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Syndrome de Lynch : mise au point d'un test diagnostique basé sur la caractérisation fonctionnelle de tolérance à la méthylation des variants des gènes du système de réparation des mésappariements

Abstract : Lynch syndrome (LS) is the leading cause of familial colorectal cancer. It is due to mono-allelic germ-line mutations affecting the genes of the MisMatch Repair (MMR) system, mainly MLH1 and MSH2. The diagnosis is based on the detection of pathogenic MMR mutations, which raises the issue of the functional interpretation of the identified variants, often equivocal since 30% of the detected MLH1 and MSH2 alterations are variants of uncertain significance (VUS). Our goal was to develop a functional test to discriminate these VUS. Inactivation of the MMR system makes the cells tolerant to DNA methylation lesions and allows them to escape apoptosis. Our experimental strategy relies on the ability of MLH1 and MSH2 variants to complement the MMR deficiency of a cell line. Briefly, a restoration of sensitivity to methylation is expected if the transfected variant is non-pathogenic. We first tested 40 MLH1 and MSH2 variants whose pathogenicity or neutrality was known. The method correctly classified 39/40 variants, which validated our approach. The technique, which was then applied to a series of 49 MLH1 and MSH2 VUS to be characterized, made it possible to propose a classification for 41/49 (83%) of the VUS. The other available data (clinical, somatic, in silico and eventually functional) confirm our screen results. In the future, this DNA damage signaling assay could be available in routine diagnostics to study all the detected VUS in patients and improve the diagnosis of LS.
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Delphine Bouvet. Syndrome de Lynch : mise au point d'un test diagnostique basé sur la caractérisation fonctionnelle de tolérance à la méthylation des variants des gènes du système de réparation des mésappariements. Génétique humaine. Sorbonne Université, 2018. Français. ⟨NNT : 2018SORUS527⟩. ⟨tel-02946934⟩

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