Acronym: CISCO / COCOneg
Study coordinator: Nicolas SEVENET
Cowden disease is a hereditary cancer predisposition syndrome characterized by the occurrence of benign and/or malignant tumors affecting multiple organs, associated with heterogeneous clinical signs. This condition is caused by deleterious mutations in the PTEN gene, one of the major genes involved in controlling cell proliferation and survival, with diagnosis established by molecular sequencing.
Despite the rise of sequencing technologies, 20% of patients presenting clinical signs suggestive of the disease show no mutations in the PTEN gene.
From a physiological perspective, gene activation is controlled at a distance by “enhancers,” genomic regions that, through DNA folding, enable the recruitment of specific factors that allow gene expression. It has been demonstrated in certain genetic diseases that alterations of these enhancers or defects in DNA folding can cause inactivation of the target gene, and we hypothesize that this could be the case in Cowden disease. These enhancers carry more or less specific marks on the genome. Using databases, we identified four regions carrying these marks located at a long distance from PTEN. Our first objective is to apply 3D genome analysis techniques on cell lines to precisely characterize the 3D conformation between these enhancers and PTEN. Our second objective is to delete these enhancers one by one in cell lines, using molecular scissors (CRISPR-Cas9), to assess their impact on PTEN.
Our final objective will be to search for alterations in these enhancers in patients affected by Cowden disease for whom no PTEN gene mutation has been identified.