Повний текст джерелаCirculating tumor cells (CTCs) represents an non invasive source of tumor material which may provide clinical and basic information. These cells derived from primary or metastatic tumors represents an heterogeneous population of very rare events which circulates in the blood. Oncology personnalized medicine is based on biopsies molecular characterization but these are sometimes which difficult to realize and poorly informative. Thereby molecular and functional characterization of CTCs presents a double interest, clinical to identify treatments biomarkers sensitivity and basic to study mechanisms underlying their tumor inititiating cell (TIC) potential. The two goals of my thesis were on the one hand to characterize by whole-exome sequencing (WES) at the single level the CTCs from patients with metastatic prostate cancers (mPCa) and on the other hand to establish and characterize CTC-derived xenografts (CDX) from patients with non-small-cell lung cancer (NSCLC) or mPCa. For the first goal we developped a global workflow which include three technological approaches to enrich and isolate individual CTCs from different phenotype (epithelial, epithelial and mesenchymal, mesenchymal), to perform whole genome amplification (WGA) and to sequence them. WES was performed on 34 CTC samples selected according to WGA quality and on corresponding metastasis biopsies from seven patients. Two patients with phenotypic heterogeneity of CTCs were deeply analyzed. We highlighted shared mutations between CTCs and matched biopsies as well as mutations only detected in CTCs. These private CTC mutations are detected in all phenotype and particularly affect genes invlved in cytoskeleton remodeling, DNA repair or invasion. The existence of common mutations between CTCs from various phenotype suggests a phylogenic link between these cells but a divergent evolution during metastatic process. This work is submitted for publication. For the second goal, we implanted CTCs from 67 NSCLC patients and 28 mPCa patients in immunocompromised mice. We established four NSCLC CDX and one mPCa CDX. The characterization of tumor biopsies, CTCs collected at the time of xenograft, CDX and CDX-derived cell lines revealed that CTCs, CDX and cell lines miror the phenotype and mutational landscape of tumor biopsies. The more deeply characterization of one cell line show the presence of a high replicative stress and genomic instability. This result directs us to the hypothesis of a possible role of the genomic instability in CTC tumorigenicity.We demonstrated in this work that CTCs mutational landscape harbors high similairities with patients tumor biopsies in mPCa. Furthermore we observed CTC private mutations not detected in tumor biopsies. Also we showed that some CTCs from NSCLC and mPCa are tumorigenic in vivo and that these CTCs mirror mutational profile of patients tumor biopsies. These models are original and interesting tools to identify new therapeutic targets and anti-tumoral strategies and understand mechanisms underlying the TIC potential of CTCs
Malek, Joël. "Genetic alterations of the metastatic lesions in ovarian carcinoma." Thesis, Paris 11, 2011. http://www.theses.fr/2011PA11T109.
Повний текст джерелаOvarian cancer is the most deadly gynecological cancer. The high rate of mortality is due to the large tumor burden with extensive metastatic lesion of the abdominal cavity. There are few studies on genetic alterations and their consequences in peritoneal metastatic tumors when compared to their matched ovarian primary tumors. Our hypothesis is that differences between the metastatic and primary lesions might be the cause of residual disease and, most importantly may have a role in post-chemotherapeutic recurrences. Methods: We conducted integrated genomics analysis on matched primary and metastatic tumors from 9 patients. In the papers presented here we analyze genome-wide Copy Number Variations (CNVs) using SNP Arrays targeting peritoneal metastasis differences, Gene expression differences using Microarrays also targeting peritoneal metastasis differences, and for some patients, Single Nucleotide Polymorphisms (SNPs) in genes through Exome sequencing.Results: Here we show that CNVs vary significantly between primary and metastatic tumors and include genes that have been considered potential chemotherapeutic targets based on primary tumor only data. Gene expression differences, while minor, showed highly statistically significant enrichment of genes in ovarian cancer critical pathways. In agreement with findings in other cancers, exome sequencing data revealed very few SNP differences of which most metastasis enriched SNPs were present at very low levels in the primary tumor. The results presented here should allow better design of therapies to target residual ovarian cancer disease
Karaderi, Tugce. "Genetics of ankylosing spondylitis." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:8c0e848a-e712-4603-b923-a96a2f1644ac.
Повний текст джерелаZhivagui, Maria. "Genome-wide modeling of mutation spectra of human cancer-risk agents using experimental systems." Thesis, Lyon, 2017. http://www.theses.fr/2017LYSE1278/document.
Повний текст джерелаCancer genomes harbour a mosaic of mutation patterns from which thirty mutational signatures have been identified, each attributable to a particular known or yet undetermined causal process. Deciphering the origins of these global mutational signatures in full could help identify the causes of human cancer, especially for about 40% of those signatures identified thus far that remain without a known etiological factor. Thus, well-controlled experimental exposure models can be used to assign particular mutational signatures to various mutagenic factors.During the time frame of my PhD work, I characterized and employed innovative in vitro and in vivo models of carcinogen exposure, namely, primary Hupki MEF cells, HepaRG and lymphoblastoid cell lines as well as rodent tumors. The cytotoxic and genotoxic conditions for each tested exposure compound were established and DNA adduct formation was assessed in select cases. Following a pre-screen by TP53 gene sequencing, genome-wide sequencing of immortalized Hupki MEF clones derived from exposure to acrylamide, glycidamide and ochratoxin A was performed, alongside whole genome sequencing of ochratoxin A induced rat renal tumors. The results reveal a novel mutational signature of acrylamide mediated by its active metabolite, glycidamide, a pattern that can be explained by the parallel analysis of individual glycidamide-DNA adducts. In addition, an integrative mutation analysis using in vitro and in vivo models suggests a lack of direct mutagenicity for OTA and possible indirect effects due to the ROS-mediated mode-of-action in MEF cells. The presented robust experimental strategy can facilitate the interpretation of mutation fingerprints identified in human tumors, thereby elucidating cancer etiology, elucidating the relationship between mutagenesis and carcinogenesis and ultimately providing mechanistic evidence for IARC’s carcinogen classification
Labreche, Karim. "Genetic Susceptibility and Molecular Characterization of Glioma." Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS161/document.
Повний текст джерелаGliomas are the most common adult malignant primary tumour of the central nervous system. Thus far, no environmental exposures has been linked to risk except for ionizing radiation, which only accounts for a very small number of cases. Direct evidence for inherited predisposition to glioma is provided by a number of rare inherited cancer syndromes, such as Turcot's and Li–Fraumeni syndromes, and neurofibromatosis. Even collectively, these diseases however account for little of the twofold increased risk of glioma seen in first-degree relatives of glioma patients. My research was centred on two complementary research activities: Identifying susceptibility genes for glioma to delineate key biological pathways contributing to disease pathogenesis and to identify new recurrent mutated genes for glioma to provide for further insights into glial oncogenesis and suggesting targets for novel therapeutic strategies. Collectively the findings in this thesis provide increased insight into the nature of genetic predisposition to glioma and substantiate the often distinct associations between susceptibility variants and glioma molecular groups. In addition the discovery of a new mutated gene in glioma offers the potential to support drug development and advance precision medicine for this tumours
Jacob, Arthur. "Apport du séquençage d'exome pour le diagnostic et le traitement des maladies complexes." Thesis, Lille 2, 2020. http://www.theses.fr/2020LIL2S011.
Повний текст джерелаSince the completion of the Human Genome Project in 2001, the field of genomicshas grown exponentially, in large part due to the introduction of Next GenerationSequencing (NGS). This technique has revolutionized the investigation methods ofgenetic diseases, allowing high-throughput genome-wide sequencing to establish thegenetic basis of diseases. The increasing accessibility of these technologies allowsthe development of precision medicine, based on the specific care of each patientaccording to his genetic profile. Sequencing can be used for the diagnosis ofdiseases, the search for genetic predispositions to a disease, or for the therapeuticchoice, in particular in oncology. Exome sequencing (WES), in particular, offers aneffective method for studying diseases, since exonic regions represent 2% of theentire genome, but can contain up to 85% of functional variants responsible fordiseases. However, the genetic analysis of patients in a clinical setting is mainly carried out by the targeted sequencing of panels of a few genes chosen according tothe clinical context. The work carried out during this CIFRE thesis in partnership withthe company Prenostics was to develop relevant WES analyzes to characterize thegenetic profile of patients with rare genetic diseases and cancers. The objective wasto assess their contribution to the diagnosis and establishment of personalizedtreatment strategies in three distinct contexts of clinical practice, by comparing it tothe conventional approach of panel sequencing.- In the field of pediatric genetic diseases, molecular diagnosis by conventionalmethods only reaches 25%, leaving the majority of families without precise geneticcounseling. Our WES analysis of a cohort of 26 children with genetic diseases notdiagnosed by conventional genetic analyzes, our WES approach resulted in apositive diagnosis in 35% of cases.- About 5 to 10% of breast cancers are hereditary, but more than half of them are notelucidated by the genes at risk of breast cancer (BRCA1, BRCA2, PALB2, etc.) thatare included in conventional panel sequencing. By analyzing the exome of fourfamilies, we attempted to identify the genes involved in familial cases non-mutatedfor the known BRCA1 / BRCA2 genes (BRCAx families). After filtering the riskvariants transmitted among affected limbs, we identified the candidate genesHIST1H1C, TYRO3, TPH1, SLC12A3 and CCNF as possible genes of predispositionto breast cancer. However, without in-depth functional studies to validate theirinvolvement, WES does not seem to provide any benefit for patient management.- Finally, in the field of oncology, the personalization of treatment is at the center ofcurrent issues. Our study of a cohort of 35 refractory solid tumors aimed atdemonstrating the feasibility and efficacy of WES for characterizing the geneticprofile of solid tumors and for decision-making in oncology. We were able to maketreatment suggestions for half of them and helped modify the treatment of at leasteight out of 35 patients.This study describes the different applications, limits and advantages of WES as amolecular investigation tool for human diseases. By demonstrating the benefit ofusing WES in the clinic, our results contribute to the ongoing efforts to integrate it intothe care pathway and the development of precision medicine