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Cancérogenèse de l'adénocarcinome des fosses nasales : analyse génomique et transcriptionnelle de cellules de la fente olfactive prélevées par méthode non invasive

Abstract : Introduction and objectives : The relationship between wood dust exposure and nasal cancer is well estbalished, but the reasons why these tumours specifically arise from the olfactory cleft and the underlying mechanisms of carcinogenesis are poorly understood. Screening is currently based on the visualization of a tumour in nasofibroscopy and the effectiveness of this screening is not proven. The objectives of this work were: 1/ to establish the link between the intestinal subtype (intestinal type adenocarcinoma, ITAC) and wood dust exposure, 2/ to explore the different reasons for such a location (study of wood dust distribution and clearance in nasal cavity and of olfactory cleft embryological origin) 3/ to confirm or refute the supposed mechanisms of carcinogenesis (metaplasia / cancer sequence, role of CDX2, genetic and epigenetic modifications usually implicated in other similar carcinogenesis models) and 4/ to develop a new non-invasive approach for screening. Results: We first studied the specific link between ITACs and wood dust exposure. Then we demonstrated on an experimental model that the olfactory cleft does not seem to be more exposed to wood dust than the rest of the nasal cavity. Wood dust might stay longer in the olfactory cleft but based on our results we hypothesized that cancerogenesis might be rather due to oncogenic reprogramming, which is possible because of olfactory cleft embryological origin. The metaplasia/cancer sequence seems plausible. The ectopic acquisition of CDX2 expression seems to be a key point in the subsequent transformation to an intestinal phenotype tumor, but CDX2 activation is not related to its promoter demethylation. Our study highlighted gene expression variations that could be part of a dedifferentiation/redifferentiation process (CDX2, OCT3, FOXA1, FOXA2, SOX2, SOX9, SATB2, and some HOX genes). With an integrated approach, we also highlighted a potential implication of CACNA1C in carcinogenesis. Thanks to a non-invasive, well-accepted and painless brushing technique, it was possible to identify transcriptomic and methylation changes which were consistent with ITACs phenotypic profiles and natural history. The predictor identified patients with adenocarcinoma with a very good sensitivity and specificity. Conclusion: Our results pave the way for a simple, non-invasive screening method for woodworkers and for a better understanding of carcinogenesis mechanisms.
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Submitted on : Monday, March 29, 2021 - 11:58:15 AM
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Patrice Gallet. Cancérogenèse de l'adénocarcinome des fosses nasales : analyse génomique et transcriptionnelle de cellules de la fente olfactive prélevées par méthode non invasive. Cancer. Université de Lorraine, 2019. Français. ⟨NNT : 2019LORR0354⟩. ⟨tel-03184193⟩



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