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Theses

Caractérisation multiparamétrique des cancers de l’oesophage et de l’estomac

Abstract : Gastric cancer is the world’s second leading cause of cancer mortality. In France, 6550 cases were diagnosed in 2012. Brittany is particularly affected; Finistère is the worst department in France. The incidence of stomach and esophageal cancer increases and the few treatment options are ineffective because of late detection, which make it a major public health problem. To dismember the genetic causes of these cancers, we conducted a series of analyzes on the Cancer Genome Atlas project database, which compiles genomics, transcriptomics and epigenomics data from more than 290 patients with stomach adenocarcinoma and 200 patients with esophagus adenocarcinoma. These analyzes allowed us to identify about fifty point mutations as insertions, deletions or substitutions in exonic, intronic and intergenic regions, and with a frequency higher than 5%. Of eight simple nucleotide deletions found in gastric cancers collected in Brest University Hospital, two could lead to a splice defect. Analysis of these mutated sequences has shown the appearance of alternative transcripts only in cancers (including beyond the stomach?) and in microsatellite instability (MSI) tumor cell lines, suggesting a link between the DNA repair machinery and the control of splicing. In addition, bioinformatics predictions indicated that hnRNPA1 splice protein could bind to the immediate vicinity of an intronic homopolymeric sequence, which would lead to skipping the next exon. In order to analyze the alternative splicing mechanism resulting from these mutations, several minigenes encompassing the alternatively spliced region were engineered from the mutated and non-mutated sequences of interest. We have also identified more than 140 genes under-expressed and 400 genes over-expressed in gastric adenocarcinoma. After integrating this data in a gene interaction network, we were able to identify several groups (« clusters ») of genes interacting together. Our attention was drawn to the behavior of a small sub-network, comprising 9 genes involved, collegially, in detoxification reactions, and all under-expressed in gastric cancer samples. We hope to understand how these pathways are deregulated and their roles in the pathogenicity mechanism of cancer, which eventually constitute new therapeutic targets.
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Submitted on : Monday, February 22, 2021 - 4:16:10 PM
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Gaël Quéré. Caractérisation multiparamétrique des cancers de l’oesophage et de l’estomac. Médecine humaine et pathologie. Université de Bretagne occidentale - Brest, 2018. Français. ⟨NNT : 2018BRES0100⟩. ⟨tel-03148941⟩

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