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Identification de nouveaux gènes de prédisposition aux parangangliomes

Abstract : Paragangliomas (PGL) are rare neuroendocrine tumors, genetically determined in around 40% of cases. Despite recent developments in PGL genetics, there is still about 15% of patients for whom no genetic cause can be identified, while their clinical presentation is suspicious of a genetic form. Moreover, it has never been demonstrated that the identification of a germline mutation in any of the PPGL predisposition genes has a positive impact on the patients’ management and clinical outcome. My PhD research project has been organized around two main objectives: 1) to evaluate the benefits for the patients of the identification of a germline mutation on one susceptibility gene at the time of PGL diagnosis; 2) to search for new PGL genes and / or new mechanisms of inactivation of the previously known genes, which could explain PGL suspected to be a genetic form but without detected mutation. Thanks to a retrospective multicenter study involving 221 patients with a PGL due to a mutation on the SDHB, SDHD, SDHC or VHL genes, I observed that the patients who benefited from the genetic analysis at the time of the diagnosis of PGL had a better follow-up than those who had the data of their genetic test later on after the initial PGL diagnosis. Knowledge of a positive genetic status in the PGL diagnosis period favored the detection of smaller recurrent PGLs and less extensive metastatic disease and improved the median of survival. These results validate the international recommendations of offering a PPGL genetic testing to all affected patients at the time of initial diagnosis. I identified germline mutations in a novel PGL gene, SLC25A11 with a whole-exome sequencing strategy, which encodes for the mitochondrial 2-oxoglutarate/malate carrier and showed that SLC25A11 germline mutations predispose to malignant PGL. I demonstrated that human tumors as well as the knockout of slc25a11 gene in a murine experimental model induces a pseudo-hypoxia and a global hypermethylation of the DNA, which explains the tumourigenesis secondary to the inactivation of this gene. The identification of this new PGL susceptibility gene expands the role of mitochondrial dysfunction in paraganglioma tumorigenesis and reveals a new pathway linking metabolic defects and cancer.
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Alexandre Buffet. Identification de nouveaux gènes de prédisposition aux parangangliomes. Cancer. Université Sorbonne Paris Cité, 2018. Français. ⟨NNT : 2018USPCB219⟩. ⟨tel-02466456⟩

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