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Master Thesis

Le séquençage ‘nouvelle génération’ à haut débit cible ; intérêt dans la prise en charge des lymphomes à cellules du manteau

Abstract : Mantle cell lymphoma (MCL) is a clinically aggressive disease for which molecular profiling-based precision medicine algorithms are lacking. Here, to address this issue we have designed and implemented a targeted deep sequencing gene panel covering 44 recurrently mutated genes in MCL. By studying a cohort of 30 patients (38 samples), we demonstrate the feasibility of our gene sequencing assay for defining mutation profiles from very small DNA quantities, in time frames compatible with clinical decision-making in MCL. Mutation frequencies largely comply with published cohorts of similar size. By studying a subgroup of refractory compared to long term remission patients who were enrolled in a LYSA phase II RiBVD (Rituximab, Bendamustine, Velcade and Dexamethasone) we identify mutations in TP53, MLL2, and MEF2B as characteristic of primary refractory disease. TP53 mutation screening by targeted deep sequencing in a further 63 MCL cases (in the clonally involved blood samples and / or bone marrow) showed very short survival for TP53 mutant cases compared to wildtype case. Gene expression profiling followed by unbiased functional annotation in TP53 wildtype versus mutant MCL point to reduced cytotoxic immune function and gain of NFKB and a MYC-regulated core stem cell pathways, respectively, as potentially important biological processes underpinning TP53-driven treatment failure in MCL. Thus implementation of our targeted deep-sequencing gene panel is feasible and presents clear potential as a useful companion precision medicine tool for MCL patient management, and for discovery of novel disease mechanisms.
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Master Thesis
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Submitted on : Tuesday, May 12, 2020 - 3:54:42 PM
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Arnaud Gauthier. Le séquençage ‘nouvelle génération’ à haut débit cible ; intérêt dans la prise en charge des lymphomes à cellules du manteau. Médecine humaine et pathologie. 2018. ⟨dumas-02571042⟩



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